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This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer. [ABSTRACT FROM AUTHOR]

Of the half a million cases of thyroid cancer diagnosed annually, 95% are differentiated thyroid cancers. Although clinical guidelines recommend surgical resection followed by radioactive iodine ablation, loss of sodium–iodine symporter expression causes up to 20% of differentiated thyroid cancers to become radioactive iodine refractory. For patients with radioactive iodine refractory disease, there is an urgent need for new diagnostic and therapeutic approaches. We evaluated the thyroid-stimulating hormone receptor as a potential target for imaging of differentiated thyroid cancer. We immunostained tissue microarrays containing 52 Hurthle cell carcinomas to confirm thyroid-stimulating hormone receptor expression. We radiolabeled chelator deferoxamine conjugated to recombinant human thyroid-stimulating hormone analog superagonist TR1402 with 89Zr (t 1/2 = 78.4 h, β + =22.7%) to produce [89Zr]Zr-TR1402. We performed in vitro uptake assays in high–thyroid-stimulating hormone receptor and low–thyroid-stimulating hormone receptor–expressing THJ529T and FTC133 thyroid cancer cell lines. We performed in vivo positron emission tomography/computed tomography and biodistribution studies in male athymic nude mice bearing thyroid-stimulating hormone receptor–positive THJ529T tumors. Immunohistochemical analysis revealed 62% of patients (27 primary and 5 recurrent) were thyroid-stimulating hormone receptor membranous immunostain positive. In vitro uptake of 1nM [89Zr]Zr-TR1402 was 38 ± 17% bound/mg in thyroid-stimulating hormone receptor–positive THJ529T thyroid cancer cell lines compared to 3.2 ± 0.5 in the low-expressing cell line (P <.01), with a similar difference seen in FTC133 cell lines (P <.0001). In vivo and biodistribution studies showed uptake of [89Zr]Zr-TR1402 in thyroid-stimulating hormone receptor–expressing tumors, with a mean percentage of injected dose/g of 1.9 ± 0.4 at 3 days post-injection. Our observation of thyroid-stimulating hormone receptor expression in tissue microarrays and [89Zr]Zr-TR1402 accumulation in thyroid-stimulating hormone receptor–positive thyroid cancer cells and tumors suggests thyroid-stimulating hormone receptor is a promising target for imaging of differentiated thyroid cancer. [ABSTRACT FROM AUTHOR]

The use of biomarkers is integral to the routine management of cancer patients, including diagnosis of disease, clinical staging and response to therapeutic intervention. Advanced imaging metrics with computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are used to assess response during new drug development and in cancer research for predictive metrics of response. Key components and challenges to identifying an appropriate imaging biomarker are selection of integral vs integrated biomarkers, choosing an appropriate endpoint and modality, and standardization of the imaging biomarkers for cooperative and multicenter trials. Imaging biomarkers lean on the original proposed quantified metrics derived from imaging such as tumor size or longest dimension, with the most commonly implemented metrics in clinical trials coming from the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and then adapted versions such as immune-RECIST (iRECIST) and Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for immunotherapy response and PET imaging, respectively. There have been many widely adopted biomarkers in clinical trials derived from MRI including metrics that describe cellularity and vascularity from diffusion-weighted (DW)-MRI apparent diffusion coefficient (ADC) and Dynamic Susceptibility Contrast (DSC) or dynamic contrast enhanced (DCE)-MRI (Ktrans, relative cerebral blood volume (rCBV)), respectively. Furthermore, Fluorodexoyglucose (FDG), fluorothymidine (FLT), and fluoromisonidazole (FMISO)-PET imaging, which describe molecular markers of glucose metabolism, proliferation and hypoxia have been implemented into various cancer types to assess therapeutic response to a wide variety of targeted- and chemotherapies. Recently, there have been many functional and molecular novel imaging biomarkers that are being developed that are rapidly being integrated into clinical trials (with anticipation of being implemented into clinical workflow in the future), such as artificial intelligence (AI) and machine learning computational strategies, antibody and peptide specific molecular imaging, and advanced diffusion MRI. These include prostate-specific membrane antigen (PSMA) and trastuzumab-PET, vascular tumor burden extracted from contrast-enhanced CT, diffusion kurtosis imaging, and CD8 or Granzyme B PET imaging. Further excitement surrounds theranostic procedures such as the combination of 68Ga/111In- and 177Lu-DOTATATE to use integral biomarkers to direct care and personalize therapy. However, there are many challenges in the implementation of imaging biomarkers that remains, including understand the accuracy, repeatability and reproducibility of both acquisition and analysis of these imaging biomarkers. Despite the challenges associated with the biological and technical validation of novel imaging biomarkers, a distinct roadmap has been created that is being implemented into many clinical trials to advance the development and implementation to create specific and sensitive novel imaging biomarkers of therapeutic response to continue to transform medical oncology. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors are found throughout the body, including the pancreas. These tumors are phenotypically and genetically heterogeneous and can be difficult to accurately image using current imaging standards. However, positron emission tomography/computed tomography with radiolabeled somatostatin analogs has shown clinical success because many neuroendocrine tumors overexpress somatostatin receptor subtype 2. Unfortunately, patients with poorly differentiated neuroendocrine tumors often have a diminished level of somatostatin receptor subtype 2. We found that histone deacetylase inhibitors can upregulate the functional expression of somatostatin receptor subtype 2. We evaluated the effect of histone deacetylase inhibitors on somatostatin receptor subtype 2 expression at the mRNA and protein level in neuroendocrine tumor cell lines. The effect of histone deacetylase inhibitors on surface somatostatin receptor subtype 2 was also investigated by fluorescence-activated cell sorting analysis. Changes in somatostatin receptor subtype 2 expression in neuroendocrine tumor xenografts after treatment were imaged using Ga68-DOTATATE positron emission tomography/computed tomography. The functional increase of somatostatin receptor subtype 2 in neuroendocrine tumors after histone deacetylase inhibitor treatment was confirmed through in vitro experiments and small animal Ga68-DOTATATE positron emission tomography/computed tomography imaging. Histone deacetylase inhibitors increased somatostatin receptor subtype 2 transcription and protein expression in neuroendocrine tumor cell lines. Small animal Ga68-DOTATATE positron emission tomography/computed tomography imaging confirmed the enhancement of radiopeptide uptake after histone deacetylase inhibitor administration. This study demonstrates a new method to potentially improve imaging and treatments that target somatostatin receptor subtype 2 in neuroendocrine tumors. [ABSTRACT FROM AUTHOR]

