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Purpose: Radiation-induced lung injury (RILI) is a progressive inflammatory process seen after irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Here, we sought to noninvasively quantify RILI using a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI., Methods and Materials: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe, to characterize the development of RILI and to assess disease mitigation after losartan treatment. The human analog probe 68 Ga-CBP8, targeting type 1 collagen, was tested on excised human lung tissue containing RILI and was quantified via autoradiography. 68 Ga-CBP8 positron emission tomography was used to assess RILI in vivo in 6 human subjects., Results: Murine models demonstrated that probe signal correlated with progressive RILI severity over 6 months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding versus unirradiated control tissue, and 68 Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68 Ga-CBP8 uptake in areas of RILI and minimal background uptake., Conclusions: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Increased demand for NetSpot and Illuccix as requirement to receive the respective Lutathera and Pluvicto radiotherapies, and monitor subsequent response to treatment, have reinforced the need to develop alternative ways of producing gallium-68 ( 68 Ga). Building on our efforts to produce 68 Ga in a liquid target on a GE PETtrace, the goal of this work is to modify the current GE Gallium Chloride cassette using the FASTLab 2 synthesis module to produce [ 68 Ga]GaCl 3 equivalent to a 1.85 GBq generator and demonstrate compatibility with FDA-approved kits for production of 68 Ga-labeled radiopharmaceuticals., Methods: 68 Ga was produced in a liquid target via the 68 Zn(p,n) 68 Ga reaction. 68 Ga was loaded onto various sizes of ZR resins (ZR Load, 0.3 mL, 1 mL, or 2 mL). The loading efficiency was determined using a dose calibrator. After washing with HNO 3 , 1.75 M HCl was used to elute the ZR Load resin through various sizes of a second ZR resin (ZR CG, 0 mL, 2 mL, 4 mL). Using 0.5 mL fractions, the elution profile was determined. Compatibility of the [ 68 Ga]GaCl 3 with NetSpot and Illuccix kits was investigated. Radiochemical purity (RCP) and 4 h stability were determined using radioTLC and radioHPLC. Using a modified [ 68 Ga]GaCl 3 cassette and new FASTLab program, 6 validation preparations were conducted using NetSpot and Illuccix kits for which RCP, stability, sterility and suitability were determined. Dual irradiation of 2 liquid targets was also performed, which was used to simultaneously prepare 1 NetSpot and 2 Illuccix kits by diluting the required activity with 0.1 M HCl., Results: The commercially available GE Cassette gave low RCP using commercial FDA kits. To optimize this, the loading efficiency onto ZR Load and the ratio of ZR resin used to load the initial activity and subsequent elution were explored. When using a 2:4 ratio of ZR Load to ZR CG, 97.89 % RCP was observed when a 3.8 mL [ 68 Ga]GaCl 3 solution was used. For Dotatate validation, 0.55 mL of buffer was added to 4.2 mL of [ 68 Ga]GaCl 3 which gave 1.35 GBq of formulated product. For Illuccix validation, [ 68 Ga]GaCl 3 was added to 2.5 mL of buffer which gave 1.52 GBq of [ 68 Ga]Ga-PSMA-11. Formulated products passed package insert quality control (QC) requirements. When dual target irradiations were performed, 2.84 GBq was delivered to an external vial and used to label 1 NetSpot and 2 Illuccix kits simultaneously, and each kit also met or exceeded established QC criteria., Conclusion: Methods are reported for using cyclotron-produced 68 Ga from a liquid target in conjunction with FDA-approved NetSpot and Illucix kits. By employing a 2 mL ZR Load resin with a 4 mL ZR CG resin, adequate resolution between residual 68 Zn and desired 68 Ga was achieved. By modifying the FASTLab procedure to retain the final 2.5 mL of eluate from the ZR CG resin, [ 68 Ga]GaCl 3 equivalent to a new 1.85 GBq generator was obtained. This was suitable for labeling NetSpot and Illucix kits, resulting in high incorporation of 68 Ga (RCP >95 %), which has not previously been demonstrated. Delivering [ 68 Ga]GaCl 3 into an external vial and diluting with 0.1 M HCl makes it possible to prepare multiple kits simultaneously. These new procedures should facilitate use of cyclotron-produced [ 68 Ga]GaCl 3 for clinical production going., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Given their role as Editor, Peter J. H. Scott had no involvement in the peer-review of this article and has no access to information regarding its peer-review., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the diagnostic efficiency and prognostic value of 68 Ga-Pentixafor PET/CT in comparison with adrenal vein sampling (AVS) for functional lateralization in primary aldosteronism (PA). Histology and long-term clinical follow-up normally serve as the gold standard for such diagnosis., Methods: We prospectively recruited 26 patients diagnosed with PA. All patients underwent 68 Ga-Pentixafor PET/CT and AVS. Postsurgical biochemical and clinical outcomes of patients with unilateral primary aldosteronism (UPA), as diagnosed by PET/CT or AVS, were assessed by applying standardized Primary Aldosteronism Surgical Outcome (PASO) criteria. Immunohistochemistry (IHC) was performed to detect the expression of aldosterone synthase (CYP11B2) and CXCR4., Results: On total, 19 patients were diagnosed with UPA; of these, 13 patients were lateralized by both PET/CT and AVS, four patients were lateralized by PET-only, and two by AVS-only. Seven subjects with no lateralization on AVS and PET received medical therapy. All patients achieved complete biochemical success except one with nodular hyperplasia lateralized by AVS alone. The consistency between PET/CT and AVS outcomes was 77% (20/26). Moreover, CYP11B2-positive nodules were all CXCR4-positive and showed positive findings on PET. Patients who achieved complete biochemical and clinical success had a higher uptake on PET as well as stronger expression levels of CXCR4 and CYP11B2., Conclusion: Our analysis showed that 68 Ga-Pentixafor PET/CT could enable non-invasive diagnosis in most patients with PA and identify additional cases of unilateral and surgically curable PA which could not be classified by AVS. 68 Ga-Pentixafor PET/CT should be considered as a first-line test for the future classification of PA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yin, Ai, Luo, Liu, Ma, Zhou, Xiang, Su, Wang and Li.)

Noninvasive imaging of amyloid-β (Aβ) species in vivo is important for the early diagnosis of Alzheimer's disease (AD). In this paper, we report a near-infrared (NIR) fluorescence (FL) and positron emission tomography (PET) bimodal probe (NIR-[ 68 Ga]) for in vivo imaging of both soluble and insoluble Aβ species. NIR-[ 68 Ga] holds a high binding affinity, high selectivity and high sensitivity toward Aβ 42 monomers, oligomers, and aggregates in vitro . In vivo imaging results show that NIR-[ 68 Ga] can cross the blood-brain-barrier (BBB), and produce significantly higher PET and NIR FL bimodal signals in the brains of APP/PS1 transgenic AD mice relative to that of age-matched wild-type mice, which are also validated by the ex vivo autoradiography and histological staining images. Our results demonstrate that NIR-[ 68 Ga] is an efficient NIR FL and PET bimodal probe for the sensitive imaging of soluble and insoluble Aβ species in AD mice.

Background: Gliomas are the most common primary central nervous system tumors, of which the malignant gliomas account for 60%-75%. The primary and secondary brain malignancies are highly treatment resistant, and their marked angiogenesis attracts interest as a potential therapeutic target. The grade of gliomas, Ki-67 index, and IDH mutation status are among the major prognostic markers in gliomas. Prostate-specific membrane antigen (PSMA) is a zinc-dependent peptidase that is not only expressed in prostate cancer cells but also in the tumor neovasculature. The initial PSMA PET studies in central nervous system tumors using 68 Ga-HBED-CC-PSMA ( 68 Ga-PSMA-11) PET tracer confirmed selective target expression in gliomas of different grades, with higher expression in high-grade glioma compared with low-grade glioma., Aims and Objectives: The aim of the present study was to correlate and compare the 68 Ga-PSMA-11 and 18 F-FDG uptake in brain tumors with their clinicopathological prognostic parameters, so as to study their prognostic implications. In addition, the study also aimed to identify patients who are likely to benefit from potential PSMA-targeted therapies., Patients and Methods: This ongoing prospective study was approved by the institutional scientific and medical ethics committee. The patients with primary or recurrent glioma lesions on MRI underwent regional brain PET/CT scanning with 68 Ga-PSMA-11 and 18 F-FDG. The final histopathology of the brain lesions (glioma grade), Ki-67 index, and IDH mutation status were compared with SUV max values of the 68 Ga-PSMA-11 and 18 F-FDG PET/CT., Results: A total of 15 patients (13 males and 2 females; age range, 21-73 years; median age, 58 years) were included in this study analysis. Among the 15 patients, 10 were treatment naive and 2 were patients with recurrent glioma. Three patients turned out to be WHO grade I-II, 6 belonged to grade III, and 6 grade IV (glioblastoma multiforme) on final histopathology. The 68 Ga-PSMA-11 PET/CT showed tracer uptake in all high-grade gliomas with good tumor-to-background ratio. It was PSMA nonavid in 2/3 low-grade gliomas, and it showed low-grade uptake in 1/3 patients. PSMA expression (as evaluated by SUV max values) was significantly higher in higher-grade tumors, those with IDH mutation wildtype status, and higher Ki-67 indices. FDG PET SUV max also showed significant correlation with these prognostic parameters., Conclusions: In these preliminary results, PSMA PET appears to be an important tool in the evaluation and prognosis of gliomas. PSMA-directed theranostics can be explored as a personalized approach in gliomas with high PSMA uptake. However, with the limitation of small sample size, larger clinical trials are warranted to draw conclusive evidence regarding the same., Competing Interests: Conflicts of interests and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

As malignancies still represent one of the major health concerns worldwide, early tumor identification is among the priorities of today's science. Given the strong association between cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), PGE2 receptors (EPs), and carcinogenesis, target-specific molecules directed towards the components of the COX2/PGE2/EP axis seem to be promising imaging probes in the diagnostics of PGE2pos. neoplasms and in the design of anti-cancer drugs. Featured with outstanding inclusion forming capability, β-cyclodextrins (CDs) including randomly methylated β-CD (RAMEB) were reported to complex with PGE2. Therefore, radiolabelled β-CDs could be valuable vectors in the molecular imaging of PGE2-related tumorigenesis. In vivo preclinical small animal model systems applying positron emission tomography (PET) ensure a well-suited scenario for the assessment of PGE2-affine labelled CD derivatives. Previous translational studies dealt with the evaluation of the tumor-homing capability of Gallium-68 ( 68 Ga) and Bismuth-205/206 ( 205/206 Bi)-appended β-CD compounds conjugated with chelator NODAGA or DOTAGA: [ 68 Ga]Ga-NODAGA-2-hydroxypropyl-β-cyclodextrin/HPBCD, [ 68 Ga]Ga-NODAGA-RAMEB, [ 68 Ga]Ga-DOTAGA-RAMEB, and [ 205/206 Bi]Bi-DOTAGA-RAMEB in experimental tumors with different PGE2 expression. These imaging probes project the establishment of tailor-made PET diagnostics of PGE2pos. malignancies. In the present review, we provide a detailed overview of the in vivo investigations of radiolabelled PGE2-directed CDs, highlighting the importance of the integration of translational discoveries into routine clinical usage.

