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Background: Several research groups have explored the potential of scandium radionuclides for theragnostic applications due to their longer half-lives and equal or similar coordination chemistry between their diagnostic and therapeutic counterparts, as well as lutetium-177 and terbium-161, respectively. Unlike the gallium-68/lutetium-177 pair, which may show different in-vivo uptake patterns, the use of scandium radioisotopes promises consistent behaviour between diagnostic and therapeutic radiopeptides. An advantage of scandium's longer half-life over gallium-68 is the ability to study radiopeptide uptake over extended periods and its suitability for centralized production and distribution. However, concerns arise from scandium-44's decay characteristics and scandium-43's high production costs. This study aimed to evaluate the dosimetric implications of using scandium radioisotopes with somatostatin analogues against gallium-68 for PET imaging of neuroendocrine tumours. Methods: Absorbed dose per injected activity (AD/IA) from the generated time-integrated activity curve (TIAC) were estimated using the radiopeptides [43/44/44mSc]Sc- and [68Ga]Ga-DOTATATE. The kidneys, liver, spleen, and red bone marrow (RBM) were selected for dose estimation studies. The EGSnrc and MCNP6.1 Monte Carlo (MC) codes were used with female (AF) and male (AM) ICRP phantoms. The results were compared to Olinda/EXM software, and the effective dose concentrations assessed, varying composition between the scandium radioisotopes. Results: Our findings showed good agreement between the MC codes, with − 3 ± 8% mean difference. Kidneys, liver, and spleen showed differences between the MC codes (min and max) in a range of − 4% to 8%. This was observed for both phantoms for all radiopeptides used in the study. Compared to Olinda/EXM the largest observed difference was for the RBM, of 21% for the AF and 16% for the AM for scandium- and gallium-based radiopeptides. Despite the differences, our findings showed a higher absorbed dose on [43/44Sc]Sc-DOTATATE compared to its 68Ga-based counterpart. Conclusion: This study found that [43/44Sc]Sc-DOTATATE delivers a higher absorbed dose to organs at risk compared to [68Ga]Ga-DOTATATE, assuming equal distribution. This is due to the longer half-life of scandium radioisotopes compared to gallium-68. However, calculated doses are within acceptable ranges, making scandium radioisotopes a feasible replacement for gallium-68 in PET imaging, potentially offering enhanced diagnostic potential with later timepoint imaging. [ABSTRACT FROM AUTHOR]

This article reports on the first-in-human administration of terbium-161-labelled somatostatin receptor subtype 2 antagonist ([161Tb]Tb-DOTA-LM3) in a patient with a metastatic neuroendocrine tumor of the ileum. The patient had previously received long-acting octreotide and underwent a test infusion of [161Tb]Tb-DOTA-LM3. The study found that [161Tb]Tb-DOTA-LM3 showed promising potential as an alternative to the current standard peptide receptor radionuclide therapy for patients with metastatic gastroenteropancreatic neuroendocrine tumors. The research was funded by the Swiss National Science Foundation and supported by other organizations. The study was conducted in accordance with ethical guidelines and the patient provided informed consent. [Extracted from the article]

The time needed until SP 161 sp Tb-based radionuclide therapy can be implemented in daily routine treatment regimens in hospitals is difficult to predict, as it will critically depend on the efforts of researchers and clinicians to continue exploring terbium-161 in (pre)clinical studies. Bone marrow toxicity is, however, a well-known risk of radioligand therapy that may occur, depending on multiple factors of patient characteristics and pre-treatments [[19]]. The selection of appropriate radiometals to improve the outcome of tumor-targeted radionuclide therapy in cancer patients requires careful consideration. [Extracted from the article]