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century. [ABSTRACT FROM AUTHOR]

Background: Sphingosine-1-phosphate receptor 1 (S1PR1) is highly expressed in vascular smooth muscle cells from intimal lesions. PET imaging using S1PR1 as a biomarker would increase our understanding of its role in vascular pathologies including in-stent restenosis.Methods: The S1PR1 compound TZ3321 was synthesized for in vitro characterization and labeled with Carbon-11 for in vivo studies. The biodistribution of [11C]TZ3321 was evaluated in normal mice; microPET and immunohistochemistry (IHC) studies were performed using a murine femoral artery wire-injury model of restenosis.Results: The high potency of TZ3321 for S1PR1 (IC 50 = 2.13 ± 1.63 nM), and high selectivity (>1000 nM) for S1PR1 over S1PR2 and S1PR3 were confirmed. Biodistribution data revealed prolonged retention of [11C]TZ3321 in S1PR1-enriched tissues. MicroPET imaging of [11C]TZ3321 showed higher uptake in the wire-injured arteries of ApoE-/- mice than in injured arteries of wild-type mice (SUV 0.40 ± 0.06 vs 0.28 ± 0.04, n = 6, P < .001); FDG-PET showed no difference (SUV 0.98 ± 0.04 vs 0.94 ± 0.01, n = 6, P > .05). Post-PET autoradiography showed >4-fold higher [11C]TZ3321 retention in the injured artery of ApoE-/- mice than in wild-type mice. Subsequent IHC staining confirmed higher expression of S1PR1 in the neointima of the injured artery of ApoE-/- mice than in wild-type mice.Conclusions: This preliminary study supports the potential use of PET for quantification of the S1PR1 expression as a biomarker of neointimal hyperplasia. [ABSTRACT FROM AUTHOR]

Imaging of hypoxia is important in many diseases states in oncology, cardiology, and neurology. The radiopharmaceutical, copper-labeled diacetyl-bis(N-methylthiosemicarbazone), has been used to assess hypoxia in many studies. In particular, copper-labeled diacetyl-bis(N-methylthiosemicarbazone) has been used in oncologic settings to investigate tumor hypoxia and the role of this parameter in response to therapy and outcome. Some groups have conducted imaging studies assessing the role of hypoxia in cardiovascular and neurologic disorders. Additionally, several groups have made significant progress into understanding the mechanism by which this compound accumulates in cells. Multiple preclinical and clinical studies have been conducted, shedding light on the importance of careful image analysis when using this tracer. This review article focuses on the recent preclinical and clinical studies with this tracer. [ABSTRACT FROM AUTHOR]

Abstract: Specific Activity (SA), defined as the amount of radioactivity per unit mass of a compound is arguably one of the most important parameters in radiopharmaceutical development, particularly in quality control of carbon-11 and fluorine-18 labeled compounds. This review article will outline the progression of improvements in SA over the last few decades. The International Symposium of Radiopharmaceutical Chemistry (ISRC/ISRS) abstracts were an excellent source of materials for this review and will be referenced throughout. [Copyright &y& Elsevier]

Abstract: Specific activity (SA), defined as the amount of radioactivity per unit mass of a compound, is arguably one of the most important parameters in radiopharmaceutical development, particularly in quality control of carbon-11- and fluorine-18-labeled compounds. This review article will outline the progression of improvements in SA over the last few decades. The International Symposium of Radiopharmaceutical Chemistry abstracts were an excellent source of materials for this review and will be referenced throughout. [Copyright &y& Elsevier]

Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the introduction of approved therapeutics in neuroendocrine tumours and prostate cancer in the last 10 years, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this Series paper we explore the issues that affect access to and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that might affect the availability of theranostic treatments for patients with cancer. [ABSTRACT FROM AUTHOR]