The voltage-gated potassium channel Kv1.3 regulates the pro-inflammatory function of microglia and is highly expressed in the post-mortem brains of individuals with Alzheimer's and Parkinson's diseases. HsTX1[R14A] is a selective and potent peptide inhibitor of the Kv1.3 channel (IC 50 ∼ 45 pM) that has been shown to decrease cytokine levels in a lipopolysaccharide (LPS)-induced mouse model of inflammation. Central nervous system exposure to HsTX1[R14A] was previously detected in this mouse model using liquid chromatography with tandem mass spectrometry, but this technique does not report on the spatial distribution of the peptide in the different brain regions or peripheral organs. Herein, the in vivo distribution of a [ 64 Cu]Cu-labeled DOTA conjugate of HsTX1[R14A] was observed for up to 48 h by positron emission tomography (PET) in mice. After subcutaneous administration to untreated C57BL/6J mice, considerable uptake of the radiolabeled peptide was observed in the kidney, but it was undetectable in the brain. Biodistribution of a [ 68 Ga]Ga-DOTA conjugate of HsTX1[R14A] was then investigated in the LPS-induced mouse model of neuroinflammation to assess the effects of inflammation on uptake of the peptide in the brain. A control peptide with very weak Kv1.3 binding, [ 68 Ga]Ga-DOTA-HsTX1[R14A,Y21A,K23A] (IC 50 ∼ 6 μM), was also tested. Significantly increased uptake of [ 68 Ga]Ga-DOTA-HsTX1[R14A] was observed in the brains of LPS-treated mice compared to mice treated with control peptide, implying that the enhanced uptake was due to increased Kv1.3 expression rather than simply increased blood-brain barrier disruption. PET imaging also showed accumulation of [ 68 Ga]Ga-DOTA-HsTX1[R14A] in inflamed joints and decreased clearance from the kidneys in LPS-treated mice. These biodistribution data highlight the potential of HsTX1[R14A] as a therapeutic for the treatment of neuroinflammatory diseases mediated by overexpression of Kv1.3.

Purpose of Review: Invasive fungal diseases (IFDs) such as invasive aspergillosis continue to be associated with high morbidity and mortality while presenting significant diagnostic challenges. Siderophores are high-affinity Fe 3+ chelators produced by Aspergillus spp. and other fungi capable of causing IFD. Previously evaluated as a treatment target in mucormycosis, siderophores have recently emerged as new diagnostic targets for invasive aspergillosis and scedosporiosis. Here, we review the diagnostic potential of siderophores for diagnosing IFD, with a particular focus on invasive aspergillosis., Recent Findings: The major secreted siderophore of A. fumigatus , triacetylfusarinine C (TAFC), has been successfully detected by mass spectrometry in serum, BALF and urine of patients with invasive aspergillosis, with promising sensitivities and specificities in single-centre studies. Intracellular uptake of siderophores has also been utilized for imaging, wherein fungal siderophores have been conjugated with the easy-to-produce radioactive isotope gallium-68 ( 68 Ga) to visualize infected body sites in PET. For the Scedosporium apiospermum complex, another siderophore N(α)-methyl coprogen B has been shown promising as a marker for airway colonization in early studies., Summary: Siderophores and particular TAFC have the potential to revolutionize diagnostic pathways for invasive aspergillosis and other mould infections. However, larger multicentre studies are needed to confirm these promising performances. Methods that allow rapid and cost-effective measurements in routine clinical practice need to be developed, particularly when TAFC is used as a biomarker in patient specimens., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Fibroblast activation protein inhibitor (FAPI) is a novel quinoline-based radiopharmaceutical that has theranostic potential, yet the limited tumor retention hinders late-time diagnosis and radionuclide treatment. This study synthesized four albumin-binding FAPIs (TE-FAPI-01 to 04) and evaluated their in vitro stability, binding affinity, in vivo biodistribution, and tumor uptake with 68 Ga, 86 Y, and 177 Lu labeling, aiming to select the best molecule that has favorable pharmacokinetics to extend the blood circulation and tumor uptake in FAP-expressing tumors. All TE-FAPIs were stable in saline and plasma and displayed high FAP-binding affinity, with IC 50 values ranging from 3.96 to 34.9 nmol/L. The capabilities of TE-FAPIs to be retained in circulation were higher than that of FAPI-04, and TE-FAPI-04 displayed minimum physiological uptake in major organs compared with other molecules. TE-FAPI-03 and TE-FAPI-04 exhibited persistent tumor accumulation, with tumor radioactivity 24 h after administration of 2.84 ± 1.19%ID/g and 3.86 ± 1.15%ID/g for 177 Lu-TE-FAPI-03 and 177 Lu-TE-FAPI-04, respectively, both of which outperformed 177 Lu-FAPI-04 (0.34 ± 0.07%ID/g). TE-FAPI-04 was recognized as the albumin-binding FAPI with the most favorable pharmacokinetics and imaging performance. The enhanced circulation half-life and tumor uptake of TE-FAPI-04 aided the theranostics of malignant tumors and warrant further clinical investigations.

The future development of personalized nuclear medicine relies on the availability of novel medical radionuclides. In particular, radiometals are attracting considerable interest since they can be used to label both proteins and peptides. Among them, the β + -emitter 68 Ga is widely used in nuclear medicine for positron emission tomography (PET). It is used in theranostics as the diagnostic partner of the therapeutic β - -emitters 177 Lu and 90 Y for the treatment of a wide range of diseases, including prostate cancer. Currently, 68 Ga is usually obtained via 68 Ge/ 68 Ga generators. However, their availability, high price and limited produced radioactivity per elution are a major barrier for a wider use of the 68 Ga-based diagnostic radiotracers. A promising solution is the production of 68 Ga by means of proton irradiation of enriched 68 Zn liquid or solid targets. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with a solid target station. In this paper, we report on the measurements of 68 Ga, 67 Ga and 66 Ga production cross-sections using natural Zn and enriched 68 Zn material, which served as the basis to perform optimized 68 Ga production tests with enriched 68 Zn solid targets., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: We present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands., Procedures: The precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [ 177 Lu]Lu-PSMA-617. The ligand [ 89 Zr]Zr-PSMA-DFO was compared with [ 68 Ga]Ga-PSMA-11 and [ 18 F]F-JK-PSMA-7 in vitro by determination of the K d value, cellular uptake, internalization in LNCaP cells, biodistribution studies with LNCaP prostate tumor xenografts in mice, and in vivo by small-animal PET imaging in LNCaP tumor mouse models. A first-in-human PET was performed with [ 89 Zr]Zr-PSMA-DFO on a patient presenting with a biochemical recurrence after brachytherapy and an ambiguous intraprostatic finding with [ 18 F]F-JK-PSMA-7 but histologically benign cells in a prostate biopsy 7 months previously., Results: [ 89 Zr]Zr-PSMA-DFO was prepared with a radiochemical purity ≥ 99.9% and a very high in vitro stability for up to 7 days at 37 °C. All radiotracers showed similar specific cellular binding and internalization, in vitro and comparable tumor uptake in biodistribution experiments during the first 5 h. The [ 89 Zr]Zr-PSMA-DFO achieved significantly higher tumor/background ratios in LNCaP tumor xenografts (tumor/blood: 309 ± 89, tumor/muscle: 450 ± 38) after 24 h than [ 68 Ga]Ga-PSMA-11 (tumor/blood: 112 ± 57, tumor/muscle: 58 ± 36) or [ 18 F]F-JK-PSMA-7 (tumor/blood: 175 ± 30, tumor/muscle: 114 ± 14) after 4 h (p < 0.01). Small-animal PET imaging demonstrated in vivo that tumor visualization with [ 89 Zr]Zr-PSMA-DFO is comparable to [ 68 Ga]Ga-PSMA-11 or [ 18 F]F-JK-PSMA-7 at early time points (1 h p.i.) and that PET scans up to 48 h p.i. clearly visualized the tumor at late time points. A late [ 89 Zr]Zr-PSMA-DFO PET scan on a patient with biochemical recurrence (BCR) had demonstrated intensive tracer accumulation in the right (SUV max 13.25, 48 h p.i.) and in the left prostate lobe (SUV max 9.47), a repeat biopsy revealed cancer cells on both sides., Conclusion: [ 89 Zr]Zr-PSMA-DFO is a promising PSMA PET tracer for detection of tumor areas with lower PSMA expression and thus warrants further clinical evaluation., (© 2021. The Author(s).)

Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector. First, 14 analogues of this compound were evaluated to check whether extending the parent structure with linkers of different lengths would not deteriorate the NK1R binding. The tested analogues had affinity similar to or better than the parent compound, and none of the linkers had a negative impact on the binding. Next, five DOTA conjugates were synthesized and used for labelling with 68 Ga and 177 Lu. The obtained radioconjugates turned out to be fairly lipophilic but showed rather limited stability in human plasma. Evaluation of the receptor affinity of the (radio)conjugates showed that neither the chelator nor the metal negatively impacts the NK1R binding. The 177 Lu-radioconjugates exhibited the binding characteristics towards NK1R similar or better than that of the 177 Lu-labelled derivative of Substance P, which is in current clinical use. The experimental results presented herein, along with their structural rationalization provided by modelling, give insight for the further molecular design of small molecular NK1R-targeting vectors.

