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A new automated radiosynthesis of [ 11 C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([ 11 C]K2), a radiopharmaceutical for the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [ 11 C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)-compliant synthesis of [ 11 C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [ 11 C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use., (© 2024 The Author(s). Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.)

Introduction: Theranostics targeting prostate-specific membrane antigen (PSMA) represent a new targeted approach for prostate cancer care that combines diagnostic and therapeutic radiopharmaceuticals to diagnose and treat the disease. Positron emission tomography (PET) is the imaging method of choice and several diagnostic radiopharmaceuticals for quantifying PSMA have received FDA approval and are in clinical use. [ 68 Ga]Ga-PSMA-11 is one such imaging agent and the focus of this article. One beta-emitting radioligand therapy ([ 177 Lu]Lu-PSMA-617) has also received FDA approval for prostate cancer treatment, and several other alpha- and beta-emitting radioligand therapies are in clinical trials., Areas Covered: Theranostics targeting PSMA in men with prostate cancer are discussed with a focus on use of [ 68 Ga]Ga-PSMA-11 for imaging PSMA-positive lesions in men with prostate cancer. The review covers [ 68 Ga]Ga-PSMA-11 manufacture, current regulatory status, comparison of [ 68 Ga]Ga-PSMA-11 to other imaging techniques, clinical updates, and emerging applications of artificial intelligence for [ 68 Ga]Ga-PSMA-11 PET., Expert Opinion: [ 68 Ga]Ga-PSMA-11 is used in conjunction with a PET/CT scan to image PSMA positive lesions in men with prostate cancer. It is manufactured by chelating precursor with 68 Ga, either from a generator or cyclotron, and has regulatory approval around the world. It is widely used clinically in conjunction with radioligand therapies like [ 177 Lu]Lu-PSMA-617.

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., Competing Interests: Declaration of interests SEL reports research support from Navidea Biopharmaceuticals, Fusion Pharmaceuticals, Cytosite Biopharma, Viewpoint Molecular Targeting, and Genzyme Corporation; has acted as an advisor for NorthStar Medical Radioisotopes and Trevarx Biomedical; and is supported by the Department of Energy as part of the Department of Energy University Isotope Network under grant DESC0021269. PJHS reports research support from Bristol Myers Squibb, Telix Pharmaceuticals, and Radionetics Oncology; has acted as an adviser to Synfast Consulting and Telix Pharmaceuticals; holds equity in Bristol Myers Squibb, Telix Pharmaceuticals, and Novartis; and is supported by National Institutes of Health R01 EB021155. AMS reports trial funding from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; research funding from Medimmune, AVID Radiopharmaceuticals, Adalta, Antengene, Humanigen, Telix Pharmaceuticals, and Theramyc; is on the advisory boards of Imagion and ImmunOs; and is supported by Australian National Health and Medical Research Council grant number 1177837. ADW reports his role as the Editor in Chief of Nuclear Medicine and Biology. BMZ holds equity in Summit Biomedical Imaging. RPB is an advisor to 3B Pharmaceuticals (Berlin, Germany), ITM, Full Life Technologies, Sinotau, Jiangsu Huayi Technology, and Telix Pharmaceuticals. APK reports clinical trial funding from Novartis, Bayer, POINT, and Merck; and unpaid consulting for Novartis. JK reports an unrestricted grant from Janssen, and consulting fees from Telix and Novartis. JSL reports research support from Clarity Pharmaceuticals and Avid Radiopharmaceuticals; has acted as an adviser of Alpha-9 Theranostics, Clarity Pharmaceuticals, Earli, Evergreen Theragnostics, Inhibrix, Precirix, and Telix Pharmaceuticals; is a co-inventor on technologies licensed to Diaprost, Elucida Oncology, Theragnostics, CheMatech, Clarity Pharmaceuticals, and Samus Therapeutics; is the co-founder of pHLIP; holds equity in Summit Biomedical Imaging, Telix Pharmaceuticals, Clarity Pharmaceuticals, and Evergreen Theragnostics; and is supported by National Institutes of Health R35 CA232130. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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., Competing Interests: Declaration of interests Outside the submitted work: AMS reports trial funding from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; research funding from Medimmune, AVID Radiopharmaceuticals, Adalta, Antengene, Humanigen, Telix Pharmaceuticals, and Theramyc; and payment for participation in advisory boards of Imagion and Immunos. BMZ reports research funding from Evergreen Theragnostics, equity in Summit Biomedical Imaging, and has licensed technologies to Clarity Pharmaceuticals. SEL reports research support from Navidea Biopharmaceuticals, Fusion Pharmaceuticals, Cytosite Biopharma, Viewpoint Molecular Targeting, and Genzyme Corporation, and has acted as an advisor for NorthStar Medical Radioisotopes and Trevarx biomedical. PJHS reports research support from Bristol Myers Squibb, Telix Pharmaceuticals, and Radionetics Oncology; has acted as an adviser to Synfast Consulting and Telix Pharmaceuticals; and holds equity in Bristol Myers Squibb, Telix Pharmaceuticals, and Novartis. ADW reports their role as Editor-in-Chief of Nuclear Medicine and Biology. JSL reports research support from Clarity Pharmaceuticals and Avid Radiopharmaceuticals; has acted as an adviser of Alpha-9 Theranostics, Clarity Pharmaceuticals, Earli, Evergreen Theragnostics, Inhibrix, Precirix, and Telix Pharmaceuticals; is a co-inventor on technologies licensed to Diaprost, Elucida Oncology, Theragnostics, CheMatech, Clarity Pharmaceuticals, and Samus Therapeutics; is the co-founder of pHLIP; and holds equity in Summit Biomedical Imaging, Telix Pharmaceuticals, Clarity Pharmaceuticals, and Evergreen Theragnostics. AMS is supported by National Health and Medical Research Council grant number 1177837. SEL is supported by the Department of Energy as part of the DOE University Isotope Network, under grant DESC0021269. PJHS is supported by grant R01 EB021155. JSL is supported by National Institutes of Health grant R35 CA232130. MA-W, AJ, AK, PK, SV, STL, SKL, DP, JZ, JLU, and FG report no competing interests. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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