Scandium-47 is a promising radionuclide for targeted radiotherapy and is also an elementally matched therapeutic partner to 43Sc and 44Sc, which are suitable for Positron Emission Tomography. The predominantly reported routes for the production of 47Sc employ expensive enriched titanium or calcium targets to achieve high radionuclidic purity. This study reports measurements of the excitation function of the natV(p,x)47Sc reaction at proton energies of 18–24 MeV to optimize bombardment parameters for the production of 47Sc using this promising approach. The cross-sections reported here demonstrate that irradiation of vanadium targets can produce >99% radionuclidically pure 47Sc with a proton energy of 24 MeV, albeit at modest yields. • Cross-sections for the natV(p,x)49,51Cr and natV(p,x)47Sc reactions were measured. • Cross-sections were used for determining optimal bombardment parameters. • A 24 MeV cyclotron can produce 47Sc in yields suitable for preclinical research. • A 26–30 MeV cyclotron can achieve higher yields with >96% radionuclidic purity. • A Python code was written to streamline and standardize calculations for the beam energy, proton flux and cross-sections. [ABSTRACT FROM AUTHOR]

A proof of concept study was undertaken where non-carrier added 186g Re was produced from the cyclotron bombardment of 186 WC. 186 WC was carbo-thermally generated from a novel precursor synthesized from 186 WO 3 , aqueous ammonia and hexamethyltetramine. The inherent high electrical and thermal conductivity of this material, coupled with its high melting point, made it an ideal candidate for proton bombardment for production of 186 Re. An18 μA irradiation for 3 h and processing via thermo-chromatography, 186 WC yielded 0.93 mCi of 186g Re which corresponds to 89% of the calculated theoretical yields. The radiochemical purity of the desired 186g Re species was found to be between 95 and 97% with small contaminants of 186 ReO 2 . The radiochemistry utility of the product was investigated using S-benzoyl-MAG3, and 100% complexation was achieved with stability being maintained for 96 h. The re-oxidation of 186 WC back to 186 WO 3 by oxygen in the thermo-chromatography method of processing ensured that the starting material was regenerated and recovered from the process in 94–98% yield. [ABSTRACT FROM AUTHOR]

The production of positron-emitting isotopes of manganese is potentially important for developing contrast agents for dual-modality positron emission tomography and magnetic resonance (PET/MR) imaging, as well as for in vivo imaging of the biodistribution and toxicity of manganese. The decay properties of 52 Mn make it an excellent candidate for these applications, and it can easily be produced by bombardment of a chromium target with protons or deuterons from a low-energy biomedical cyclotron. Several parameters that are essential to this mode of production—target thickness, beam energy, beam current, and bombardment time—depend heavily on the availability of reliable, reproducible cross-section data. This work contributes to the routine production of 52g Mn for biomedical research by contributing experimental cross-sections for natural chromium ( nat Cr) targets for the nat Cr( p , x ) 52g Mn reaction, as well as for the production of the radiocontaminants 52m,54 Mn. [ABSTRACT FROM AUTHOR]

Beryllium-7 (7Be) was created by proton irradiation of natural (natB) and enriched (10B) boron targets. The targets were dissolved in nitric acid, and the 7Be was separated from the bulk boron target material by cation-exchange chromatography. An average recovery of (99.4 ± 3.7)% was obtained for 6 separations. The purified 7Be sample was placed into a batch-mode ion source to create a 7Be beam that was delivered at an average rate of 5 × 105 pps to end users at the National Superconducting Cyclotron Laboratory. • Production method for 7Be from proton irradiated natural boron and enriched 10B pellet target without 7Li impurity. • Radiochemical separation method for extracting 7Be from boron pellet target with high purity. • 7Be source preparation for use with a batch-mode ion source at heavy-ion radioisotope beam facility. • Pure 7Be4+ ion beam delivered to scientific users. [ABSTRACT FROM AUTHOR]

Hypoxia within the tumor microenvironment is a critical factor influencing the efficacy of immunotherapy, including immune checkpoint inhibition. Insufficient oxygen supply, characteristic of hypoxia, has been recognized as a central determinant in the progression of various cancers. The reemergence of evofosfamide, a hypoxia-activated prodrug, as a potential treatment strategy has sparked interest in addressing the role of hypoxia in immunotherapy response. This investigation sought to understand the kinetics and heterogeneity of tumor hypoxia and their implications in affecting responses to immunotherapeutic interventions with and without evofosfamide. This study aimed to investigate the influence of hypoxia on immune checkpoint inhibition, evofosfamide monotherapy, and their combination on colorectal cancer (CRC). Employing positron emission tomography (PET) imaging, we developed novel analytical methods to quantify and characterize tumor hypoxia severity and distribution. Murine CRC models were longitudinally imaged with [18F]-fluoromisonidazole (FMISO)-PET to quantify tumor hypoxia during checkpoint blockade (anti-CTLA-4 + and anti-PD1 +/− evofosfamide). Metrics including maximum tumor [18F]FMISO uptake (FMISOmax) and mean tumor [18F]FMISO uptake (FMISOmean) were quantified and compared with normal muscle tissue (average muscle FMISO uptake (mAvg) and muscle standard deviation (mSD)). Histogram distributions were used to evaluate heterogeneity of tumor hypoxia. Severe hypoxia significantly impeded immunotherapy effectiveness consistent with an immunosuppressive microenvironment. Hypoxia-specific PET imaging revealed a striking degree of spatial heterogeneity in tumor hypoxia, with some regions exhibiting significantly more severe hypoxia than others. The study identified FMISOmax as a robust predictor of immunotherapy response, emphasizing the impact of localized severe hypoxia on tumor volume control during therapy. Interestingly, evofosfamide did not directly reduce hypoxia but markedly improved the response to immunotherapy, uncovering an alternative mechanism for its efficacy. These results enhance our comprehension of the interplay between hypoxia and immune checkpoint inhibition within the tumor microenvironment, offering crucial insights for the development of personalized cancer treatment strategies. Non-invasive hypoxia quantification through molecular imaging evaluating hypoxia severity may be an effective tool in guiding treatment planning, predicting therapy response, and ultimately improving patient outcomes across diverse cancer types and tumor microenvironments. It sets the stage for the translation of these findings into clinical practice, facilitating the optimization of immunotherapy regimens by addressing tumor hypoxia and thereby enhancing the efficacy of cancer treatments. [Display omitted] [ABSTRACT FROM AUTHOR]