Introduction: Thyroid cancer is the main endocrine neoplasia worldwide, for which 131 I therapy is the cornerstone treatment. One of the main problems of follow up in patients with this type of cancer, is the need for thyroglobulin stimulation, not to mention the poor availability of 123 I or 124 I, to perform studies with a higher degree of sensitivity. Prostatic Specific Membrane Antigen (PSMA) PET/CT has demonstrated to be quite useful in a diversified number of neoplasms, on behalf of its capacity of evaluating the extent of type II carboxypeptidase expression in vascular endothelium. The end point of this article is to assess whether this novel image method possesses applicability in thyroid neoplasms follow up, for diagnostic and potentially therapeutic purposes., Methods: We retrospectively evaluated well differentiated metastatic thyroid cancer patients, who underwent a post therapeutic 131 I dose whole body scan (WBS) and complementary SPECT/CT, as well as 68 Ga-PSMA-11 PET/CT., Results: Ten patients with differentiated thyroid cancer were included, of whom 80% were women and 20% men, mean age was 58 years old (± 11.6). Sixty-four metastatic lesions were analyzed, 67.19% had papillary histology and 32.81% were follicular type, the most affected site of metastases was bone in 57.81%, followed by lung 17.19%, lymph nodes 7.81%, postoperative thyroid bed 4.69%, brain 4.69% and others 7.81%. 68 Ga PSMA-11 PET/CT detected 64/64 lesions, all of them also identified by computed tomography (CT), whereas 131 I SPECT/CT detected 55/64 lesions. Discrepant lesions were localized in lung 44.4%, brain 22.2%, postoperative thyroid bed 11.1%, lymph nodes 11.1% and bone 11.1%. The degree of correspondence among observers was outstanding for both radiotracers, but close upon perfect for PSMA-11 (κ = 0.98; 95% CI, 0.80 - 0.91), as opposed to 131 I (κ = 0.86; 95% CI, 0.71 - 0.76)., Conclusions: 68 Ga-PSMA PET/CT showed an utterly superior capability for metastatic lesion detection when compared to 131 I SPECT/CT. These findings suggest that PSMA PET/CT could possibly and precociously identify radioiodine refractoriness. PSMA uptake values not only expedite diagnosis, but also award it the ability to be used for therapeutic intents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pitalua-Cortes, García-Perez, Vargas-Ahumada, Gonzalez-Rueda, Gomez-Argumosa, Ignacio-Alvarez, Soldevilla-Gallardo and Torres-Agredo.)

We developed a novel therapeutic radioligand, [ 177 Lu] 1h , with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an in vitro competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([ 68 Ga] 1e , [ 68 Ga] 1g , [ 68 Ga] 1h , and [ 68 Ga] 1k ) were screened for tumor targeting efficiency by micro-positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [ 177 Lu] 1h compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro-single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound 1h showed a high binding affinity ( K i value = 4.08 ± 0.08 nmol/L), and [ 177 Lu] 1h showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [ 177 Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [ 177 Lu] 1h was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [ 177 Lu] 1h showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [ 177 Lu] 1h survived for the entire monitoring period. The estimated human effective dose of [ 177 Lu] 1h was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [ 177 Lu] 1h has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials., (©2021 American Association for Cancer Research.)

Purpose: Prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) has been shown to have significant success in detecting local and distant metastases that cannot not be detected by conventional imaging. Initial staging in intermediate- and high-risk patients with prostate cancer is important for management. In addition, PSMA uptake has been shown to have a relation with grade of disease, and thus could be considered a separate noninvasive prognostic factor. In this study, we aimed to investigate the effect of PSMA PET/CT in the staging and management of prostate cancer patients as well as the relation to maximum standardized uptake value (SUVmax)., Methods: The patients referred to our department for staging prostate cancer were evaluated retrospectively (n = 65). Patients were grouped as positive for lymph node or distant metastatic disease. Primary tumor SUVmax data were compared with the prognostic factors of the disease. In addition, decisions about treatment protocol before and after PSMA PET/CT imaging were noted., Results: All the patients except one were accepted as positive for primary tumor. Of the patients, 46.2% were positive for lymph node and 24.6% for distant metastases. After evaluation by PSMA PET/CT, the clinical choice of treatment changed for 43.1% of our patients. Primary tumor SUVmax and tumor-to-background SUVmax ratios were found to have a significant relation with D'Amico risk classification. We found a positive correlation between SUVmax and prostate-specific antigen, Gleason scores, and age., Conclusion: PSMA PET/CT images have a nonnegligible effect on staging, clinical decisions, and change in treatment protocol. SUVmax data have a positive correlation with risk classification and could be identified as a potential independent and non-invasive prognostic factor., Competing Interests: None

Ischemic vascular diseases are associated with elevated tissue expression of angiomotin (AMOT), a promising molecular target for PET imaging. On that basis, we developed an AMOT-targeting radiotracer, 68 Ga-sCD146 and performed the first in vivo evaluation on a myocardial infarction mice model and then, compared AMOT expression and α v β 3 -integrin expression with 68 Ga-sCD146 and 68 Ga-RGD 2 imaging. After myocardial infarction (MI) induced by permanent ligation of the left anterior descending coronary artery, myocardial perfusion was evaluated by Doppler ultrasound and by 18 F-FDG PET imaging. 68 Ga-sCD146 and 68 Ga-RGD 2 PET imaging were performed. In myocardial infarction model, heart-to-muscle ratio of 68 Ga-sCD146 imaging showed a significantly higher radiotracer uptake in the infarcted area of MI animals than in sham (* p = 0.04). Interestingly, we also observed significant correlations between 68 Ga-sCD146 imaging and delayed residual perfusion assessed by 18 F-FDG (* p = 0.04), with lowest tissue fibrosis assessed by histological staining (* p = 0.04) and with functional recovery assessed by ultrasound imaging (** p = 0.01). 68 Ga-sCD146 demonstrated an increase in AMOT expression after MI. Altogether, significant correlations of early post-ischemic 68 Ga-sCD146 uptake with late heart perfusion, lower tissue fibrosis and better functional recovery, make 68 Ga-sCD146 a promising radiotracer for tissue angiogenesis assessment after MI.

Background: High-risk prostate cancer is associated with adverse pathology and unfavorable outcomes after radical prostatectomy. 68 Ga-PSMA PET/CT is more accurate than conventional imaging for preoperative staging. We aimed to evaluate whether lymph node involvement on 68 Ga-PSMA PET/CT prior to radical prostatectomy in patients with high-risk prostate cancer is associated with worse short-term oncologic outcomes., Methods: We retrospectively reviewed 149 patients with high-risk localized or locoregional prostate cancer who underwent 68 Ga-PSMA PET/CT prior to radical prostatectomy between 2015 and 2020. None of the patients received neoadjuvant or adjuvant treatment. The study endpoints were PSA persistence and biochemical recurrence. Logistic regression models were used to identify preoperative predictors of PSA persistence. Kaplan-Meier analyses were used to estimate biochemical recurrence-free survival., Results: Of 149 identified patients, 19 (13%) were found to have lymph node involvement on preoperative 68 Ga-PSMA PET/CT. The sensitivity, specificity, and accuracy of 68 Ga-PSMA PET/CT for identifying pathologic lymph node involvement were 68%, 95%, and 92%, respectively. PSA persistence rate was lower among patients with PET-negative lymph nodes than those with PET-positive nodes (15 vs. 84%, p < 0.001). Positive nodes on imaging (OR = 41.03, p < 0.001) and clinical T2c-T3 stage (OR = 6.96, p = 0.002) were associated with PSA persistence on multivariable analysis. Among patients with PET-negative nodes the 1- and 2-year biochemical recurrence-free survival rates were 87% and 76%, respectively., Conclusions: Preoperative staging with 68 Ga-PSMA PET/CT may identify a subgroup of high-risk prostate cancer patients with favorable short-term outcomes after radical prostatectomy without adjuvant treatment. Future studies will evaluate whether these results are sustained during long-term follow-up., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Pretargeted imaging has emerged as a promising approach to advance nuclear imaging of malignant tumors. Herein, we combine the enzyme-mediated fluorogenic reaction and in situ self-assembly with the inverse electron demand Diels-Alder (IEDDA) reaction to develop an activatable pretargeted strategy for multimodality imaging. The trans-cyclooctene (TCO) bearing small-molecule probe, P-FFGd-TCO, can be activated by alkaline phosphatase and in situ self-assembles into nanoaggregates (FMNPs-TCO) retained on the membranes, permitting to (1) amplify near-infrared (NIR) fluorescence (FL) and magnetic resonance imaging (MRI) signals, and (2) enrich TCOs to promote IEDDA ligation. The Gallium-68 ( 68 Ga) labeled tetrazine can readily conjugate the tumor-retained FMNPs-TCO to enhance radioactivity uptake in tumors. Strong NIR FL, MRI, and positron emission tomography (PET) signals are concomitantly achieved, allowing for pretargeted multimodality imaging of ALP activity in HeLa tumor-bearing mice., (© 2021 Wiley-VCH GmbH.)