Purpose: The angiotensin converting enzyme-2 (ACE2)—entry receptor of SARS-CoV-2—and its homologue, the angiotensin-converting enzyme (ACE), play a pivotal role in maintaining cardiovascular homeostasis. Potential changes in ACE2 expression levels and dynamics after SARS-CoV-2 infection have been barely investigated. The aim of this study was to develop an ACE2-targeting imaging agent as a noninvasive imaging tool to determine ACE2 regulation. Methods: DOTA-DX600, NODAGA-DX600 and HBED-CC-DX600 were obtained through custom synthesis and labeled with gallium-67 (T1/2 = 3.26 d) as a surrogate radioisotope for gallium-68 (T1/2 = 68 min). ACE2- and ACE-transfected HEK cells were used for the in vitro evaluation of these radiopeptides. The in vivo tissue distribution profiles of the radiopeptides were assessed in HEK-ACE2 and HEK-ACE xenografted mice and imaging studies were performed using SPECT/CT. Results: The highest molar activity was obtained for [67Ga]Ga-HBED-CC-DX600 (60 MBq/nmol), whereas the labeling efficiency of the other peptides was considerably lower (20 MBq/nmol). The radiopeptides were stable over 24 h in saline (> 99% intact peptide). All radiopeptides showed uptake in HEK-ACE2 cells (36–43%) with moderate ACE2-binding affinity (KD value: 83–113 nM), but no uptake in HEK-ACE cells (< 0.1%) was observed. Accumulation of the radiopeptides was observed in HEK-ACE2 xenografts (11–16% IA/g) at 3 h after injection, but only background signals were seen in HEK-ACE xenografts (< 0.5% IA/g). Renal retention was still high 3 h after injection of [67Ga]Ga-DOTA-DX600 and [67Ga]Ga-NODAGA-DX600 (~ 24% IA/g), but much lower for [67Ga]Ga-HBED-CC-DX600 (7.2 ± 2.2% IA/g). SPECT/CT imaging studies confirmed the most favorable target-to-nontarget ratio for [67Ga]Ga-HBED-CC-DX600. Conclusions: This study demonstrated ACE2 selectivity for all radiopeptides. [67Ga]Ga-HBED-CC-DX600 was revealed as the most promising candidate due to its favorable tissue distribution profile. Importantly, the HBED-CC chelator enabled 67Ga-labeling at high molar activity, which would be essential to obtain images with high signal-to-background contrast to detect (patho)physiological ACE2 expression levels in patients. [ABSTRACT FROM AUTHOR]

Background: Based on theoretical and preclinical results, terbium-161 may be a valid alternative to lutetium-177 and yttrium-90 in radionuclide therapies. The large low-energy electron emission from terbium-161 is a favorable feature in the treatment of disseminated disease, but its impact on the radiosensitive bone marrow needs to be evaluated. Using voxel-based skeletal dosimetry models in which active bone marrow is defined as regions containing stem cells and progenitor cells of the hematopoietic lineage, we generated S-values (absorbed dose per decay) for terbium-161 and evaluated its distribution-dependence in bone marrow cavities. Methods: S-values in the active bone marrow were calculated for terbium-161, lutetium-177, and yttrium-90 irradiation using two (male/female) image-based bone marrow dosimetry models. The radionuclides were distributed to one of the three structures that define the spongiosa bone region in the skeletal models: (i) active bone marrow, (ii) inactive bone marrow, or (iii) surface or whole volume of the trabecular bone. Decay data from ICRP 107 were combined with specific absorbed fractions to calculate S-values for 13 skeletal sites. To increase the utility, the skeletal site-specific S-values were averaged to produce whole-body average S-values and spongiosa average S-values. Results: For yttrium-90, the high-energy β particles irradiate the active marrow regardless of the source compartment, consistently generating the highest S-values (65–90% higher). Between terbium-161 and lutetium-177, the largest differences in S-values were with an active marrow source (50%), such as self-irradiation, due to the contribution of the short-ranged conversion and Auger electrons from terbium-161. Their influence decreased as the source moved to inactive marrow or the surface or volume of the trabecular bone, reducing the S-values and the differences between terbium-161 and lutetium-177 (15–35%). Conclusion: The S-values of terbium-161 for active bone marrow and, consequently, the bone marrow toxicity profile were more dependent on the radionuclide distribution within the bone marrow cavity than the S-values of lutetium-177 and yttrium-90. This effect was attributed to the considerable low-energy electron emission of terbium-161. Therefore, it will be critical to investigate the bone marrow distribution of a particular radiopharmaceutical for accurate estimation of the active bone marrow dose. [ABSTRACT FROM AUTHOR]

[177Lu]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [177Lu]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [177Lu]Lu-PSMA-617 and the previously developed [177Lu]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands's therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [177Lu]Lu-Ibu-DAB-PSMA (~ 6.6 Gy/MBq) was more effective to inhibit tumor growth than [177Lu]Lu-PSMA-617 (~ 4.5 Gy/MBq) and only moderately less potent than [177Lu]Lu-PSMA-ALB-56 (~ 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [177Lu]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [177Lu]Lu-Ibu-DAB-PSMA or [177Lu]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [177Lu]Lu-Ibu-DAB-PSMA or 30 MBq [177Lu]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [177Lu]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [177Lu]Lu-Ibu-DAB-PSMA over [177Lu]Lu-PSMA-617 and a more favorable safety profile as compared to that of [177Lu]Lu-PSMA-ALB-56. Based on these results, [177Lu]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation. [ABSTRACT FROM AUTHOR]

Purpose: The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods: The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides' tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results: In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion: The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs. [ABSTRACT FROM AUTHOR]