Positron Emission Tomography is an important molecular imaging technique for detection and diagnoses of various disease states. This work aims to develop novel titanium-45 (t ½ = 3.08 h) PET tracers using Prostate Specific Membrane Antigen (PSMA) targeting vectors for imaging of prostate cancer as proof of concept for this relatively unexplored isotope. Titanium-45 was produced on the University of Alabama at Birmingham (UAB) TR24 cyclotron using proton bombardments on natural scandium foils and separated using procedures described previously [1]. After purification, Titanium-45 was used to radiolabel two PSMA-targeting molecules; DFO-DUPA and LDFC-DUPA. Radiochemical yields were determined via radio-high purity liquid chromatography (radioHPLC). The radiolabeled compounds were tested both in vitro and in vivo using PSMA+ cell lines (LNCaP and 22Rv1) and PSMA− cell lines (PC3). Titanium-45 was produced and purified in yields suitable for research studies. Radiochemical yields of up to 98 ± 1% were achieved with DFO-DUPA and 92 ± 7% with LDFC-DUPA. PSMA specific targeting was observed in vitro in PSMA positive cells (LNCaP (0.6% ± 0.05%) and confirmed by blocking (0.15% ± 0.04%) (P < 0.0001)), compared to uptake in the PSMA negative cells (PC3 (0.07% ± 0.008%)) and confirmed by blocking (0.07% ± 0.01%) (P = 0.5253). In vivo studies demonstrated statistically significant uptake in LNCaP tumors (2.3% ± 0.3% ID/g) compared to PC3 tumor uptake (0.1% ± 0.07%). This work shows that titanium-45 can be used to radiolabel PSMA targeting compounds with high radiochemical yields. These radiolabeled compounds remain intact in serum for at least two half-lives of titanium-45, showing that these compounds would be appropriate for implementation in the clinical setting. This study shows the feasibility of using titanium-45 as positron emitting radiometal for use in imaging PSMA+ prostate cancer, and illustrates that further research is in this area is warranted. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: An investigative study of the 100Mo (p,2n)99mTc reaction on a medical cyclotron using 100Mo2C is reported. This is the first report of this compound being used as a target for this reaction. 100Mo2C, a refractory carbide with high thermal conductivity, properties which underscore its use on a cyclotron, was synthesized using 100MoO3. Its ease of oxidation back to 100MoO3 under air at elevated temperatures facilitates the use of thermo-chromatography, a high temperature gas phase separation technique for the separation and isolation of 99mTc. Activity yields for 99mTc averaged 84% of the calculated theoretical yields. Additionally, the percent recovery of MoO3, the precursor for Mo2C, was consistently high at 85% ensuring a good life cycle for this target material. The produced 99mTc was radio-chemically pure and easily labeled MDP for imaging purposes. [Copyright &y& Elsevier]

Prostate cancer is the most common malignancy and leading cause of cancer deaths in men. Thus, the development of novel strategies for performing combined prostate cancer imaging and therapy methods is crucial and could have a significant impact on patient care. This current study aimed to design a multimodality nanoconjugate to be used for both PET and optical imaging and as a therapeutic radio/photo sensitizer and anti-angiogenesis agent. Initial characterization of this novel nanoconjugate was performed via HPLC, FTIR, TEM and DLS analyses. Pt@TiO 2 -SPHINX was further evaluated using fluorometric and radiochromatographic methods. Cytotoxicity, cell uptake and internalization were also investigated as well as therapy with photodynamic/radio therapy combinations. Both nanoparticles and nanoconjugates were robustly synthesized according to literature methods. Radiochemistry and cell culture assays showed high 89Zr radiolabeling efficiency with sufficient stability for studies at later time points. Pt@TiO 2 -SPHINX was shown to target prostate cancer cells (PC3 and LNCaP), and was non-toxic to normal prostate cells (RWPE-1). This finding was supported by the WST-8 assay and AFM images. The uptake of the compound in prostate cancer cells is significantly higher than prostate normal cells and according to ELISA results, Pt@TiO 2 -SPHINX can increase anti-angiogenic VEGFA 165b. Additionally, Pt@TiO 2 -SPHINX dramatically decreased the cell viability of prostate cancer cells when photodynamic and radio therapy were performed at the same time. In vitro results are promising for future studies of Pt@TiO 2 -SPHINX as a PET imaging agent and anti-angiogenic radio sensitizer. [Display omitted] [ABSTRACT FROM AUTHOR]