Aim of the Study: This study aims to assess the diagnostic efficacy of Gallium-68-prostate-specific membrane antigen positron emission tomography (PET)/computed tomography (CT) (68Ga PSMA PET-CT) in primary nodal staging of high-risk prostate cancer (PCa) when compared to pathologic findings of extended pelvic lymph-node dissection (eLND)., Materials and Methods: The records of high-risk PCa patients who were preoperatively staged through 68Ga PSMA PET-CT and who underwent robot-assisted radical prostatectomy with eLND either alone or as part of multimodal definitive therapy between August 2016 and November 2019 were retrospectively reviewed. Surgeons were not blinded to the results of the 68Ga PSMA PET-CT scan. Pathologic uptake was defined as any anomalous uptake which was not better explained by another cause and was suggestive of PCa. The reference standard for this study was the pathologic confirmation using a node-based analysis. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 68Ga PSMA PET-CT were calculated in a per-patient analysis using IBM SPSS Statistics version 25., Results: Seventeen patients met the selection criteria. Mean age was 63 years (range 44-77) and mean and median preoperative serum prostate specific antigen was 19.25 and 9 ng/ml (range 6-131), respectively. The most common pathologic Gleason score was 8 (52.9% of cases). Seven patients (41%) had positive surgical margins and were submitted to adjuvant radiotherapy. Mean number of per patient removed lymph-nodes was 13 (±2.19). 68Ga PSMA PET-CT showed findings compatible with lymph node metastases in 4/17 patients and with locally-confined disease in 13/17 patients. Following pathologic confirmation, the per-patient sensibility of the 68Ga PSMA PET-CT was calculated at 75% (1 false negative) and the specificity at 92.3% (1 false positive) for detection of lymph node metastasis on primary staging of high-risk PCa patients. Positive and negative predictive value were 75% and 92.3%, respectively; accuracy of the test was calculated at 88.2%. All patients were submitted to 68Ga PSMA PET-CT re-evaluation 6 months after surgery and tested negative for local, nodal, or distant recurrence of disease., Conclusions: 68Ga PSMA PET-CT appears to have a high negative predictive value for local lymph node metastases in high-risk primary PCa when compared to pathologic findings of eLND. Its role in the primary nodal staging of high-risk PCa patients worths further evaluation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Defining the extent of disease spread with imaging modalities is crucial for therapeutic decision-making and definition of treatment. This study aimed to investigate whether clinical parameters and nomograms predict prostate-specific membrane antigen (PSMA)-positive lymph nodes in treatment-naïve nonmetastatic prostate cancer (PC) patients., Materials and Methods: The clinical data of 443 PC patients (83.3% high-risk and 16.7% intermediate-risk) were retrospectively analyzed. Receiver operating characteristic (ROC) curves with areas under the curve (AUC) were generated to evaluate the accuracy of clinical parameters (prostate-specific antigen [PSA], T stage, Gleason score [GS], International Society of Urological Pathology [ISUP] grade) and nomograms (Roach formula [RF], Yale formula [YF], and a new formula [NF]) in predicting lymph node metastasis. The AUCs of the various parameters and clinical nomograms were compared using ROC and precision-recall (PR) curves., Results: A total of 288 lymph node metastases were identified in 121 patients (27.3%) using 68 Ga-PSMA-11-positron emission tomography (PET)/computed tomography (CT). Most PSMA-avid lymph node metastases occurred in external or internal iliac lymph nodes (142; 49.3%). Clinical T stage, PSA, GS, and ISUP grade were significantly associated with PSMA-positive lymph nodes according to univariate logistic regression analysis. The PSMA-positive lymph nodes were more frequently detected in patients with PSA >20 ng/ml, GS ≥7 or high risk disease compared to their counterparts. The clinical T stage, serum PSA level, GS, and ISUP grade showed similar accuracy in predicting PSMA-positive metastasis, with AUC values ranging from 0.675 to 0.704. The median risks for PSMA-positive lymph nodes according to the RF, YF, and NF were 31.3% (range: 12.3%-100%), 22.3% (range: 4.7%-100%), and 40.5% (range: 12.3%-100%), respectively. The AUC values generated from ROC and PR curve analyses were similar for all clinical nomograms, although the RF and YF had higher accuracy compared to NF., Conclusion: The clinical T stage, PSA, GS, and ISUP grade are independent predictors of PSMA-positive lymph nodes. The RF and YF can be used to identify patients who can benefit from 68 Ga-PSMA-11 PET/CT for the detection of lymph node metastasis. Together with nomograms, 68 Ga-PSMA-11 PET/CT images help to localize PSMA-positive lymph node metastases and can thus assist in surgery and radiotherapy planning., (© 2021 Wiley Periodicals LLC.)

Background: Myocardial infarction (MI) evokes an organized remodeling process characterized by the activation and transdifferentiation of quiescent cardiac fibroblasts to generate a stable collagen rich scar. Early fibroblast activation may be amenable to targeted therapy, but is challenging to identify in vivo . We aimed to non-invasively image active fibrosis by targeting the fibroblast activation protein (FAP) expressed by activated (myo)fibroblasts, using a novel positron emission tomography (PET) radioligand [ 68 Ga]MHLL1 after acute MI. Methods: One-step chemical synthesis and manual as well as module-based radiolabeling yielded [ 68 Ga]MHLL1. Binding characteristics were evaluated in murine and human FAP-transfected cells, and stability tested in human serum. Biodistribution in healthy animals was interrogated by dynamic PET imaging, and metabolites were measured in blood and urine. The temporal pattern of FAP expression was determined by serial PET imaging at 7 d and 21 d after coronary artery ligation in mice as percent injected dose per gram (%ID/g). PET measurements were validated by ex vivo autoradiography and immunostaining for FAP and inflammatory macrophages. Results: [ 68 Ga]MHLL1 displayed specific uptake in murine and human FAP-positive cells (p = 0.0208). In healthy mice the tracer exhibited favorable imaging characteristics, with low blood pool retention and dominantly renal clearance. At 7 d after coronary artery ligation, [ 68 Ga]MHLL1 uptake was elevated in the infarct relative to the non-infarcted remote myocardium (1.3 ± 0.3 vs. 1.0 ± 0.2 %ID/g, p < 0.001) which persisted to 21 d after MI (1.3 ± 0.4 vs. 1.1 ± 0.4 %ID/g, p = 0.013). Excess unlabeled compound blocked tracer accumulation in both infarct and non-infarct remote myocardium regions (p < 0.001). Autoradiography and histology confirmed the regional uptake of [ 68 Ga]MHLL1 in the infarct and especially border zone regions, as identified by Masson trichrome collagen staining. Immunostaining further delineated persistent FAP expression at 7 d and 21 d post-MI in the border zone, consistent with tracer distribution in vivo . Conclusion: The simplified synthesis of [ 68 Ga]MHLL1 bears promise for non-invasive characterization of fibroblast activation protein early in remodeling after MI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: Pancreatic neuroendocrine tumours (panNETs) arise sporadically or as part of a genetic predisposition syndrome. CT/MRI, endoscopic ultrasonography and functional imaging using Octreoscan localise and stage disease. This study aimed to evaluate the complementary role of 68 Gallium ( 68 Ga)-DOTA PET/CT in managing patients with panNETs., Design: A retrospective study conducted across three tertiary UK NET referral centres., Methods: Demographic, clinical, biochemical, cross-sectional and functional imaging data were collected from patients who had undergone a 68 Ga-DOTA PET/CT scan for a suspected panNET., Results: We collected data for 183 patients (97 male): median (SD) age 63 (14.9) years, 89.1 vs. 9.3% (n=163 vs. 17) alive vs. dead (3 data missing), 141 sporadic vs. 42 familial (MEN1, n=36; 85.7%) panNETs. Non-functional vs. functional tumours comprised 73.2 vs. 21.3% (n=134 vs. 39) (10 missing). Histological confirmation was available in 89% of individuals (n=163) but tumour grading (Ki67 classiifcation) was technically possible only in a smaller cohort (n=143): grade 1, 50.3% (n=72); grade 2, 46.2% (n=66) and grade 3, 3.5% (n=5) (40 histopathological classification either not technically feasible or biopsy not perfomed). 60.1% (n=110) were localised, 14.2% (n=26) locally advanced and 23.5% (n=43) metastatic (4 missing). 224 68 Ga-DOTA PET/CT scans were performed in total for: diagnosis/staging 40% (n=88), post-operative assessment/clinical surveillance 53% (n=117) and consideration of peptide receptor radionuclide therapy (PRRT) 8% (n=17) (2 missing). PET/CT results confirmed other imaging findings (53%), identified new disease sites (28.5%) and excluded suspected disease (5%). Overall, 68 Ga-DOTA PET/CT imaging findings provided additional information in 119 (54%) patients and influenced management in 85 (39%) cases., Conclusion: 68 Ga-DOTA PET/CT imaging more accurately stages and guides treatment in patients with sporadic/familial panNETs with newly diagnosed/recurrent disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cuthbertson, Barriuso, Lamarca, Manoharan, Westwood, Jaffa, Fenwick, Nuttall, Lalloo, Prachalias, Pizanias, Wieshmann, McNamara, Hubner, Srirajaskanthan, Vivian, Ramage, Weickert, Pritchard, Vinjamuri, Valle and Yip.)

The checkpoint blockade immunotherapy has become a potent treatment strategy for cancers, and programmed death ligand-1 (PD-L1) is a prominent checkpoint ligand that is highly expressed in some cancers. The identification of immune checkpoint marker PD-L1 is critical for improving the success of immunotherapy. Accordingly, the binding specificity and dynamic monitoring property of a non-blocking nanobody tracer 68 Ga-NOTA-Nb109 to PD-L1 were assessed in this study. The endogenous expression level of PD-L1 in several cancer cells was measured by flow cytometry, Western blot, and cellular uptake assay. Sensitivity and specificity of 68 Ga-NOTA-Nb109 in monitoring the expression of PD-L1 in vivo were evaluated by PET imaging of different tumor-bearing models (U87, high PD-L1 expression; HCT 116, medium PD-L1 expression; and NCI-H1299, low PD-L1 expression). In vivo PET imaging results agreed well with those detected in vitro. In addition, PET imaging of PD-L1 expression in U87 and NCI-H1299 xenografts using 18 F-FDG was also performed for comparison. The maximum tumor-to-muscle uptake ratio of 68 Ga-NOTA-Nb109 was more than twofold that of 18 F-FDG in U87 xenograft. The change of PD-L1 expression in NCI-H1299 cells and xenografts induced by cisplatin (CDDP) was sensitively monitored by 68 Ga-NOTA-Nb109. This study demonstrated the feasibility of tracer 68 Ga-NOTA-Nb109 for specifically targeting endogenous PD-L1 and dynamic monitoring the change of PD-L1 expression, and could guide the immunotherapy and immunochemotherapy for refractory cancers.