Purpose: Various preclinical study designs are described in the literature for the evaluation of PSMA radioligands. In this study, [177Lu]Lu-Ibu-DAB-PSMA, an albumin-binding radioligand, and [177Lu]Lu-PSMA-617 were investigated and compared under variable experimental conditions. Methods: In vitro cell uptake studies were performed with PC-3 PIP and LNCaP tumor cells using a range of molar concentrations (0.75–500 nM) of both radioligands. Biodistribution and SPECT/CT imaging studies were carried out with the respective tumor mouse models using 0.05 nmol and 1.0 nmol injected ligand per mouse. Results: In both tumor cell lines, the uptake of the radioligands was increased when using low molar concentrations of the respective ligand. The observed saturation effect at high ligand concentrations was more pronounced for LNCaP cells that express PSMA at lower levels than for PC-3 PIP cells. At all investigated timepoints, the in vivo uptake of both radioligands was higher in PC-3 PIP tumors than in LNCaP tumors. A low molar amount of injected ligand increased the PC-3 PIP tumor uptake mainly for [177Lu]Lu-Ibu-DAB-PSMA; however, the molar amount of ligand was relevant for both radioligands when using LNCaP tumors. Renal retention of both radioligands was, however, up to fourfold higher during the first hours after application of a low ligand amount compared to the high ligand amount. Conclusion: The results of this preclinical study underline the relevance of the tumor model and applied ligand amount for the characterization of PSMA radioligands. The application of equal preclinical study designs is crucial to allow the comparison of novel radioligands with existing ones and, thus, predict potential advantages of new radioligands in view of a clinical application. [ABSTRACT FROM AUTHOR]

Purpose: It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods: In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results: [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion: Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates. [ABSTRACT FROM AUTHOR]

Purpose: The folate receptor (FR) is frequently overexpressed in a variety of tumor types and, hence, an interesting target for radionuclide therapy. The aim of this study was to evaluate a new class of albumin-binding radioconjugates comprising 5-methyltetrahydrofolate (5-MTHF) as a targeting agent and to compare their properties with those of the previously established folic acid-based [177Lu]Lu-OxFol-1. Methods: [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 were investigated in vitro using FR-positive KB tumor cells. Biodistribution studies were performed in KB tumor-bearing mice, and the areas under the curve (AUC0 → 120h) were determined for the uptake in tumors and kidneys. [177Lu]Lu-6R-RedFol-1 was compared with [177Lu]Lu-OxFol-1 in a therapy study over 8 weeks using KB tumor-bearing mice. Results: Both radioconjugates demonstrated similar in vitro properties as [177Lu]Lu-OxFol-1; however, the tumor uptake of [177Lu]Lu-6R-RedFol-1 and [177Lu]Lu-6S-RedFol-1 was significantly increased in comparison with [177Lu]Lu-OxFol-1. In the case of [177Lu]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [177Lu]Lu-6R-RedFol-1 was similar to that of [177Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC0 → 120h ratio of [177Lu]Lu-6R-RedFol-1 as compared with [177Lu]Lu-6S-RedFol-1 and [177Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [177Lu]Lu-6R-RedFol-1 was better than that of [177Lu]Lu-OxFol-1, reflected by a slower tumor growth and, consequently, an increased median survival time (49 days vs. 34 days). Conclusion: This study demonstrated the promising potential of 5-MTHF-based radioconjugates for FR-targeting. Application of [177Lu]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [177Lu]Lu-OxFol-1. These findings, together with the absence of early side effects, make [177Lu]Lu-6R-RedFol-1 attractive in view of a future clinical translation. [ABSTRACT FROM AUTHOR]

Introduction: PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. Methods: Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120–160 μg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. Results: [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. Conclusion: Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the 18F-AzaFol (3′-aza-2′-[18F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα. Material and methods: Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299–399 MBq) of 18F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results. Results: No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6–60.5 μGy/MBq). Conclusions: 18F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance. Trial registration: ClinicalTrial.gov, NCT03242993, posted on August 8, 2017 [ABSTRACT FROM AUTHOR]

In this study, it was aimed to investigate 149Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer. 149Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors. 149Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Day 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia. The tumor growth was significantly delayed in mice of the treated groups as compared to untreated controls (p < 0.05). TAT was most effective in mice injected with 2 × 3 MBq (Day 0 & 1) resulting in a median lifetime of 36 days, whereas in untreated mice, the median lifetime was only 20 days. Due to the β+-emission of 149Tb, tumor localization was feasible using PET/CT after injection of 149Tb-PSMA-617 (5 MBq). The PET images confirmed the selective accumulation of 149Tb-PSMA-617 in PC-3 PIP tumor xenografts. The unique characteristics of 149Tb for TAT make this radionuclide of particular interest for future clinical translation, thereby, potentially enabling PET-based imaging to monitor the radioligand's tissue distribution. [ABSTRACT FROM AUTHOR]

Purpose: The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161Tb (T1/2 = 6.89 days; Eβ͞av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile. Methods: 161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice. Results: 161Tb-PSMA-617 and 177Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu. Conclusion: 161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC. [ABSTRACT FROM AUTHOR]