Recent developments in 68 Ga-radiopharmaceuticals, including a number of regulatory approvals for clinical use, has created a hitherto unprecedented demand for 68 Ga. Reliable access to enough 68 Ga to meet growing clinical demand using only 68 Ge/ 68 Ga generators has been problematic in recent years. To address this challenge, we have optimized the direct production of 68 Ga on a cyclotron via the 68 Zn(p,n) 68 Ga reaction using a liquid target. This protocol describes the cyclotron-based production of [ 68 Ga]GaCl 3 implemented at the University of Michigan using a liquid target on GE PETtrace instrumentation. The protocol provides 56 ± 4 mCi (n = 3) of [ 68 Ga]GaCl 3 that meets the necessary quality control criteria to use for the preparation of 68 Ga-radiopharmaceuticals for human use., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Positron emission tomography (PET) is a highly sensitive and versatile molecular imaging modality that leverages radiolabeled molecules, known as radiotracers, to interrogate biochemical processes such as metabolism, enzymatic activity, and receptor expression. The ability to probe specific molecular and cellular events longitudinally in a noninvasive manner makes PET imaging a particularly powerful technique for studying the central nervous system (CNS) in both health and disease. Unfortunately, developing and translating a single CNS PET tracer for clinical use is typically an extremely resource-intensive endeavor, often requiring synthesis and evaluation of numerous candidate molecules. While existing in vitro methods are beginning to address the challenge of derisking molecules prior to costly in vivo PET studies, most require a significant investment of resources and possess substantial limitations. In the context of CNS drug development, significant time and resources have been invested into the development and optimization of computational methods, particularly involving machine learning, to streamline the design of better CNS therapeutics. However, analogous efforts developed and validated for CNS radiotracer design are conspicuously limited. In this Perspective, we overview the requirements and challenges of CNS PET tracer design, survey the most promising computational methods for in silico CNS drug design, and bridge these two areas by discussing the potential applications and impact of computational design tools in CNS radiotracer design.