Purpose: To evaluate the differential impact of postoperative radiotherapy (RT) on recurrence patterns in patients treated with radical prostatectomy (RP) using [ 68 Ga]Ga-PSMA HBED-CC conjugate 11 positron emission tomography (PSMA 11-PET)., Methods: We assessed 162 consecutive patients who experienced biochemical recurrence (BCR) after RP for nonmetastatic prostate cancer (PC). All had at least one positive lesion on imaging. No patient was on androgen deprivation therapy (ADT). Patients were categorized into those who had received adjuvant/salvage RT ± ADT and those who did not (RP only). Lesion- and patient-based analyses were performed. The impact of the radiation field was assessed., Results: Overall, 57 BCR patients underwent RP only, 105 received postoperative RT. Median PSA was 1.01 ng/ml (IQR 0.58-2). In the lesion-based analysis, compared to the RP only patients, those who had received postoperative RT, had less lymph node (LN) recurrences distal to the common iliac bifurcation (35.2 vs. 57.9%, p = 0.05), but were more likely to harbor positive LNs proximal to the iliac bifurcation and in the presacral (34.2 vs. 12.3%, p = 0.002) areas as well as bone metastases (25.7 vs. 8.8%, p = 0.01). In the patient-based analysis, the patients with postoperative RT after RP had less recurrence in the pelvis only (pelvic LNs and/or prostate bed) (52.4 vs. 79%, p = 0.002), but were more likely to harbor extrapelvic recurrence (41.9 vs. 15.8%, p = 0.001). Patients who received RT to the prostate bed only had more recurrence to the pelvic LN only (54.2% vs. 23.4%, p = 0.002), but less extrapelvic recurrence (31.3 vs. 53.2%, p = 0.03) and less bone recurrence (16.7 vs. 36.2%, p = 0.031) compared to those patients, who received RT to the prostate bed and pelvic nodes., Conclusions: Postoperative radiation treatment alters the recurrence pattern in BCR patients after RP. Further prospective studies are needed to establish a decision tree for optimal imaging/management according to previous treatments.

Immuno-oncology (IO) with immune checkpoint inhibitors (ICIs) is the new landmark in cancer treatment. However, due to its economical-related burden and the possibility of tumor pseudoprogression with late response patterns, it is imperative to find new ways for early discrimination of patients with IO-sensitive versus IO-resistant disease. ICI-mediated antitumor responses depend on tumor immune infiltration by T-cells capable of recognizing and killing tumor cells. Nevertheless, patients may experience different responses to immunotherapy according to their tumor microenvironment and inflammatory infiltration. T-cell infiltrated tumors are referred to as 'hot' and are potential candidates for a good response to ICIs, whereas 'cold' are those tumors lacking T-cell infiltration and exhibit a narrow likelihood of response to IO therapy. Gallium-67 ( 67 Ga) scintigraphy may hold potential for separating 'hot' from 'cold' tumors, thus providing an imaging tool to distinguish 'hot' ICI-induced pseudoprogression from real early 'cold' progression. Even so, various tumors (lymphomas, lung cancer, breast cancer, hepatoma, malignant melanoma) exhibit an inherent affinity for 67 Ga that is independent of the ICI-induced immune infiltration, and this raises issues about false positivity. For that reason, future investigational studies to evaluate the prospective role of this radiotracer in the early prediction of ICI response should be confined to tumors with an inherently low 67 Ga affinity (thyroid carcinoma, gastrointestinal and genitourinary tract tumors). We describe our experience with a patient with recurrent metastatic lung adenocarcinoma under ICI therapy that was submitted to 67 Ga scanning for a fever of unknown origin and we discuss the aforementioned topics, alongside current imaging trends and future perspectives in the field., (Copyright © 2021. Published by Elsevier Ltd.)

Imaging of prostate cancer has recently had new modalities. Ga-68 Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography/Computed Tomography (PET/CT) has gained important diagnostic role in the management of the patients with prostate cancer. Patients with progressively elevated serum prostate specific antigen (PSA) level may be evaluated by Ga-68 PSMA PET/CT imaging. This case report presents a seventy five year old man with diagnosis of prostate cancer and progressive serum PSA increase. Local recurrence of the tumor as well as spread to the penis, perineum and skeleton was determined by Ga-68 PSMA imaging. This case illustrates that Ga-68 PSMA imaging may show unexpected sites of disease spread., Competing Interests: None

Objective: The aim of current study is to evaluate the role of diuretic assisted 68Ga-PSMA PET-CT, on image quality and clinical interpretation of indeterminate/equivocal lesions in pre-Lasix imaging of Prostate cancer., Materials and Methods: Forty-five patients underwent baseline 68Ga-PSMA-11 scan 45-60 minutes post tracer injection followed by post Lasix study after ±15 minutes. The contrast to noise ratios (CNR), noise and SUVmax were determined for the focal uptakes in both pre and post Lasix images. All continuous variables were expressed as mean ± SD. Images were assessed by two experienced physicians in order to  evaluate lesion detectability and delineations that have an impact on clinical interpretation., Results: Of total 45 patients, 12/45 (27%) showed unremarkable scan along with 33/45 (73%) showing metastases. Sixteen out of 45 (36%) of the metastatic scans showed indeterminate/equivocal lesions. In these cases, post Lasix study showed false negative findings in 7/45 (16%), better delineation of lesions 10/45 (22%), better confidence towards reporting lesions as abnormal in 5/45 (11%) with an overall 11/45 (24%) of the cases who showed increase in the number of the lesions after the Lasix study. The overall CNR was evaluated using Wilcoxon Rank test (p-value = 0.02) which suggested significant improved ratios in the post-Lasix imaging by 49.6%±24.5. There was a substantial agreement (k =0.76) between the physicians when comparing the lesion clarity and delineation in post Lasix images. The average score for physician one and two being 2.4 ±0.71 and 2.53±0.52 respectively., Conclusion: Post diuretic 68Ga-PSMA imaging at ± 15 minutes clears the unwanted activity in the urinary tract which in turn improves the contrast to noise ratios. Thus leading to decline in false positive findings, improved diagnostic certainty of physician and better detection of indeterminate lesions in 68Ga-PSMA imaging.

Introduction: Early detection of liver fibrosis and monitoring response to treatment crucial for the management of patients are currently not feasible in clinical practice. Platelet derived growth factor receptor β (PDGFR-β) expression is regarded as a potential biomarker to determine the stages of fibrotic diseases including liver fibrosis. [ 68 Ga]Ga-BOT5035 comprising a bicyclic peptide was developed for specific targeting of PDGFR-β overexpressed in pathological fibrosis. The realization of microdosing phase 0 study using [ 68 Ga]Ga-BOT5035 positron emission tomography required automated good manufacturing practice (GMP) compliant production of [ 68 Ga]Ga-BOT5035 presented herein. Moreover, the investigation of radiation dosimetry was conducted to ensure possibility of multiple annual examinations for disease monitoring in clinical setup., Methods: The active pharmaceutical ingredient starting material BOT5035 (GMP grade) was provided by BiOrion Technologies BV. The 68 Ga-labelling process was developed and automated using synthesis platform (Modular-Lab PharmTrace, Eckert & Ziegler), disposable cassettes for 68 Ga-labelling, and pharmaceutical grade 68 Ge/ 68 Ga generator (GalliaPharm®) purchased from Eckert & Ziegler. Radiolysis sensitive BOT5035 required development and systematic optimization of the labelling synthesis parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration and pH. The validation process was conducted with regard to the product quality and quantity, as well as production reproducibility. Human organ equivalent doses and total body effective doses were calculated using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1), based on ex vivo organ distribution in Sprague-Dawley rats., Results: The GMP compliant automated production of [ 68 Ga]Ga-BOT5035 with on-line documentation demonstrated high reproducibility. The time for the labelling synthesis and quality control was approximately 60 min. The non-decay corrected radiochemical yield and radiochemical purity of the radiopharmaceutical were 43.7 ± 7.6% (n = 3, process validation) and 97.7 ± 0.4% (n = 3, process validation), respectively. Predefined acceptance criteria were met for the sterility, endotoxins level, radionuclidic purity and residual solvent content. The stability at ambient temperature was controlled for 120 min with approved results. Ex vivo organ distribution data revealed fast blood clearance and washout from most of the organs. The dose-limiting organs were kidney and bone marrow. The total effective dose as limiting parameter would allow for up to 3-4 PET scans per annum., Conclusion: The fully automated and GMP compliant production of [ 68 Ga]Ga-BOT5035 was developed and thoroughly validated. The radiopharmaceutical was approved by Swedish Medicinal Products Agency and the Ethical Review Authority for the Phase 0 clinical study of the quantitative imaging of liver fibrosis. Human dosimetry calculations extrapolated from animal experiment indicated possibility of 3-4 PET examinations per year., Competing Interests: Disclosures Herman Steen and Guus van Scharrenburg are an employee of BiOrion Technologies BV. Otherwise, the authors have nothing to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Bruton tyrosine kinase inhibitor ibrutinib is effective in treating chronic lymphocytic leukemia (CLL). However, after ibrutinib treatment initiation, patients frequently experience an increase of CLL blood cell count. This phenomenon in clinical practice is thought to reflect a "compartment shift" of CLL cells from lymph nodes to the peripheral blood, but the actual shifting has not yet been demonstrated. Using [ 68 Ga]Pentixafor-PET/MRI for in vivo CXCR4 visualization, we here provide images of topical changes of CLL cells upon ibrutinib treatment. Within the first month of ibrutinib treatment, mean standardized [ 68 Ga]Pentixafor uptake decreased in the bone marrow and lymph nodes, whereas [ 68 Ga]Pentixafor uptake increased in the spleen. Leukocytosis rose, as did numbers of CXCR4 high (tissue-resident) CLL cells. Volumes of lymph nodes and spleen decreased. Upon longer ibrutinib treatment, leukocytosis decreased, followed by a decrease of [ 68 Ga]Pentixafor uptake in the spleen. These results support the preexisting clinical hypothesis of a "compartment shift" of CLL cells from the lymph nodes to the peripheral blood, but also refine the mechanistic model by describing early clearing of the bone marrow and redistribution of CLL cells to the orthotopic splenic cavernous system in response to ibrutinib treatment., (©2020 American Association for Cancer Research.)