Background: The favorable decay properties of Sc and Sc for PET make them promising candidates for future applications in nuclear medicine. An advantage Sc (T = 3.89 h, Eβ = 476 keV [88%]) exhibits over Sc, however, is the absence of co-emitted high energy γ-rays. While the production and application of Sc has been comprehensively discussed, research concerning Sc is still in its infancy. This study aimed at developing two different production routes for Sc, based on proton irradiation of enriched Ti and Ca target material. Results: Sc was produced via the Ti(p,α)Sc and Ca(p,n)Sc nuclear reactions, yielding activities of up to 225 MBq and 480 MBq, respectively. Sc was chemically separated from enriched metallic Ti (97.0%) and CaCO (57.9%) targets, using extraction chromatography. In both cases, ~90% of the final activity was eluted in a small volume of 700 μL, thereby, making it suitable for direct radiolabeling. The prepared products were of high radionuclidic purity, i.e. 98.2% Sc were achieved from the irradiation of Ti, whereas the product isolated from irradiated Ca consisted of 66.2% Sc and 33.3% Sc. A PET phantom study performed with Sc, via both nuclear reactions, revealed slightly improved resolution over Sc. In order to assess the chemical purity of the separated Sc, radiolabeling experiments were performed with DOTANOC, attaining specific activities of 5-8 MBq/nmol, respectively, with a radiochemical yield of >96%. Conclusions: It was determined that higher Sc activities were accessible via the Ca production route, with a comparatively less complex target preparation and separation procedure. The product isolated from irradiated Ti, however, revealed purer Sc with minor radionuclidic impurities. Based on the results obtained herein, the Ca route features some advantages (such as higher yields and direct usage of the purchased target material) over the Ti path when aiming at Sc production on a routine basis. [ABSTRACT FROM AUTHOR]

Background: Radiotheragnostics makes use of the same molecular targeting vectors, labeled either with a diagnostic or therapeutic radionuclide, ideally of the same chemical element. The matched pair of scandium radionuclides, Sc and Sc, satisfies the desired physical aspects for PET imaging and radionuclide therapy, respectively. While the production and application of Sc was extensively studied, Sc is still in its infancy. The aim of the present study was, therefore, to investigate and compare two different methods of Sc production, based on the neutron irradiation of enriched Ca and Ti targets, respectively. Methods: Sc was produced by thermal neutron irradiation of enriched Ca targets via the Ca(n,γ)Ca → Sc nuclear reaction and by fast neutron irradiation of Ti targets via the Ti(n,p)Sc nuclear reaction, respectively. The product was compared with regard to yield and radionuclidic purity. The chemical separation of Sc was optimized in order to obtain a product of sufficient quality determined by labeling experiments using DOTANOC. Finally, preclinical SPECT/CT experiments were performed in tumor-bearing mice and compared with the PET image of the Sc labeled counterpart. Results: Up to 2 GBq Sc was produced by thermal neutron irradiation of enriched Ca targets. The optimized chemical isolation of Sc from the target material allowed formulation of up to 1.5 GBq Sc with high radionuclidic purity (>99.99%) in a small volume (~700 μL) useful for labeling purposes. Three consecutive separations were possible by isolating the in-grown Sc from the Ca-containing fraction. Sc produced by fast neutron irradiated Ti targets resulted in a reduced radionuclidic purity (99.95-88.5%). The chemical purity of the separated Sc was determined by radiolabeling experiments using DOTANOC achievable at specific activities of 10 MBq/nmol. In vivo the Sc-DOTANOC performed equal to Sc-DOTANOC as determined by nuclear imaging. Conclusion: The production of Sc via the Ca(n,γ)Ca nuclear reaction demonstrated significant advantages over the Ti production route, as it provided higher quantities of a radionuclidically pure product. The subsequent decay of Ca enabled the repeated separation of the Sc daughter nuclide from the Ca parent nuclide. Based on the results obtained from this work, Sc shows potential to be produced in suitable quality for clinical application. [ABSTRACT FROM AUTHOR]