• Quetiapine lowers myelin, transthyretin, and copper transporter gene expression. • Dysbindin-1 knockout and quetiapine treatment alter serum copper levels. • Loss of dysbindin-1 expression results in hyperactive mice. • Dysbindin-1 loss impairs neurological function; quetiapine selectively rescues it. DTNBP1 gene variation and lower dysbindin-1 protein are associated with schizophrenia. Previous evidence suggests that downregulated dysbindin-1 expression results in lower expression of copper transporters ATP7A (intracellular copper transporter) and SLC31A1 (CTR1; extracellular copper transporter), which are required for copper transport across the blood brain barrier. However, whether antipsychotic medications used for schizophrenia treatment may modulate these systems is unclear. The current study measured behavioral indices of neurological function in dysbindin-1 functional knockout (KO) mice and their wild-type (WT) littermates with or without quetiapine treatment. We assessed serum and brain copper levels, ATP7A and CTR1 mRNA, and copper transporter-expressing cellular population transcripts: TTR (transthyretin; choroid plexus epithelial cells), MBP (myelin basic protein; oligodendrocytes), and GJA1 (gap-junction protein alpha-1; astrocytes) in cortex and hippocampus. Regardless of genotype, quetiapine significantly reduced TTR, MBP, CTR1 mRNA, and serum copper levels. Neurological function of untreated KO mice was abnormal, and ledge instability was rescued with quetiapine. KO mice were hyperactive after 10 min in the open-field assay, which was not affected by treatment. Dysbindin-1 KO results in hyperactivity, altered serum copper, and neurological impairment, the last of which is selectively rescued with quetiapine. Antipsychotic treatment modulates specific cellular populations, affecting myelin, the choroid plexus, and copper transport across the blood brain barrier. Together these results indicate the widespread impact of antipsychotic treatment, and that alteration of dysbindin-1 may be sufficient, but not necessary, for specific schizophrenia pathology. [ABSTRACT FROM AUTHOR]

The radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality 76Br, 77Br, and 80mBr. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel 77Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein. 76Br, 77Br, and 80mBr were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co76Se, Co77Se, and Co80Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The 77Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination. Cyclotron production yields were 103 ± 10 MBq∙μA−1∙h−1 for 76Br, 88 ± 10 MBq∙μA−1∙h−1 for 80mBr at 16 MeV and 17 ± 1 MBq∙μA−1∙h−1 for 77Br at 13 MeV. Radiobromide isolation yields were 76 ± 11% in a small volume of aqueous solution. The synthesized 77Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/μmol at end of synthesis. A novel selenium alloy target enabled clinical-scale production of 76Br, 77Br, and 80mBr with high apparent molar activities, which was used to for the production of a new 77Br-labeled inhibitor of PARP-1. New methods for the cyclotron production and isolation of radiobromine improved the production capacity of 77Br by a factor of three and 76Br by a factor of six compared with previous methods. Preclinical translational research of 77Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale 77Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co77Se. [ABSTRACT FROM AUTHOR]

Due to its decay and chemical properties, interest in manganese-52 has increased for development of long-lived PET radiopharmaceuticals. Its long half-life of 5.6 days, low average positron energy (242 keV), and sufficient positron decay branching ratio make it suitable for radiolabeling macromolecules for investigating slow biological processes. This work aims to establish suitable chelators for manganese-52 that can be radiolabeled at mild conditions through the evaluation of commercially available chelators. Manganese-52 was produced through the nuclear reaction NatCr(p,n)52Mn by irradiation of natural chromium targets on a TR24 cyclotron followed by purification through ion exchange chromatography. The radiolabeling efficiencies of chelators: DOTA, DiAmsar, TETA, DO3A, NOTA, 4′-Formylbenzo-15-crown-5, Oxo-DO3A, and DFO, were assessed by investigating the impact of pH, buffer type, and temperature. In vitro stability of [52Mn]Mn(DO3A)−, [52Mn]Mn(Oxo-DO3A)−, and [52Mn]Mn(DOTA)2− were evaluated in mouse serum. The radiocomplexes were also evaluated in vivo in mice. Crystals of [Mn(Oxo-DO3A)]− were synthesized by reacting Oxo-DO3A with MnCl 2 and characterized by single crystal X-ray diffraction. Yields of 185 ± 19 MBq (5.0 ± 0.5 mCi) (n = 4) of manganese-52 were produced at the end of a 4 h, 15 μA, bombardment with 12.5 MeV protons. NOTA, DO3A, DOTA, and Oxo-DO3A chelators were readily radiolabeled with >96 % radiochemical purity at all conditions. Manganese radiocomplexes of Oxo-DO3A, DOTA, and DO3A remained stable in vitro up to 5 days and exhibited different biodistribution profiles compared to [52Mn]MnCl 2. The solid-state structure of Mn-Oxo-DO3A complex was determined by single-crystal X-ray diffraction. DO3A and Oxo-DO3A are suitable chelators for manganese-52 which are readily radiolabeled at mild conditions with high molar activity, and demonstrate both in vitro and in vivo stability. Radiolabeling and biodistribution of [52Mn]Mn-Chelates in mice. [Display omitted] [ABSTRACT FROM AUTHOR]

Chelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in 68Ga and increasing availability of new radiometals such as 43Sc/47Sc and 45Ti, there is a growing demand for tailored chelators that can form stable complexes with these metals. This work reports the synthesis and characterization of a hexadentate tris-1,2-hydroxypyridonone chelator HOPO-O 6 -C4 and its in vitro and in vivo evaluation with the above mentioned radiometals. To investigate the affinity of HOPO-O 6 -C4, macroscopic studies were performed with Sc3+, and Ga3+ followed by DFT structural optimization of the Sc3+, Ga3+ and Ti4+ complexes. Further tracer studies with 43Sc (and 47Sc), 45Ti, and 68Ga were performed to determine the potential for positron emission tomography (PET) imaging with these complexes. In vitro stability studies followed by in vivo imaging and biodistribution studies were performed to understand the kinetic stability of the resultant radiometal-complexes of HOPO-O 6 -C4. Promising radiolabeling results with HOPO-O 6 -C4 were obtained with 43Sc, 47Sc, 45Ti, and 68Ga radionuclides; rapid radiolabeling was observed at 37 °C and pH 7 in under 30-min. Apparent molar activity measurements were performed for radiolabeling of HOPO-O 6 -C4 with 43Sc (4.9 ± 0.26 GBq/μmol), 47Sc (1.58 ± 0.01 GBq/μmol), 45Ti (11.5 ± 1.6 GBq/μmol) and 68Ga (5.74 ± 0.7 GBq/μmol), respectively. Preclinical in vivo imaging studies resulted in promising results with [68Ga]Ga-HOPO-O 6 -C4 indicating a rapid clearance through hepatic excretion route and no decomplexation whereas [43Sc]Sc-HOPO-O 6 -C4, [47Sc]Sc-HOPO-O 6 -C4 and [45Ti]Ti-HOPO-O 6 -C4 showed modest and significant evidence of decomplexation, respectively. The tris-1,2-HOPO chelator HOPO-O 6 -C4 is a promising scaffold for elaboration into a 68Ga- based radiopharmaceutical. [Display omitted] [ABSTRACT FROM AUTHOR]

Manganese-52g, 54 and Chromium-51 production cross-section measurements were conducted using natural chromium foils and copper monitor foils. Proton beam energies between 10 and 20 MeV were used for target bombardment. After bombardment, the irradiated foils were allowed to decay for at least 48 h and radioactivity was quantified using a high-purity germanium detector. The maximum 52gMn cross-section was 90.8 ± 16.0 mb at 14.3 ± 0.8 MeV. These data contribute to the existing nuclear data for cyclotron production of 52gMn at low to medium proton energies. • Investigating the cyclotron production of 52gMn using a proton beam. • Using Cu monitor reactions for the determination of energy. • Measuring the cross-sections of 52g,54Mn and 51Cr over an energy range of 10–20 MeV. [ABSTRACT FROM AUTHOR]

Neurotensin receptor 1 (NTSR1) can stimulate tumor proliferation through neurotensin (NTS) activation and are overexpressed by a variety of cancers. The high binding affinity of NTS/NTSR1 makes radiolabeled NTS derivatives interesting for cancer diagnosis and staging. Internalization of NTS/NTSR1 also suggests therapeutic application with high LET alpha particles and low energy electrons. We investigated the therapeutic efficacy of [58mCo]Co-NOTA-NT-20.3 in vivo using murine models xenografted with NTSR1-positive HT29 human colorectal adenocarcinoma cells, and utilized [55Co]Co-NOTA-NT-20.3 for dosimetry. Targeting properties and cytotoxicity of [55/58mCo]Co-NOTA-NT-20.3 were assessed with HT29 cells. Female nude mice were xenografted with HT29 tumors and administered [55Co or 58mCo]Co-NOTA-NT-20.3 to evaluate pharmacokinetics or for therapy, respectively. Dosimetry calculations followed the Medical Internal Radiation Dose (MIRD) formalism and human absorbed dose rate per unit activity were obtained from OpenDose. The pilot therapy study consisted of two groups (each N = 3) receiving 110 ± 15 MBq and 26 ± 6 MBq [58mCo]Co-NOTA-NT-20.3 one week after tumor inoculation, and control (N = 3). Tumor sizes and masses were measured twice a week after therapy. Complete blood count and kidney histology were also performed to assess toxicity. HPLC measured radiochemical purity of [55,58mCo]Co-NOTA-NT-20.3 > 99 %. Labeled compounds retained NTS targeting properties. [58mCo]Co-NOTA-NT-20.3 exhibited cytotoxicity for HT29 cells and was >15× more potent than [58mCo]CoCl 2. Xenografted tumors responded modestly to administered doses, but mice showed no signs of radiotoxicity. Absorbed dose to tumor and kidney with 110 MBq [58mCo]Co-NOTA-NT-20.3 were 0.6 Gy and 0.8 Gy, respectively, and other organs received less than half of the absorbed dose to tumor. Off-target radiation dose from cobalt-58g was small but reduces the therapeutic window. The enhanced in vitro cytotoxicity and high tumor-to-background led us to investigate the therapeutic efficacy of [58mCo]Co-NOTA-NT-20.3 in vivo. Although we were unable to induce tumor response commensurate with [177Lu]Lu-NT127 (NLys-Lys-Pro-Tyr-Tle-Leu) studies involving similar time-integrated activity, the absence of observed toxicity may constitute an opportunity for targeting vectors with improved uptake and/or retention to avoid the aftereffects of other high-LET radioactive emissions. Future studies with higher uptake, activity and/or multiple dosing regimens are warranted. The theranostic approach employed in this work was crucial for dosimetry analysis. [Display omitted] • First in vivo therapy study of 58mCo with an internalizing targeting vector • [58mCo]Co-NOTA-NT-20.3 was >15× more cytotoxic to HT29 cells in vitro than [58mCo]CoCl 2. • Theranostic approach with 55Co enabled visualization of tumor uptake and dosimetry. [ABSTRACT FROM AUTHOR]