[ 68 Ga]Ga-PSMA-11, a urea-based peptidomimetic, is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that targets the prostate-specific membrane antigen (PSMA). The recent Food and Drug Administration approval of [ 68 Ga]Ga-PSMA-11 for PET imaging of patients with prostate cancer, expected follow-up approval of companion radiotherapeutics (e.g., [ 177 Lu]Lu-PSMA-617, [ 225 Ac]Ac-PSMA-617) and large prostate cancer patient volumes requiring access are poised to create an unprecedented demand for [ 68 Ga]Ga-PSMA-11 in nuclear medicine clinics around the world. Meeting this global demand is going to require a variety of synthesis methods compatible with 68 Ga eluted from a generator or produced on a cyclotron. To address this urgent need in the PET radiochemistry community, herein we report detailed protocols for the synthesis of [ 68 Ga]Ga-PSMA-11, (also known as HBED-CC, Glu-urea-Lys(Ahx)-HBED-CC and PSMA-HBED-CC) using both generator-eluted and cyclotron-produced 68 Ga and contrast the pros and cons of each method. The radiosyntheses are automated and have been validated for human use at two sites (University of Michigan (UM), United States; Royal Prince Alfred Hospital (RPA), Australia) and used to produce [ 68 Ga]Ga-PSMA-11 for patient use in good activity yields (single generator, 0.52 GBq (14 mCi); dual generators, 1.04-1.57 GBq (28-42 mCi); cyclotron method (single target), 1.47-1.89 GBq (40-51 mCi); cyclotron method (dual target), 3.63 GBq (98 mCi)) and high radiochemical purity (99%) (UM, n = 645; RPA, n > 600). Both methods are appropriate for clinical production but, in the long term, the method employing cyclotron-produced 68 Ga is the most promising for meeting high patient volumes. Quality control testing (visual inspection, pH, radiochemical purity and identity, radionuclidic purity and identity, sterile filter integrity, bacterial endotoxin content, sterility, stability) confirmed doses are suitable for clinical use, and there is no difference in clinical prostate cancer PET imaging using [ 68 Ga]Ga-PSMA-11 prepared using the two production methods., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Positron emission tomography (PET) studies with radioligands for 18-kDa translocator protein (TSPO) have been instrumental in increasing our understanding of the complex role neuroinflammation plays in disorders affecting the brain. However, (R)-[ 11 C]PK11195, the first and most widely used TSPO radioligand has limitations, while the next-generation TSPO radioligands have suffered from high interindividual variability in binding due to a genetic polymorphism in the TSPO gene (rs6971). Herein, we present the biological evaluation of the two enantiomers of [ 18 F]GE387, which we have previously shown to have low sensitivity to this polymorphism., Methods: Dynamic PET scans were conducted in male Wistar rats and female rhesus macaques to investigate the in vivo behaviour of (S)-[ 18 F]GE387 and (R)-[ 18 F]GE387. The specific binding of (S)-[ 18 F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[ 18 F]GE387 was further evaluated in a rat model of lipopolysaccharide (LPS)-induced neuroinflammation. Sensitivity to polymorphism of (S)-GE387 was evaluated in genotyped human brain tissue., Results: (S)-[ 18 F]GE387 and (R)-[ 18 F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[ 18 F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[ 18 F]GE387 was found in the inflamed striatum of LPS-treated rodents. In genotyped human brain tissue, (S)-GE387 was shown to bind similarly in low affinity binders (LABs) and high affinity binders (HABs) with a LAB to HAB ratio of 1.8., Conclusion: We established that (S)-[ 18 F]GE387 has favourable kinetics in healthy rats and non-human primates and that it can distinguish inflamed from normal brain regions in the LPS model of neuroinflammation. Crucially, we have reconfirmed its low sensitivity to the TSPO polymorphism on genotyped human brain tissue. Based on these factors, we conclude that (S)-[ 18 F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation., (© 2021. The Author(s).)