Background: The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane- N, N′, N′′, N′′′-tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging (Ga) and radionuclide therapy (Lu) in the clinics. In this study, PSMA-617 was labeled with cyclotron-produced Sc ( T = 4.04 h) and investigated preclinically for its use as a diagnostic match to Lu-PSMA-617. Results: Sc was produced at the research cyclotron at PSI by irradiation of enriched Ca targets, followed by chromatographic separation. Sc-PSMA-617 was prepared under standard labeling conditions at elevated temperature resulting in a radiochemical purity of >97% at a specific activity of up to 10 MBq/nmol. Sc-PSMA-617 was evaluated in vitro and compared to the Lu- and Ga-labeled match, as well as Ga-PSMA-11 using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu prostate cancer cells. In these experiments it revealed similar in vitro properties to that of Lu- and Ga-labeled PSMA-617. Moreover, Sc-PSMA-617 bound specifically to PSMA-expressing PC-3 PIP tumor cells, while unspecific binding to PC-3 flu cells was not observed. The radioligands were investigated with regard to their in vivo properties in PC-3 PIP/flu tumor-bearing mice. Sc-PSMA-617 showed high tumor uptake and a fast renal excretion. The overall tissue distribution of Sc-PSMA-617 resembled that of Lu-PSMA-617 most closely, while the Ga-labeled ligands, in particular Ga-PSMA-11, showed different distribution kinetics. Sc-PSMA-617 enabled distinct visualization of PC-3 PIP tumor xenografts shortly after injection, with increasing tumor-to-background contrast over time while unspecific uptake in the PC-3 flu tumors was not observed. Conclusions: The in vitro characteristics and in vivo kinetics of Sc-PSMA-617 were more similar to Lu-PSMA-617 than to Ga-PSMA-617 and 68Ga-PSMA-11. Due to the almost four-fold longer half-life of Sc as compared to Ga, a centralized production of Sc-PSMA-617 and transport to satellite PET centers would be feasible. These features make Sc-PSMA-617 particularly appealing for clinical application. [ABSTRACT FROM AUTHOR]

Background: Recently, 44 Sc (T1/2 =3.97h,Eβ+av = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of 44Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with 44Sc compared with its 68Ga-labeled counterparts. DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with 44Sc and 68Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe3+ and Cu2+. Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice. Results: Both RGD- and NOC-based peptides with a DOTA chelator were readily labeled with 44Sc and 68Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with 44Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. 44Sc-NODAGA peptides were clearly more susceptible to metal challenge than 44Sc-DOTA peptides under the same conditions. Instability of 68Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu2+. Biodistribution data of the 44Sc-labeled peptides were largely comparable with the data obtained with the 68Ga-labeled counterparts. It was only in the liver tissue that the uptake of 68Ga-labeled DOTA compounds was markedly higher than for the 44 Sc-labeled version and this was also visible on PET/CT images. The 44Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability. Conclusions: Although DOTA revealed to be the preferred chelator for stable coordination of 44Sc, the data presented in this work indicate the possibility of using NODAGA in combination with 44 Sc. In view of a clinical study, thorough investigations will be necessary regarding the labeling conditions and storage solutions in order to guarantee sufficient stability of 44 Sc-labeled NODAGA compounds. [ABSTRACT FROM AUTHOR]

Background: Terbium has attracted the attention of researchers and physicians due to the existence of four medically interesting radionuclides, potentially useful for SPECT and PET imaging, as well as for α- and β-radionuclide therapy. The aim of this study was to produce Tb ( T = 17.5 h, E = 1140 keV) and evaluate it in a preclinical setting in order to demonstrate its potential for PET imaging. For this purpose, DOTANOC was used for targeting the somatostatin receptor in AR42J tumor-bearing mice. Methods: Tb was produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. After separation of Tb using cation exchange chromatography, it was directly employed for radiolabeling of DOTANOC. PET/CT scans were performed with AR42J tumor-bearing mice at different time points after injection of Tb-DOTANOC which was applied at variable molar peptide amounts. Lu-DOTANOC was prepared and used in biodistribution and SPECT/CT imaging studies for comparison with the PET results. Results: After purification, Tb was obtained at activities up to ~600 MBq. Radiolabeling of DOTANOC was achieved at a specific activity of 10 MBq/nmol with a radiochemical purity >98 %. The PET/CT scans of mice allowed visualization of AR42J tumor xenografts and the kidneys, in which the radiopeptide was accumulated. After injection of large peptide amounts, the tumor uptake was reduced as compared to the result after injection of small peptide amounts. PET images of mice, which received Tb-DOTANOC at small peptide amounts, revealed the best tumor-to-kidney ratios. The data obtained with Lu-DOTANOC in biodistribution and SPECT/CT imaging studies confirmed the Tb-based PET results. Conclusions: Production of 30-fold higher quantities of Tb as compared to the previously performed pilot study was feasible. This allowed, for the first time, labeling of a peptide at a reasonable specific activity and subsequent application for in vivo PET imaging. As a β-particle-emitting radiolanthanide, Tb would be of distinct value for clinical application, as it may allow exact prediction of the tissue distribution of therapeutic radiolanthanides. [ABSTRACT FROM AUTHOR]