Background: Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTRs), which is the molecular basis for 68 Ga-DOTATOC positron-emission tomography (PET) and radiopeptide therapy (PRRT). However, SSTR expression fluctuates and can be subject to treatment-related changes. The aim of this retrospective study was to assess, which changes in PET and apparent diffusion coefficient (ADC) occur for different treatments and if pre-therapeutic 68 Ga-DOTATOC-PET/MRI was able to predict treatment response to PRRT., Methods: Patients with histopathologically confirmed NET, at least one liver metastasis > 1 cm and at least two 68 Ga-DOTATOC-PET/MRI including ADC maps were eligible. 68 Ga-DOTATOC-PET/MRI of up to 5 liver lesions per patients was subsequently analyzed. Extracted features comprise conventional PET parameters, such as maximum and mean standardized uptake value (SUVmax and SUVmean) and ADC values. Furthermore, textural features (TFs) from both modalities were extracted. In patients with multiple 68 Ga-DOTATOC-PET/MRI a pair of 2 scans each was analyzed separately and the parameter changes between both scans calculated. The same image analysis was performed in patients with 68 Ga-DOTATOC-PET/MRI before PRRT. Differences in PET and ADC maps parameters between PRRT-responders and non-responders were compared using Mann-Whitney test to test differences among groups for statistical significance., Results: 29 pairs of 68 Ga-DOTATOC-PET/MRI scans of 18 patients were eligible for the assessment of treatment-related changes. In 12 cases patients were treated with somatostatin analogues between scans, in 9 cases with PRRT and in 2 cases each patients received local treatment, chemotherapy and sunitinib. Treatment responders showed a statistically significant decrease in lesion volume and a borderline significant decrease in entropy on ADC maps when compared to non-responders. Patients treated with standalone SSA showed a borderline significant decrease in mean and maximum ADC, compared to patients treated with PRRT. No parameters were able to predict treatment response to PRRT on pre-therapeutic 68 Ga-DOTATOC-PET/MRI., Conclusions: Patients responding to current treatment showed a statistically significant decrease in lesion volume on ADC maps and a borderline significant decrease in entropy. No statistically significant changes in PET parameters were observed. No PET or ADC maps parameters predicted treatment response to PRRT. However, the sample size of this preliminary study is small and further research needed.

Ga study was performed in a 10-year-old boy who had a history of motor vehicle accident to evaluate occult infection. No abnormal activity typical of active infection was noted. However, there was significantly decreased activity in the right side of the head, which was related to his head trauma.

The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays an important role in tumor development and formation of metastases. It was earlier reported that cyclodextrin derivatives have a high affinity to form complexes with PGE2. Based on these results radiolabeled cyclodextrins - as new radiopharmaceuticals - may open a new pathway in the in vivo imaging and diagnosis of PGE2 positive tumors. The aims of this study were to synthetize the PGE2 specific 68 Ga-labeled NODAGA-randomly methylated beta-cyclodextrin ( 68 Ga-NODAGA-RAMEB) and investigate its tumor-targeting properties. NODAGA-RAMEB was labeled with Gallium-68 ( 68 Ga), and the radiochemical purity (RCP%), partition coefficient (logP values), and in vitro-in vivo stability of 68 Ga-NODAGA-RAMEB were determined. After intravenous injection of 68 Ga-NODAGA-RAMEB the accumulation in organs and tissues was monitored in vivo by positron emission tomography (PET) and ex vivo by gamma counter in BxPC-3 and PancTu-1 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized 68 Ga-NODAGA-RAMEB was higher than 98%. The molar activity was 15.34 ± 1.93 GBq/μmol. The logP of 68 Ga labeled NODAGA-RAMEB was - 3.63 ± 0.04. Biodistribution studies showed high accumulation of 68 Ga-NODAGA-RAMEB in PGE2 positive BxPC-3 tumors; approximately 15-20-fold higher radiotracer uptake was observed, than that of the background. 68 Ga-labeled RAMEB is a promising radiotracer in PET diagnostics of PGE2 positive tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THP Me as a high-affinity pair capable of combining in vivo. After confirming the ability of THP Me to bind 68 Ga in vivo at low concentrations, the bifunctional THP Me -NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THP Me -NCS-huA33, followed after 24 h by 8-10 MBq of 68 Ga 3+ ) with both a directly labelled radioimmunoconjugate ( 89 Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68 Ga-only negative control (8-10 MBq of 68 Ga 3+ ). Imaging was performed 25 h after antibody administration (1 h after 68 Ga 3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of "unchelated" 68 Ga 3+ in the tumour was found (12.9 %ID/g) even without prior administration of THP Me -NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68 Ga-only experiment was repeated using THP Me (20 μg, 1 h after 68 Ga 3+ administration) to clear circulating 68 Ga 3+ , producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THP Me as a 68 Ga clearing agent in imaging applications with gallium citrate.

Purpose: The increasing interest and availability of non-standard positron-emitting radionuclides has heightened the relevance of radionuclide choice in the development and optimization of new positron emission tomography (PET) imaging procedures, both in preclinical research and clinical practice. Differences in achievable resolution arising from positron range can largely influence application suitability of each radionuclide, especially in small-ring preclinical PET where system blurring factors due to annihilation photon acollinearity and detector geometry are less significant. Some resolution degradation can be mitigated with appropriate range corrections implemented during image reconstruction, the quality of which is contingent on an accurate characterization of positron range., Procedures: To address this need, we have characterized the positron range of several standard and non-standard PET radionuclides (As-72, F-18, Ga-68, Mn-52, Y-86, and Zr-89) through imaging of small-animal quality control phantoms on a benchmark preclinical PET scanner. Further, the Particle and Heavy Ion Transport code System (PHITS v3.02) code was utilized for Monte Carlo modeling of positron range-dependent blurring effects., Results: Positron range kernels for each radionuclide were derived from simulation of point sources in ICRP reference tissues. PET resolution and quantitative accuracy afforded by various radionuclides in practicable imaging scenarios were characterized using a convolution-based method based on positron annihilation distributions obtained from PHITS. Our imaging and simulation results demonstrate the degradation of small animal PET resolution, and quantitative accuracy correlates with increasing positron energy; however, for a specific "benchmark" preclinical PET scanner and reconstruction workflow, these differences were observed to be minimal given radionuclides with average positron energies below ~ 400 keV., Conclusion: Our measurements and simulations of the influence of positron range on PET resolution compare well with previous efforts documented in the literature and provide new data for several radionuclides in increasing clinical and preclinical use. The results will support current and future improvements in methods for positron range corrections in PET imaging.

Purpose: There are several important positron emission tomography (PET) imaging scenarios that require imaging with very low photon statistics, for which both quantitative accuracy and visual quality should not be neglected. For example, PET imaging with the low photon statistics is closely related to active efforts to significantly reduce radiation exposure from radiopharmaceuticals. We investigated two examples of low-count PET imaging: (a) imaging [ 90 Y]microsphere radioembolization that suffers the very small positron emission fraction of Y-90's decay processes, and (b) cancer imaging with [ 68 Ga]citrate with uptake time of 3-4 half-lives, necessary for visualizing tumors. In particular, we investigated a type of penalized likelihood reconstruction algorithm, block sequential regularized expectation maximization (BSREM), for improving both image quality and quantitative accuracy of these low-count PET imaging cases., Procedures: The NEMA/IEC Body phantom filled with aqueous solution of Y-90 or Ga-68 was scanned to mimic the low-count scenarios of corresponding patient data acquisitions on a time-of-flight (TOF) PET/magnetic resonance imaging system. Contrast recovery, background variation, and signal-to-noise ratio were evaluated in different sets of count densities using both conventional TOF ordered subset expectation (TOF-OSEM) and TOF-BSREM algorithms. The regularization parameter, beta, in BSREM that controls the tradeoff between image noise and resolution was evaluated to find a value for improved confidence in image interpretation. Visual quality assessment of the images obtained from patients administered with [ 68 Ga]citrate (n = 6) was performed. We also made preliminary visual image quality assessment for one patient with [ 90 Y]microspheres. In Y-90 imaging, the effect of 511-keV energy window selection for minimizing the number of random events was also evaluated., Results: Quantitatively, phantom images reconstructed with TOF-BSREM showed improved contrast recovery, background variation, and signal-to-noise ratio values over images reconstructed with TOF-OSEM. Both phantom and patient studies of delayed imaging of [ 68 Ga]citrate show that TOF-BSREM with beta = 500 gives the best tradeoff between image noise and image resolution based on visual assessment by the readers. The NEMA-IQ phantom study with [ 90 Y]microspheres shows that the narrow energy window (460-562 keV) recovers activity concentrations in small spheres better than the regular energy window (425-650 keV) with the beta value of 2000 using the TOF-BSREM algorithm. For the images obtained from patients with [ 68 Ga]citrate using TOF-BSREM with beta = 500, the visual analogue scale (VAS) was improved by 17 % and the Likert score was increased by 1 point on average, both in comparison to corresponding scores for images reconstructed using TOF-OSEM., Conclusion: Our investigation shows that the TOF-BSREM algorithm improves the image quality and quantitative accuracy in low-count PET imaging scenarios. However, the beta value in this algorithm needed to be adjusted for each radiopharmaceutical and counting statistics at the time of scans.

Imaging diagnosis of infection and inflammation has been challenging for many years. Infection imaging agents commonly used in nuclear medicine, such as [ 67 Ga]citrate, 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG), and radionuclide-labeled leukocytes, have their own shortcomings. Identification of a tracer with considerable economic benefit, high specificity, and low radiation dose has become clinically urgent. In the twenty-first century, with the increasing availability of positron emission tomography (PET) devices and the commercialization of Ge-68/Ga-68 generators, the study of [ 68 Ga]citrate applications for infection and inflammation has increased and shown good potential. In this report, the research progress that supports [ 68 Ga]citrate PET's applications various infectious diseases and inflammation is reviewed.

C-X-C chemokine receptor type 4 (CXCR4) constitutes a promising target for tumor diagnosis and therapy. Herein, we evaluate a new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CXCR4 antagonist derived from LY2510924, FRM001, and its metal complexes as CXCR4-targeting probes. FRM001 was synthesized by modifying the C-terminus of LY2510924 with maleimido-mono-amide-DOTA via a cysteine linker. FRM001 exhibited CXCR4-specific binding with an affinity similar to that of the parental LY2510924. The binding affinity of FRM001 remained unchanged after complexation with Ga, Lu, and Y. The internalization of 67 Ga-FRM001 into the cells was hardly observed. In mice biodistribution studies, 67 Ga-FRM001 exhibited high accumulation in the tumor and the liver with rapid elimination rates from the blood. The hepatic accumulation of 67 Ga-FRM001 was preferentially and significantly reduced by co-injecting a CXCR4 antagonist, AMD3100. The C-terminal-modified LY2510924 would constitute a versatile scaffold to develop CXCR4-targeting probes or therapeutics for tumor imaging or therapy.