Introduction Cardiovascular disease is the leading cause of death in the United States. The identification of vulnerable plaque at risk of rupture has been a major focus of research. Hypoxia has been identified as a potential factor in the formation of vulnerable plaque, and it is clear that decreased oxygen plays a role in the development of plaque angiogenesis leading to plaque destabilization. The purpose of this study is to demonstrate the feasibility of copper-64 labeled diacetyl-bis (N 4 -methylthiosemicarbazone) ( 64 Cu-ATSM), a positron-emitting radiopharmaceutical taken up in low-oxygen-tension cells, for the identification of hypoxic and potentially unstable atherosclerotic plaque in a mouse model. Methods 64 Cu-ATSM PET was performed in 21 atherosclerotic apolipoprotein E knockout (ApoE −/− ) mice, 6 of which were fed high-fat diet (HFD) while the others received standard-chow diet (SCD), and 13 control wild type mice fed SCD. 4 SCD ApoE −/− mice and 4 SCD wild type mice also underwent 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) imaging one day prior to 64 Cu-ATSM PET. Results 64 Cu-ATSM uptake was increased in the aortic arch in SCD ApoE −/− mice (average aortic arch/muscle (A/M) standardized uptake value ratio 7.5–30 min post injection: (5.66 ± 0.23) compared to control mice (A/M SUV ratio 7.5–30 min post injection (3.87 ± 0.22), p < 0.0001). HFD ApoE −/− mice also showed similarly increased aortic arch uptake on PET imaging in comparison to control mice. Immunohistochemistry in both HFD and SCD ApoE −/− mice revealed noticeable hypoxia by pimonidazole stain in atherosclerosis which was co-localized to macrophage by CD68 staining. Autoradiography assessment demonstrated the presence of hypoxia by 64 Cu-ATSM uptake correlated with pimonidazole uptake within the ex vivo atherosclerotic aortic arch specimens. A significant increase in 18 F-FDG uptake in the SCD ApoE −/− mice in comparison to controls was also observed at delayed time points. Conclusion This pre-clinical study suggests that 64 Cu-ATSM is a potential PET tracer for hypoxia imaging in atherosclerosis. Advances in Knowledge and Implications for Patient Care While studies in humans are necessary for conclusive data, in the long term, a 64 Cu-ATSM PET imaging strategy could help facilitate the study of plaque biology in human patients. [ABSTRACT FROM AUTHOR]

For PET radionuclides, the radioactivity of a sample can be conveniently measured by a dose calibrator. These devices depend on a “calibration setting number”, but many recommended settings from manuals were interpolated based on standard sources of other radionuclide(s). We conducted HPGe gamma-ray spectroscopy, resulting in a reference for determining settings in two types of vessels containing one of several PET radionuclides. Our results reiterate the notion that in-house, experimental calibrations are recommended for different radionuclides and vessels. [ABSTRACT FROM AUTHOR]

Abstract: Effective specific activity of 64Cu (amount of radioactivity per µmol metal) is important in order to determine purity of a particular 64Cu lot and to assist in optimization of the purification process. Metal impurities can affect effective specific activity and therefore it is important to have a simple method that can measure trace amounts of metals. This work shows that ion chromatography (IC) yields similar results to ICP mass spectrometry for copper, nickel and iron contaminants in 64Cu production solutions. [Copyright &y& Elsevier]