Tb represents a powerful alternative to currently used α-emitters: the relatively short half-life (T = 4.1 h), low α-energy (3.97 MeV, I = 16.7 %), absence of α-emitting daughters and stable coordination via DOTA are favorable features for potential clinical application. In this letter, we wish to highlight the unique characteristics of Tb for PET imaging, based on its positron emission (E = 730 keV, I = 7.1 %) in addition to it's a therapeutic value. To this end, a preclinical study with a tumor-bearing mouse is presented. The perspective of alpha-PET makes Tb highly appealing for radiotheragnostic applications in future clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: The radiolanthanide Tb ( T = 6.90 days, Eβ = 154 keV) was recently proposed as a potential alternative to Lu ( T = 6.71 days, Eβ = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare Tb and Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). Methods: Tb-cm09 and Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo Tb-cm09 and Lu-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using Tc-dimercaptosuccinic acid (DMSA). Results: To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for Tb-cm09 (IC ~0.014 MBq/ml and ~2.53 MBq/ml) compared to Lu-cm09 (IC ~0.063 MBq/ml and ~4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies Tb-cm09 reduced tumour growth more efficiently than Lu-cm09. These findings were in line with the higher absorbed tumour dose for Tb-cm09 (3.3 Gy/MBq) compared to Lu-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Conclusion: Compared to Lu-cm09 we demonstrated equal imaging features for Tb-cm09 but an increased therapeutic efficacy for Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of Tb. [ABSTRACT FROM AUTHOR]

Purpose: The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a (18) F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio.Procedures: The novel (18) F-folate was prepared by conjugation of a (18) F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice.Results: The radiosynthesis of the albumin-binding [(18) F]fluorodeoxyglucose-folate ([(18) F]3) resulted in a radiochemical yield of 1-2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [(18) F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [(18) F]3 to KB tumor cells. In vivo we found an increasing uptake of [(18) F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published (18) F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging.Conclusions: [(18) F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [(18) F]3. [ABSTRACT FROM AUTHOR]

Purpose: The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a 18 F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio. Procedures: The novel 18 F-folate was prepared by conjugation of a 18 F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice. Results: The radiosynthesis of the albumin-binding [ 18 F]fluorodeoxyglucose–folate ([ 18 F]3) resulted in a radiochemical yield of 1–2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [ 18 F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [ 18 F]3 to KB tumor cells. In vivo we found an increasing uptake of [ 18 F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published 18 F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging. Conclusions: [ 18 F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [ 18 F]3. [ABSTRACT FROM AUTHOR]

Prostate-specific antigen (PSA)-based screening for prostate cancer (PC) has dramatically increased early diagnosis. Current imaging techniques are not optimal to stage early PC adequately. A promising alternative to PC imaging is peptide-based scintigraphy using radiolabelled bombesin (BN) analogues that bind to gastrin-releasing peptide receptors (GRPR) being overexpressed in PC. When labelled to appropriate radionuclides BN targeting of GRPRs may also provide applications for peptide radionuclide receptor therapy (PRRT). Assessment studies under identical experimental conditions allowing a reliable comparison of the potential of such analogues are lacking. This study was performed to evaluate and directly compare five promising radiolabelled BN analogues for their targeting efficacy for PC under standardised conditions. The BN agonists [111In]DOTA-PESIN, [111In]AMBA, [111In]MP2346 and [111In]MP2653 and one antagonist [99mTc]Demobesin-1 were evaluated in GRPR-overexpressing human PC-3 tumour-bearing mice to determine peptide stability in vivo, biodistribution and GRPR targeting potential by animal SPECT/CT imaging and ex vivo autoradiography. HPLC analysis of blood showed intact Demobesin-1 at 5 and 15 min after injection (64.1 ± 1.6% and 41.0 ± 01%, respectively) being much less for the other compounds. AMBA, the second most stable analogue, showed 36.1 ± 2.7% and 9.8 ± 1.1% intact peptide after 5 and 15 min. PC-3 tumour uptake at 1 h was comparable for Demobesin-1, AMBA, PESIN and MP2346 (3.0 ± 0.4, 2.7 ± 0.5, 2.3 ± 0.5 and 2.1 ± 0.9%ID/g, respectively), but very low for MP2653 (0.9 ± 0.2%ID/g). In addition, MP2346 showed undesirably high uptake in the kidneys (7.9 ± 1.9%ID/g) being significantly less for the other analogues. AMBA, MP2346 and PESIN revealed favourable increases in tumour to blood ratios over time while changes in tumour to kidney and pancreas ratios for Demobesin-1 from 1 to 24 h after injection were significantly better than for the other analogues. All analogues visualised PC-3 tumours by SPECT/CT and autoradiography. In the present study the BN antagonist Demobesin-1 was the best performing analogue showing superior in vivo stability, highest tumour uptake and retention while pancreatic and renal clearance were rapid. PESIN and AMBA were the best GRP agonists with sufficient in vivo stabilities as well as high tumour uptake and retention. Based on these results all three analogues deserve further evaluation for clinical use in PC patients. [ABSTRACT FROM AUTHOR]