Artificial intelligence and machine learning are poised to disrupt PET imaging from bench to clinic. In this perspective, the authors offer insights into how the technology could be applied to improve the radiosynthesis of new radiopharmaceuticals for PET imaging, including identification of an optimal labeling approach as well as strategies for radiolabeling reaction optimization., Competing Interests: Disclosure The authors declare that they have no conflicts of interest relating to the subject matter of the present review., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Since the earliest days of nuclear medicine, there has been interest in using PET and SPECT imaging to interrogate and quantify the cholinergic system. In this Viewpoint we highlight key milestones in the development of cholinergic imaging agents, including identification of radiopharmaceuticals targeting the receptors, transporters, and enzymes of the cholinergic synapse, as well as fundamental developments in the radiopharmaceutical sciences (e.g., cyclotron targetry, radiochemistry) that have enabled translation of the most promising agents into clinical use. We also provide an overview of the current state-of-the-art in cholinergic PET imaging, with an emphasis on radiotracers that are in human studies at PET centers around the world.

A new method for the synthesis of the highly selective delta opioid receptor (DOR) antagonist radiotracer N 1 '-([ 11 C]methyl)naltrindole ([ 11 C]MeNTI) is described. The original synthesis required hydrogenation of a benzyl protecting group after 11 C-labeling, which is challenging in modern radiochemistry laboratories that tend to be heavily automated and operate according to current good manufacturing practice. To address this challenge, we describe development of a novel MeNTI precursor bearing a methoxymethyl acetal (MOM) protecting group, which is easily removed with HCl, and employ it in an updated synthesis of [ 11 C]MeNTI. The new synthesis is fully automated and validated for clinical use. The total synthesis time is 45 min and provides [ 11 C]MeNTI in good activity yield (49 ± 8 mCi), molar activity (3,926 ± 326 Ci/mmol) and radiochemical purity (97% ± 2%)., (© 2020 John Wiley & Sons, Ltd.)

When utilizing [ 18 F]tetrabutylammonium fluoride ([ 18 F]TBAF) in the synthesis of 18 F-labeled radiotracers for clinical positron emission tomography (PET) imaging, it is necessary to confirm that residual TBA levels in formulated doses do not exceed established specifications (≤2.6 mg per patient dose). Historically this has been accomplished using HPLC, but this is time consuming for short-lived PET radiotracers and limited by the need for expensive equipment. This motivated us to introduce a TLC spot test for determining residual TBA, and we have developed a new method which employs the Dragendorff reagent. Herein we report details of the TLC method and use it to quantify residual TBA in different formulations of 6-[ 18 F]fluoro-DOPA.

Advances in drug discovery and diverse radiochemical methodologies have led to the discovery of novel positron emission tomography (PET) radiotracers used to image the GABAergic system, shaping our fundamental understanding of a variety of brain health illnesses, including epilepsy, stroke, cerebral palsy, schizophrenia, autism, Alzheimer's disease, and addictions. In this Viewpoint, we review the state-of-the art of PET imaging with radiotracers that target the GABA A -benzodiazepine receptor complex, challenges and opportunities for imaging GABA B receptors and GABA transporters, and highlight an ongoing need to develop more sensitive radiotracers for imaging GABA release in the central nervous system.

To celebrate the 50th anniversary of the founding of the SNMMI Technologist Section in 1970, the Radiopharmaceutical Sciences Council board of directors is pleased to contribute to this celebratory supplement of the Journal of Nuclear Medicine Technology with a perspective highlighting major developments in the radiopharmaceutical sciences that have occurred in the last 50 years., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

A one-pot two-step synthesis of 6-[ 18 F]fluoro-l-DOPA ([ 18 F]FDOPA) has been developed involving Cu-mediated radiofluorination of a pinacol boronate ester precursor. The method is fully automated, provides [ 18 F]FDOPA in good activity yield (104 ± 16 mCi, 6 ± 1%), excellent radiochemical purity (>99%) and high molar activity (3799 ± 2087 Ci mmol -1 ), n = 3, and has been validated to produce the radiotracer for human use.