Purpose: Macrophage mannose receptor (MMR, CD206) expressing tumor-associated macrophages (TAM) are protumorigenic and was reported to negatively impact therapy responsiveness and is associated with higher chances of tumor relapse following multiple treatment regimens in preclinical tumor models. Since the distribution of immune cells within the tumor is often heterogeneous, sampling "errors" using tissue biopsies will occur. In order to overcome this limitation, we propose positron emission tomography (PET)/X-ray computed tomography (CT) imaging using 68 Ga-labeled anti-MMR single-domain antibody fragment (sdAb) to assess the presence of these protumorigenic TAM., Procedures: Cross-reactive anti-MMR-sdAb was produced according to good manufacturing practice (GMP) and conjugated to p-SCN-Bn-NOTA bifunctional chelator for 68 Ga-labeling. Biodistribution and PET/CT studies were performed in wild-type and MMR-deficient 3LL-R tumor-bearing mice. Biodistribution data obtained in mice were extrapolated to calculate radiation dose estimates for the human adult using OLINDA software. A 7-day repeated dose toxicity study for NOTA-anti-MMR-sdAb was performed in healthy mice up to a dose of 1.68 mg/kg., Results: [ 68 Ga]Ga-NOTA-anti-MMR-sdAb was obtained with 76 ± 2 % radiochemical yield, 99 ± 1 % radiochemical purity, and apparent molar activity of 57 ± 11 GBq/μmol. In vivo biodistribution analysis showed fast clearance via the kidneys and retention in MMR-expressing organs and tumor, with tumor-to-blood and tumor-to-muscle ratios of 6.80 ± 0.62 and 5.47 ± 1.82, respectively. The calculated effective dose was 0.027 mSv/MBq and 0.034 mSv/MBq for male and female, respectively, which means that a proposed dose of 185 MBq in humans would yield a radiation dose of 5.0 and 6.3 mSv to male and female patients, respectively. In the toxicity study, no adverse effects were observed., Conclusions: Preclinical validation of [ 68 Ga]Ga-NOTA-anti-MMR-sdAb showed high specific uptake of this tracer in MMR-expressing TAM and organs, with no observed toxicity. [ 68 Ga]Ga-NOTA-anti-MMR-sdAb is ready for a phase I clinical trial.

Objective: The aim of this study was to evaluate the frequency and relative significance of incidental cardiac uptake on 68Ga-DOTA-peptide PET-CT scans in patients with neuroendocrine tumours/genetic syndromes expressing somatostatin receptors., Methods: Scans of 1463 patients who underwent 68Ga-DOTA-peptide PET-CT scans in our department between 2013 and 2018 were retrospectively evaluated for the presence of uptake in the heart and/or its appendages., Results: out of 1463 patients (1.3%) demonstrated uptake of radio-peptide in the heart and/or its appendages. In 18 out of these 19 patients, the clinicians were unaware of possible cardiac involvement (one patient was a known case of cardiac paraganglioma). The primary neuroendocrine tumours and genetic syndromes associated with those with cardiac uptake of 68Ga-DOTA-peptide were as follows: unknown primary (n = 7), small bowel (n = 6), colon (n = 2), caecum (n = 1), pancreas (n = 1), cardiac paraganglioma (n = 1), Von Hippel Lindau syndrome (n = 1). Amongst the patients with neuroendocrine tumours, demonstrating cardiac uptake of 68Ga-DOTA-peptide, there was no clear association with carcinoid heart disease., Discussion: Our results are in agreement with established literature. The exact prognostic implication of cardiac involvement in patients with neuroendocrine tumours as well as other genetic syndromes expressing somatostatin receptors is unknown. We hypothesize that early detection and confirmation of cardiac metastasis(es) in these patients and introduction of different treatment regimes (such as Peptide Receptor Radionuclide Therapy), earlier in the course of the disease would reduce the disease burden on the heart and therefore contribute to better patient outcomes., Conclusion: Cardiac involvement is a rare and hitherto less well-studied occurrence in neuroendocrine tumours, with an incidence in the range of 1%. To assess the possible prognostic implications, further detailed multicentre studies are required.

Objectives: Localization of ectopic ACTH-secreting tumours causing Cushing syndrome (ECS) is essential for clinical management, yet often difficult. [ 68 Ga]-DOTATATE PET/CT ([ 68 Ga]-DOTA-(Tyr 3 )-octreotate)] is an FDA-approved high-resolution diagnostic tool for imaging neuroendocrine tumours. Data on the clinical utility of [ 68 Ga]-DOTATATE in patients with ECS, however, are scarce. The objectives of this study were to determine the efficacy for ECS localization and the clinical benefit of [ 68 Ga]-DOTATATE imaging., Method: We conducted a retrospective review of all cases with ECS evaluated with [ 68 Ga]-DOTATATE from November 2016 through October 2018 at three referral centres. The clinical benefit of [ 68 Ga]-DOTATATE was based on detection of new tumours and resultant changes in management., Results: Over the study period, 28 patients with ECS underwent [ 68 Ga]-DOTATATE: 17 for identification of the primary tumour and 11 during follow-up. [ 68 Ga]-DOTATATE identified the suspected primary ECS in 11/17 patients (65%). Of these, nine patients underwent surgery: eight with confirmed ECS (5 bronchial, 1 thymic, 1 pancreatic and 1 metastatic neuroendocrine tumour of unknown primary origin) and one patient with a false-positive scan (adrenal gland). Of the 11 patients with ECS who underwent [ 68 Ga]-DOTATATE evaluation during follow-up, the study led to changes in clinical management in 7/11 (64%) patients., Conclusions: [ 68 Ga]-DOTATATE is sensitive in detecting primary and metastatic ECS, often identifies occult tumours after conventional imaging, and impacts clinical care in the majority of patients., (© 2019 John Wiley & Sons Ltd.)

Objectives: To optimize 68 Ga production using a liquid cyclotron target, investigations were performed to compare production yields using different concentrations of [ 68 Zn]Zn(NO 3 ) 2 , nitric acid, and irradiation parameters., Methods: Different concentrations of [ 68 Zn]Zn(NO 3 ) 2 (0.6 M, 1.2 M and 1.42 M) in varying normality of nitric acid (0.8-1.5 N) were prepared and irradiated with protons (incident energy ~14 MeV) using a BMLT-2 liquid target at different beam currents (30-50 μA) and irradiation times (30-60 min). The 68 Ga production and saturation yields were calculated and compared. [ 68 Ga]GaCl 3 was isolated using in-house developed hydroxamate resin and optimized for routine application. Recycling of [ 68 Zn]Zn(NO 3 ) 2 from the recovered target solution was also investigated., Results: On increasing concentration of [ 68 Zn]Zn(NO 3 ) 2 from 0.6 M to 1.2 M in 0.8 N nitric acid, decay corrected yield of 68 Ga at EOB was found to be 1.64 GBq (44.4 mCi) and 3.37 GBq (91.0 mCi), respectively at 30 μA beam current, indicating production yield was proportional to zinc nitrate concentration for a 30 min irradiation. However, when beam current was increased to 40 μA while maintaining nitric acid concentration at 0.8 N, the proportional relationship of 68 Zn-concentration with 68 Ga production yield was lost [0.6 M, 2.29 GBq (61.9 mCi); 1.2 M, 3.6 GBq (97.3 mCi)] for a 30 min irradiation. In fact, the effect was more profound for 60 min irradiations [0.6 M, 2.96 GBq (80.0 mCi); 1.2 M, 4.25 GBq (115 mCi)]. Increasing nitric acid concentration to 1.25-1.5 N improved 68 Ga production yield for 40 μA, 60-min irradiations (1.2 M; 5.17 GBq (140 mCi)). MP-AES analysis showed metal impurities as <0.20 μg Ga (n = 3), <0.93 μg Zn (n = 3) and < 2.7 μg Fe (n = 3). Based on above finding, 1.42 M [ 68 Zn]Zn(NO 3 ) 2 in 1.2 N-HNO 3 solutions were also studied to achieve highest production yields of 9.85 ± 2.09 GBq (266 ± 57 mCi) for 60 min irradiation at 40 μA beam current. After recycling,> 99% pure recycled [ 68 Zn]zinc nitrate was obtained in 82.6 ± 13.6% yield., Conclusions: 68 Ga production yields were dependent on all four variables: concentrations of [ 68 Zn]Zn(NO 3 ) 2 and nitric acid, beam current and duration of irradiation. Of note, increasing beam current and irradiation time may require increased concentrations of nitric acid to achieve expected increments in 68 Ga production yield., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The demand for Gallium-68 ( 68 Ga) for labelling PET radiopharmaceuticals has increased over the past few years. 68 Ga is obtained through the decayed parent radionuclide 68 Ge using commercial 68 Ge/ 68 Ga generators. The principal limitation of commercial 68 Ge/ 68 Ga generators is that only a limited and finite quantity of 68 Ga (<1.85 GBq at start of synthesis) may be accessed. The focus of this study was to investigate the use of a low energy medical cyclotron for the production of greater quantities of 68 Ga and to develop an automated and rapid procedure for processing the product., Methods: Enriched ZnCl 2 was electrodeposited on a platinum backing using a NH 4 Cl (pH 2-4) buffer. The Zn target was irradiated with GE PETtrace 880 at 35 μA and 14.5 and 12.0 MeV beam energy. The irradiated Zn target was purified using octanol resin on an automated system., Results: Following the described procedure, 68 Ga was obtained in 6.30 ± 0.42 GBq after 8.5 min bombardment and with low radionuclidic impurities ( 66 Ga (<0.005%) and 67 Ga (<0.09%)). Purification on a single octanol resin gave 82% recovery with resulting [ 68 Ga]GaCl 3 obtained in 3.5 mL of 0.2 M HCl. [ 68 Ga]GaCl 3 production from irradiation to final product was <45 min. To highlight the utility of the automated procedure, [ 68 Ga]Ga-DOTA-TATE labelling was incorporated to give 1.56 GBq at EOS of the labelled peptide with RCY of >70%., Conclusions: A straightforward procedure for producing 68 Ga on a low energy medical cyclotron was described. Current efforts are focus on high activity production and radiolabelling using solid target produced 68 Ga., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