Folate-based radiopharmaceuticals have the potential to be used for imaging and therapy of tumours positive for the folate receptor (FR). We describe the in vitro and in vivo evaluation of a DOTA–folate conjugate. Radiolabelling of the DOTA-folate was carried out via standard procedures using 111InCl3 and 177LuCl3, respectively. The distribution coefficient (log D) was determined in octanol/PBS (pH 7.4). Tissue distribution was investigated in nude mice bearing KB tumour xenografts at different time points after administration of 111In-DOTA-folate (radiofolate 1) or 177Lu-DOTA-folate (radiofolate 2) (1 MBq, 1 nmol per mouse). Pemetrexed (PMX, 400 μg) was injected 1 h prior to the radiofolate in order to reduce renal uptake. Images were acquired with a SPECT/CT camera 24 h after injection of the radiofolate (40–50 MBq, 3 nmol per mouse). The hydrophilic character of the DOTA-folate was represented by a low log D value ( radiofolate 1 −4.21±0.11). In vivo, maximal tumour uptake was found 4 h after injection ( radiofolate 1 5.80±0.55% ID/g; radiofolate 2 7.51±1.25% ID/g). In FR-positive kidneys there was considerable accumulation of the radiofolates ( radiofolate 1 55.88±3.91% ID/g; radiofolate 2 57.22±11.05% ID/g; 4 h after injection). However, renal uptake was reduced by preinjection of PMX ( radiofolate 1 9.52±1.07% ID/g; radiofolate 2 13.43±0.54% ID/g; 4 h after injection) whereas the tumour uptake was retained ( radiofolate 1 6.32±0.41% ID/g; radiofolate 2 8.99±0.43% ID/g; 4 h after injection). SPECT/CT images clearly confirmed favourable tissue distribution of the novel radiofolates and the positive effect of PMX. The preliminary requirements for the therapeutic use of the novel DOTA-folate are met by its favourable tissue distribution that can be ascribed to its hydrophilic properties and combined administration with PMX. [ABSTRACT FROM AUTHOR]

Purpose: For the assessment of folate-based radiopharmaceuticals, human nasopharyngeal KB carcinoma cells are traditionally used although nasopharyngeal cancer is rare. On the other hand, the folate receptor (FR) is frequently overexpressed on diverse cancer types, the highest frequency (>90%) being on ovarian carcinomas. The goal of our study was the in vitro and in vivo assessment of different FR-positive human carcinoma cells. In addition, a murine sarcoma cell line was assessed as a pre-clinical alternative to human xenograft models. Methods: FR-positive human nasopharyngeal, cervical, ovarian and colorectal cancer cell lines and the transgenic mouse sarcoma (24JK-FBP) cell line were targeted with a novel 99mTc-tricarbonyl folate derivative 2. Comparative in vitro cell binding studies were carried out under standardised folate-deficient conditions. In vivo studies were performed in nude mice and C6 black mice. Results: The in vitro cell experiments revealed only FR-specific binding (unspecific <0.02%), ranging from 3.5% to 52% of complex 2 owing to variable levels of FR expression of the cell lines. In vivo tumour uptake of radiotracer 2 varied less than in vitro. It ranged from 0.66± 0.17% ID/g (LoVo) through 1.16±0.64% ID/g (IGROV-1) and 1.55±0.43% ID/g (24JK-FBP) to 2.33±0.36% ID/g (KB) 4 h p.i. Conclusion: These pre-clinical studies indicate that in vitro data obtained in FR-positive cancer cells do not necessarily correspond with or predict in vivo radiofolate uptake in corresponding (xeno)grafts. In addition, the murine 24JK-FBP cell line proved to be a valuable preclinical alternative to human tumour models. [ABSTRACT FROM AUTHOR]

Purpose: The folate receptor (FR) is a valuable tumour marker, since it is frequently overexpressed on various cancer types. The purpose of the present study was to pre-clinically evaluate novel site-specifically modified 99mTc(CO)3 folate (γ-derivative 4, α-derivative 5) and pteroate (6) conjugates for FR targeting. Methods: The 99mTc(CO)3 radiotracers 4-6 were prepared by a kit-like procedure. In vitro characterisation (KD and Bmax) of the radiotracers was performed with FR-positive KB cells. Tissue distribution was studied in tumour-bearing mice. SPECT/CT experiments were performed with a dedicated small animal SPECT/CT scanner. Results: The complexes 4-6 were formed in high yields (>92%). Binding constants of the radiotracers (KD in nM: 4: 2.09; 5: 2.51; 6: 14.52) were similar to those of 3H-folic acid (KD in nM: 7.22). In vivo the folate derivatives showed significantly better tumour uptake (4: 2.3±0.4% ID/g and 5: 1.2±0.2% ID/g, 4 h p.i.) than the pteroate derivative (6: 0.4±0.2% ID/g, 4 h p.i.). Clearance of all radiotracers from the blood pool and from non-targeted tissues was efficient (tumour to blood ratio approx. 200-350, 24 h p.i.). FR-positive tissue and organs were successfully visualised via small animal SPECT/CT. Conclusion: Radiotracers 4-6 are the first 99mTc(CO)3 tracers prepared via a kit formulation which exhibit full biological activity in vitro and in vivo. Folate derivatives 4 and 5 revealed significantly better pharmacokinetic properties than the pteroate derivative 6. Promising preclinical SPECT results warrant further assessment of 99mTc (CO)3 radiofolates for detection of FR-positive tumours. [ABSTRACT FROM AUTHOR]