The tropomyosin receptor kinase TrkA/B/C family is responsible for human neuronal growth, survival, and differentiation from early nervous system development stages onward. Downregulation of TrkA/B/C receptors characterizes numerous neurological disorders including Alzheimer's disease (AD). Abnormally expressed Trk receptors or chimeric Trk fusion proteins are also well-characterized oncogenic drivers in a variety of neurogenic and non-neurogenic human neoplasms and are currently the focus of intensive clinical research. Previously, we have described the clinical translation of a highly selective and potent carbon-11-labeled pan-Trk radioligand and the preclinical characterization of the optimized fluorine-18-labeled analogue, [ 18 F]TRACK, for in vivo Trk positron emission tomography (PET) imaging. We describe herein central nervous system selectivity assessment and first-in-human study of [ 18 F]TRACK.

A simple technique for the preparation of [18F]HF has been developed and applied to the generation of an [18F]FeF species for opening sterically hindered epoxides. This method has been successfully employed to prepare four drug-like molecules, including 5-[18F]fluoro-6-hydroxy-cholesterol, a potential adrenal/endocrine PET imaging agent. This easily automated one-pot procedure produces sterically hindered fluorohydrin PET imaging agents in good yields and high molar activities.

In this Viewpoint, we highlight the history of positron emission tomography (PET) radiotracer development to quantify changes in monoamine oxidase (MAO)-A and -B enzyme expression or activity. MAO-A and MAO-B are critical for understanding monoaminergic pathways in psychiatric addiction disorders, and more recently in neurodegenerative disorders with MAO-B expression in astrogliosis. Unique radiochemical innovations have been shown for neuroimaging of MAOs including the clinical translation of irreversible propargylamine-based suicide inhibitors, application of deuterium-substitution to slow down metabolism, development of trapped metabolite imaging agents, and unique 11 C-carbonylation chemistry toward novel high-affinity reversibly binding inhibitors.

Visualizing the in vivo activity of monoamine oxidase B (MAO-B) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. Existing strategies for imaging changes in MAO enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (PET) ligands. As an alternative approach, we developed 4-methyl-7-[(1-[ 11 C]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 H-chromen-2-one ([ 11 C]Cou) as a metabolic trapping agent for MAO-B. Trapping of [ 11 C]Cou in rhesus monkey brain demonstrated MAO-B selectivity. In this work, we have attempted to improve on the in vivo pharmacokinetics of [ 11 C]Cou by using the deuterium kinetic isotope effect (KIE) to slow the MAO-B-mediated oxidation step and thus reduce the rate of trapping in brain tissues. However, in vitro assays of enzyme kinetics and in vivo PET imaging of pharmacokinetics in primate brain showed no effects of deuterium substitution on the tetrahydropyridine ring of [ 11 C]Cou. The results are possibly due to masking of the KIE by a second step in the overall metabolism of the new imaging agent.

In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[ 11 C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [ 18 F]fluoride was used to prepare the desired candidate radiotracer ( R, E/ Z)-1-(2-((4-fluoro-2-(4-[ 18 F]fluorobenzoyl)styryl)oxy)ethyl)piperidine-3-carboxylic acid (( R, E/ Z)-[ 18 F]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of ( R, E/ Z)-[ 18 F]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of ( R, E/ Z)-[ 18 F]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres.

In this paper, we describe the use of Cu-mediated [ 18 F]fluorodeboronation for the automated production of positron emission tomography radiotracers suitable for clinical use. Two recurrent issues with the method, low radiochemical conversion on automation and protoarene byproduct purification issues, have been successfully addressed. The new method was utilized to produce sterile injectable doses of [ 18 F]-(±)-IPMICF17, a positron emission tomography radiotracer for tropomyosin receptor kinase B/C, using an automated synthesis module. The product was isolated in 1.9 ± 0.1% isolated radiochemical yield, excellent radiochemical purity (>99%), and high specific activity (5294 ± 1227 Ci/mmol). Quality control testing confirmed that doses were suitable for clinical use., (Copyright © 2017 John Wiley & Sons, Ltd.)