Abstract: Objective: The goal of this study was to develop dually radiolabeled peptides for simultaneous imaging of cancer cell localization by targeting the αvβ3 integrin and their pathophysiology by targeting the activity of the proteolytic enzyme MMP2, involved in the metastatic process. Methods: A hybrid peptide c(RGDfE)K(DOTA)PLGVRY containing an RGD motif for binding to the αvβ3integrin, a metal chelator (DOTA) for radiolabeling with [64Cu], and the MMP2 substrate cleavage sequence PLGVRY with terminal tyrosine for labeling with [123I] was synthesized, labeled with [64Cu] and [123I], and evaluated in vitro as a potential imaging agent. Results: The peptide was synthesized and labeled with [64Cu] and [123I] with 300 and 40μCi/μg (542 and 72.2mCi/μmol) specific activities, respectively, and radiochemical purity of >98%. c(RGDfE)K(DOTA)PLGVRY demonstrated high affinity for αvβ3 integrins (Kd=83.4 + 13.2nM) in both substrate competition and cell binding assays. c(RGDfE)K(DOTA)PLGVRY peptide, but not the scrambled version, c(RGDfE)K(DOTA)GRPLVY was specifically cleaved by MMP2. Conclusions: These results demonstrate the feasibility of developing dually radiolabeled peptides for the simultaneous imaging of cancer cells and their pathophysiologic activity. [Copyright &y& Elsevier]

Abstract: Interest in using 68Ga is rapidly increasing for clinical PET applications due to its favorable imaging characteristics and increased accessibility. The focus of this study was to provide our long-term evaluations of the two TiO2-based 68Ge/68Ga generators and develop an optimized automation strategy to synthesize [68Ga]DOTATOC by using HEPES as a buffer system. This data will be useful in standardizing the evaluation of 68Ge/68Ga generators and automation strategies to comply with regulatory issues for clinical use. [Copyright &y& Elsevier]

The radionuclide 149Tb (t 1/2 = 4.1 h) is a potential theranostic isotope which can simultaneously be used for targeted-alpha-particle therapy and positron-emission tomography. Feasibility experiments were performed to test a near-symmetric heavy-ion reaction of 63Cu bombardment on monoisotopic 89Y. The indirect reaction was studied to avoid isomer production. Offline gamma spectroscopy was used to quantify thick-target physical yields and experimental results show modest agreement to the fusion-evaporation code PACE4. A near-symmetric fission yield was also observed. • Indirect heavy-ion reactions were investigated for the production of 149Tb. • Gamma spectroscopy was used to quantify thick-target physical yields. • PACE4 fusion-evaporation predictions show modest agreement to experimental results. • A near-symmetric fission yield was observed for the compound nucleus 152Er. [ABSTRACT FROM AUTHOR]

This work focused on the production and purification of the positron emitter 52Mn (t 1/2 = 5.6 d) via the natCr(p,n)52Mn reaction, using a TR24 cyclotron and a semi-automated system for the purification of 52Mn. Based on two-column and three-column systems, the recovery of 52Mn was 79.7 ± 6.2% (n = 3) and 70.8 ± 3.3% (n = 3), with processing times of 6.9 ± 0.5 h and 8.2 ± 0.6 h, respectively. • 52Mn was produced via irradiation of Cr foils using a solid-target coin system. • A semi-automated module was designed, constructed and optimized for the purification of 52Mn. • ICP-MS was used for elemental analysis of the starting material, after each column and waste for purifications of 52Mn. • HPGe was utilized for the irradiated samples to verify a high purity product with 54Mn contaminants <0.25%. [ABSTRACT FROM AUTHOR]

Titanium-45 (t 1/2 = 3.08 h) is a radiometal with excellent nuclear characteristics, including a high positron branching ratio (85%) and low average positron energy (0.439 MeV), for the development of PET imaging agents. 45Ti was produced via the 45Sc(p,n)45Ti reaction on the University of Alabama at Birmingham TR24 cyclotron in GBq quantities. Optimized separation methods were developed and preliminary radiochemistry studies were also carried out. This work shows 45Ti is a promising radiometal for future studies. • 45Ti was produced via irradiation of Sc foil using a solid-target coin system. • Radionuclidically pure product at yields suitable for research were obtained. • An optimized separation method for the use of 45Ti was developed. • Complexation studies of 45Ti with deferoxamine were conducted. [ABSTRACT FROM AUTHOR]

As part of an effort to develop aqueous isotope harvesting techniques at radioactive beam facilities, 48V and a cocktail of primary- and secondary-beam ions created by the fragmentation reaction of a 160 MeV/nucleon 58Ni beam were stopped in an aqueous target cell. After collection, 48V was separated from the mixture of beam ions using cation-exchange chromatography. The extraction efficiency from the aqueous solution was (47.0 ± 2.5)%, and the isolated 48V had a radiochemical purity of 95.8%. This proof-of-concept work shows that aqueous isotope harvesting could provide significant quantities of rare isotopes which are currently unavailable at conventional facilities. • A selective method was developed to separate the multivalent element vanadium from a complex mixture of elements (Z ~ 1–28). • Vanadium-48 was produced via heavy-ion fragmentation of a 58Ni beam at the National Superconducting Cyclotron Laboratory. • The primary- and secondary-beam ions, including 48V, were stopped in an aqueous target cell and characterized. • By way of cation-exchange chromatography, the 48V recovery was 47.0 ± 2.5%. • The radionuclidic purity of the recovered 48V was 95.8 ± 2.5%. [ABSTRACT FROM AUTHOR]