Background: For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined β−/Auger-e−-therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). Results: 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. Conclusions: The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients. [ABSTRACT FROM AUTHOR]

Background: 161Tb is an interesting radionuclide for cancer treatment, showing similar decay characteristics and chemical behavior to clinically-employed 177Lu. The therapeutic effect of 161Tb, however, may be enhanced due to the co-emission of a larger number of conversion and Auger electrons as compared to 177Lu. The aim of this study was to produce 161Tb from enriched 160Gd targets in quantity and quality sufficient for first application in patients. Methods: No-carrier-added 161Tb was produced by neutron irradiation of enriched 160Gd targets at nuclear research reactors. The 161Tb purification method was developed with the use of cation exchange (Sykam resin) and extraction chromatography (LN3 resin), respectively. The resultant product (161TbCl3) was characterized and the 161Tb purity compared with commercial 177LuCl3. The purity of the final product (161TbCl3) was analyzed by means of γ-ray spectrometry (radionuclidic purity) and radio TLC (radiochemical purity). The radiolabeling yield of 161Tb-DOTA was assessed over a two-week period post processing in order to observe the quality change of the obtained 161Tb towards future clinical application. To understand how the possible drug products (peptides radiolabeled with 161Tb) vary with time, stability of the clinically-applied somatostatin analogue DOTATOC, radiolabeled with 161Tb, was investigated over a 24-h period. The radiolytic stability experiments were compared to those performed with 177Lu-DOTATOC in order to investigate the possible influence of conversion and Auger electrons of 161Tb on peptide disintegration. Results: Irradiations of enriched 160Gd targets yielded 6–20 GBq 161Tb. The final product was obtained at an activity concentration of 11–21 MBq/μL with ≥99% radionuclidic and radiochemical purity. The DOTA chelator was radiolabeled with 161Tb or 177Lu at the molar activity deemed useful for clinical application, even at the two-week time point after end of chemical separation. DOTATOC, radiolabeled with either 161Tb or 177Lu, was stable over 24 h in the presence of a stabilizer. Conclusions: In this study, it was shown that 161Tb can be produced in high activities using different irradiation facilities. The developed method for 161Tb separation from the target material yielded 161TbCl3 in quality suitable for high-specific radiolabeling, relevant for future clinical application. [ABSTRACT FROM AUTHOR]

Background: Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter 152Tb [(T1/2 = 17.5 h, Eβ+mean = 1140 keV (20.3%)]. Image-based absorbed dose estimates were compared with those obtained from the extrapolation to 152Tb of a classical biodistribution experiment using the same antibody fragment labeled with 111In. 152Tb was produced by proton-induced spallation in a tantalum target, followed by mass separation and cation exchange chromatography. The endosialin-targeting scFv78-Fc fusion protein was conjugated with the chelator p-SCN-Bn-CHX-A"-DTPA, followed by labeling with either 152Tb or 111In. Micro-PET images of four immunodeficient female mice bearing RD-ES tumor xenografts were acquired 4, 24, and 48 h after the i.v. injection of 152Tb-CHX-DTPA-scFv78-Fc. After count/activity camera calibration, time-integrated activity coefficients (TIACs) were obtained for the following compartments: heart, lungs, liver, kidneys, intestines, tumor, and whole body, manually segmented on CT. For comparison, radiation dose estimates of 152Tb-CHX-DTPA-scFv78-Fc were extrapolated from mice dissected 4, 24, 48, and 96 h after the injection of 111In-CHX-DTPA-scFv78-Fc (3–5 mice per group). Imaging-derived and biodistribution-derived organ TIACs were used as input in the 25 g mouse model of OLINDA/EXM® 2.0, after appropriate mass rescaling. Tumor absorbed doses were obtained using the OLINDA2 sphere model. Finally, the relative percent difference (RD%) between absorbed doses obtained from imaging and biodistribution were calculated. Results: RD% between microPET-based dosimetry and biodistribution-based dose extrapolations were + 12, − 14, and + 17 for the liver, the kidneys, and the tumors, respectively. Compared to biodistribution, the imaging method significantly overestimates the absorbed doses to the heart and the lungs (+ 89 and + 117% dose difference, respectively). Conclusions: MicroPET-based dosimetry of 152Tb is feasible, and the comparison with organ harvesting resulted in acceptable dose discrepancies for body districts that can be segmented on CT. These encouraging results warrant additional validation using radiolabeled biomolecules with a different biodistribution pattern. [ABSTRACT FROM AUTHOR]