Radiotracers, or radiopharmaceuticals, are bioactive molecules tagged with a radionuclide used for diagnostic imaging or radiotherapy and, when a positron-emitting radionuclide is chosen, the radiotracers are used for PET imaging. The development of novel PET radiotracers in many ways parallels the development of new pharmaceuticals, and small molecules dominate research and development pipelines in both disciplines. The 4 decades since the introduction of [ 18 F]FDG have seen the development of many small molecule PET radiotracers. Ten have been approved by the US Food and Drug Administration as of 2016, whereas hundreds more are being evaluated clinically. These radiotracers are being used in personalized medicine and to support drug discovery programs where they are greatly improving our understanding of and ability to treat diseases across many areas of medicine including neuroscience, cardiovascular medicine, and oncology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Radiolabeled peptides are a valuable class of radiotracer that occupies the space between small molecules and large biologics, and are able to exploit the advantages of both classes of compound. To date, radiolabeled peptides have mainly been utilized in oncology, where the same peptide can often be exploited for diagnostic imaging and targeted radiotherapy by simply varying the radionuclide. In this review, we introduce the main strategies used for synthesis of radiolabeled peptides, and highlight the state of the art for clinical imaging (and therapy) in oncology using the main classes of radiolabeled peptides that have been translated to date. Beyond oncology, radiolabeled peptides are also increasingly being used in other PET applications such as diabetes and cardiac imaging, and we review progress for the new applications., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [ 11 C]-(R)-3 ([ 11 C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [ 11 C]-(R)-3 readily crosses the blood-brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimer's disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [ 11 C]-(R)-3 in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human.

In a relatively short period of time, transition metal-mediated radiofluorination reactions have changed the PET radiochemistry landscape. These reactions have enabled the radiofluorination of a wide range of substrates, facilitating access to radiopharmaceuticals that were challenging to synthesize using traditional fluorine-18 radiochemistry. However, the process of adapting these new reactions for automated radiopharmaceutical production has revealed limitations in fitting them into the confines of traditional radiochemistry systems. In particular, the presence of bases (e.g. K 2 CO 3 ) and/or phase transfer catalysts (PTC) (e.g. kryptofix 2.2.2) associated with fluorine-18 preparation has been found to be detrimental to reaction yields. We hypothesized that these limitations could be addressed through the development of alternate techniques for preparing [ 18 F]fluoride. This approach also opens the possibility that an eluent can be individually tailored to meet the specific needs of a metal-catalyzed reaction of interest. In this communication, we demonstrate that various solutions of copper salts, bases, and ancillary ligands can be utilized to elute [ 18 F]fluoride from ion exchange cartridges. The new procedures are effective for fluorine-18 radiochemistry and, as proof of concept, have been used to optimize an otherwise base-sensitive copper-mediated radiofluorination reaction.

The receptor for advanced glycation endproducts (RAGE) is a 35 kDa transmembrane receptor that belongs to the immunoglobulin superfamily of cell surface molecules. Its role in Alzheimer's disease (AD) is complex, but it is thought to mediate influx of circulating amyloid-β into the brain as well as amplify Aβ-induced pathogenic responses. RAGE is therefore of considerable interest as both a diagnostic and a therapeutic target in AD. Herein we report the synthesis and preliminary preclinical evaluation of [(18)F]RAGER, the first small molecule PET radiotracer for RAGE (Kd = 15 nM). Docking studies proposed a likely binding interaction between RAGE and RAGER, [(18)F]RAGER autoradiography showed colocalization with RAGE identified by immunohistochemistry in AD brain samples, and [(18)F]RAGER microPET confirmed CNS penetration and increased uptake in areas of the brain known to express RAGE. This first generation radiotracer represents initial proof-of-concept and a promising first step toward quantifying CNS RAGE activity using PET. However, there were high levels of nonspecific [(18)F]RAGER binding in vitro, likely due to its high log P (experimental log P = 3.5), and rapid metabolism of [(18)F]RAGER in rat liver microsome studies. Therefore, development of second generation ligands with improved imaging properties would be advantageous prior to anticipated translation into clinical PET imaging studies.