68 Ga-labeled cyclic RGD dimers and trimer were evaluated as PET radiotracers. It was found that the linker group had little impact on α v β 3 binding affinity of RGD dimers, which share similar α v β 3 binding affinity with the RGD trimer despite of their different multiplicity. Biodistribution properties of 68 Ga radiotracers depend on RGD peptides and radiometal chelates. Among the 68 Ga radiotracers evaluated, 68 Ga-I2P-RGD 2 has the best tumor uptake with good tumor-to-background ratios, and is a good PET radiotracer for imaging gliomas., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Indium-111 when formulated as indium-111 oxine remains the gold standard for long term cell tracking, whereas radiometals for improved PET applications still have to be established. We here describe the on-cartridge formation of gallium-68, zirconium-89 and copper-64 complexes in small volumes suitable for cell labelling, including labelling of red blood cells (RBC) and white blood cells (WBC) and their biological evaluation in vivo., Methods: Small volumes (1-2 mL) of tracers (oxine, tropolone) were directly prepared on an anion exchange cartridge (Sep-Pak QMA). Cells were radiolabelled and the labelling efficiency and efflux were evaluated. The in vivo biodistribution of copper-64-labelled WBC using [ 64 Cu][Cu(oxinate) 2 ] and [ 64 Cu][Cu(tropolonate) 2 ] was monitored in an infection and inflammation animal model using BALB/c mice., Results: On-cartridge concentration of gallium-68, zirconium-89 and copper-64 enabled formation of oxine and tropolone tracers in small volumes with good yields (≥50%) and quality (extraction ≥90%). Prepared tracers radiolabelled the RBC comparable to indium-111 tracers and in vivo biodistribution of copper-64 labelled WBC showed clear accumulation of cells at the site of infection and inflammation., Conclusions: This on-cartridge preparation method enables simple formation of various PET tracers for cell radiolabelling. Zirconium-89 and copper-64 tracers radiolabelled cells with sufficient stability. Due to their longer half-life this approach could be promising for routine applications where longer evaluation periods for cell tracking are needed., Advances in Knowledge and Implications for Patient Care: This novel approach for on-cartridge concentration and preparation of oxine and tropolone precursors with different positron emitters, in small volume and suitable pH, offers a versatile tool towards cell labelling for preclinical and clinical PET applications., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Integrin α v β 3 has been considered as a promising biomarker for vulnerable atherosclerotic plaques, and it is highly expressed by those instability-associated factors, such as macrophages, vessel endothelial cells, and smooth muscle cells. Our previous study successfully showed that the 64 Cu-labeled divalent (containing two RGD motifs) cystine knot peptide, 64 Cu-NOTA-3-4A, had high binding affinity and specificity in targeting vulnerable carotid atherosclerotic plaques with increased α v β 3 levels. Therefore, considering that 68 Ga has excellent nuclear physical properties for positron emission tomography (PET), this study aimed to investigate the feasibility of using 68 Ga-NOTA-3-4A for PET study of vulnerable atherosclerotic plaques. The vulnerable carotid atherosclerotic plaques were induced and maintained in ApoE -/- mice through carotid artery ligation and a high-fat diet. Divalent knottin peptide 3-4A was synthesized through solid-phase peptide synthesis chemistry and radiolabeled with 68 Ga after being conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The probe stability was analyzed in phosphate buffered saline (PBS) buffer and mouse serum. ApoE -/- mice with atherosclerotic plaques ( n = 4) were imaged by PET/CT at 1 and 2 h after the tail vein injection of 68 Ga-NOTA-3-4A. The targeting specificity was determined by coinjection of 68 Ga-NOTA-3-4A and nonradioactive c(RGDyK) peptide. The carotid artery tissues were removed, and immunofluorescent staining was performed to evaluate α v β 3 integrin expression. It was found that 68 Ga-NOTA-3-4A displayed high stability in both PBS buffer and mouse serum. Small animal PET/CT images and quantification analysis indicated the quick and high plaque uptake of 68 Ga-NOTA-3-4A (6.67 ± 1.44 and 2.97 ± 0.46%ID/g at 1 and 2 h, respectively). The plaque-to-normal artery ratio was 15.88 and 9.90 at 1 and 2 h, respectively. Furthermore, the plaque accumulation of 68 Ga-NOTA-3-4A was significantly inhibited via coinjection of c(RGDyK). Finally, immunostaining identified integrin α v β 3 expressed by macrophages, vessel endothelial cells, and smooth muscle cells. In summary, 68 Ga-NOTA-3-4A has high potential to be a promising PET tracer for imaging vulnerable atherosclerotic plaques.

Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women worldwide. We have recently reported that curcuminoid complexes labelled with gallium-68 have demonstrated preferential uptake in HT29 colorectal cancer and K562 lymphoma cell lines compared to normal human lymphocytes. In the present study, we report a new gallium-68-labelled curcumin derivative ( 68 Ga-DOTA-C21) and its initial validation as marker for early detection of colorectal cancer. The precursor and non-radioactive complexes were synthesized and deeply characterized by analytical methods then the curcuminoid was radiolabelled with gallium-68. The in vitro stability, cell uptake, internalization and efflux properties of the probe were studied in HT29 cells, and the in vivo targeting ability and biodistribution were investigated in mice bearing HT29 subcutaneous tumour model. 68 Ga-DOTA-C21 exhibits decent stability (57 ± 3% after 120 min of incubation) in physiological media and a curcumin-mediated cellular accumulation in colorectal cancer cell line (121 ± 4 KBq of radiotracer per mg of protein within 60 min of incubation). In HT29 tumour-bearing mice, the tumour uptake of 68 Ga-DOTA-C21 is 3.57 ± 0.3% of the injected dose per gram of tissue after 90 min post injection with a tumour to muscle ratio of 2.2 ± 0.2. High amount of activity (12.73 ± 1.9% ID/g) is recorded in blood and significant uptake of the radiotracer occurs in the intestine (13.56 ± 3.3% ID/g), lungs (8.42 ± 0.8% ID/g), liver (5.81 ± 0.5% ID/g) and heart (4.70 ± 0.4% ID/g). Further studies are needed to understand the mechanism of accumulation and clearance; however, 68 Ga-DOTA-C21 provides a productive base-structure to develop further radiotracers for imaging of colorectal cancer.

This study explores the possibility of formulation of a cold kit for fast and easy preparation of a PET radiopharmaceutical, 68 Ga-NOTA-UBI (29-41) for clinical translation. In this study, Circular dichroism (CD) spectroscopy to study conformation of NOTA-UBI (29-41) and its comparison with conformation of UBI (29-41) was done. Pharmaceutical grade cold kits of NOTA-UBI (29-41) were formulated for radiolabeling with 68 Ga and necessary quality control tests were carried out. 68 Ga-NOTA-UBI (29-41) could be prepared in >90% radiochemical yield and radiochemical purity using cold kits of NOTA-UBI (29-41). In vitro and in vivo evaluation of 68 Ga-NOTA-UBI (29-41) was done to demonstrate specificity of the agent for imaging infection. Kits were utilized for preparation of patient dose of 68 Ga-NOTA-UBI (29-41). Simple instant thin layer chromatography (ITLC) method for estimating radiolabeling yield of 68 Ga-NOTA-UBI (29-41) at hospital radiopharmacy was demonstrated. Clinical evaluation was done in patients with suspected infection. 148-185 MBq of 68 Ga-NOTA-UBI (29-41) was injected intravenously in three patients. 68 Ga-NOTA-UBI (29-41) uptake could clearly delineate infection foci from non target normal tissues. This is the first report on formulation of a cold kit of NOTA-UBI (29-41) for preparation of 68 Ga labeled NOTA-UBI(29-41) at hospital radiopharmacy for infection imaging. Initial clinical evaluation reveal it to be a prospective agent for imaging infection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111 In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE) 3 DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C 59 -DEAVDANS-ADAPT6-GSSC and DOTA-C 61 -(HE) 3 DANS-ADAPT6-GSSC) were stably labeled with 111 In for SPECT and 68 Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111 In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68 Ga-labeled counterparts. The best performing variant was DOTA-C 61 -(HE) 3 DANS-ADAPT6-GSSC, which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111 In and 68 Ga labels, respectively.

Background: P-selectin is activated early after stroke, followed by a rapid decline. This time course can be used to generate important information on stroke onset. The latter is crucial for therapeutic decision-making of wake-up strokes (i.e. thrombolysis or not). Here, we evaluated the specific p-selectin inhibitor fucoidan labeled with gallium-68 (68Ga-Fucoidan) as an imaging biomarker for assessing p-selectin activation in acute ischemic stroke using Positron Emission Tomography (PET)., Methods: 68Ga-Fucoidan was investigated in rats brain at 2-5 h (n=16), and additionally at 24-26 h (n=9) and 48 h (n=3) after induction of photothrombic stroke or in sham-operated animals (n=6). Correlation of cerebral 68Ga-Fucoidan uptake with p-selectin expression was determined by exposing freshly cut brain cryosections to autoradiography and immunostaining using specific antibodies against p-selectin., Results: PET scans showed an increased accumulation of 68Ga-Fucoidan in the histologically proven ischemic stroke, as compared to the corresponding contralateral hemisphere in all except one animal. The median ratio between the uptake in the ischemic lesion and the contralateral region was 1.95 (1.45-2.41) at 2-5 h, 1.38 (1.05-1.89) at 24-26 h, and 1.09 (0.81-1.38) at 48 h after stroke, compared to 1.22 (0.99-1.49) for sham-operated animals. In the ex vivo autoradiography, 68Ga-Fucoidan accumulation co-localized with p-selectin as assessed by immunostaining. Control animals and those scanned at 24-26 h and 48 h after stroke exhibited no elevated 68Ga-Fucoidan uptake in either hemisphere., Conclusion: PET imaging using 68Ga-Fucoidan represents a valuable tool for assessing p-selectin activation in vivo discriminating ischemic stroke early after stroke onset., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)