The most commonly utilized PET radionuclide is fluorine-18 ((18)F) because of its convenient half-life and excellent imaging properties. In this review, we present the first analysis of patents issued for radiotracers labeled with fluorine-18 (between 2009 and 2015), and provide perspective on current trends and future directions in PET radiotracer development.

A copper-mediated radiofluorination of aryl- and vinylboronic acids with K(18)F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [(18)F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors.

Green strategies for late-stage fluorination with (18)F, in which ethanol and water are the only solvents used throughout the entire radiolabeling process (azeotropic drying, nucleophilic fluorination, purification and formulation), have been developed and applied to the radiosyntheses of a range of radiopharmaceuticals commonly employed in clinical PET imaging.

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

The principles of green chemistry have been applied to a radiochemistry setting. Eleven carbon-11 labeled radiopharmaceuticals have been prepared using ethanol as the only organic solvent throughout the entire manufacturing process. The removal of all other organic solvents from the process simplifies production and quality control (QC) testing, moving our PET Center towards the first example of a green radiochemistry laboratory. All radiopharmaceutical doses prepared are suitable for clinical use., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Positron (β(+)) emission tomography (PET) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiological structures and biochemical pathways. The continued growth of PET imaging relies on a corresponding increase in access to radiopharmaceuticals (biologically active molecules labeled with short-lived radionuclides such as fluorine-18). This unique need to incorporate the short-lived fluorine-18 atom (t1/2 = 109.77 min) as late in the synthetic pathway as possible has made development of methodologies that enable rapid and efficient late stage fluorination an area of research within its own right. In this review we describe strategies for radiolabeling with fluorine-18, including classical fluorine-18 radiochemistry and emerging techniques for late stage fluorination reactions, as well as labeling technologies such as microfluidics and solid-phase radiochemistry. The utility of fluorine-18 labeled radiopharmaceuticals is showcased through recent applications of PET imaging in the healthcare, personalized medicine and drug discovery settings.

(-)-[(18) F]Flubatine was selected for clinical imaging of α4 β2 nicotinic acetylcholine receptors because of its high affinity and appropriate kinetic profile. A fully automated synthesis of (-)-[(18) F]flubatine as a sterile isotonic solution suitable for clinical use is reported, as well as the first evaluation in nonhuman primates (rhesus macaques). (-)-[(18) F]Flubatine was prepared by fluorination of the Boc-protected trimethylammonium iodide precursor with [(18) F]fluoride in an automated synthesis module. Subsequent deprotection of the Boc group with 1-M HCl yielded (-)-[(18) F]flubatine, which was purified by semi-preparative HPLC. (-)-[(18) F]Flubatine was prepared in 25% radiochemical yield (formulated for clinical use at end of synthesis, n = 3), >95% radiochemical purity, and specific activity = 4647 Ci/mmol (171.9 GBq/µmol). Doses met all quality control criteria confirming their suitability for clinical use. Evaluation of (-)-[(18) F]flubatine in rhesus macaques was performed with a Concorde MicroPET P4 scanner (Concorde MicroSystems, Knoxville, TN). The brain was imaged for 90 min, and data were reconstructed using the 3-D maximum a posteriori algorithm. Image analysis revealed higher uptake and slower washout in the thalamus than those in other areas of the brain and peak uptake at 45 min. Injection of 2.5 µg/kg of nifene at 60 min initiated a slow washout of [(18) F]flubatine, with about 25% clearance from the thalamus by the end of imaging at 90 min., (Copyright © 2013 John Wiley & Sons, Ltd.)

In order to image the translocator protein (TSPO) 18kDa in the clinic using positron emission tomography (PET) imaging, we had a cause to prepare [(11)C]PBR28. In this communication we highlight our novel, recently developed, one-pot synthesis of the desmethyl-PBR28 precursor, as well as present an optimized fully automated preparation of [(11)C]PBR28 using a GE TRACERlab FX(C-Pro). Following radiolabelling, purification is achieved by HPLC and, to the best of our knowledge, the first reported example of reconstituting [(11)C]PBR28 into ethanolic saline using solid-phase extraction (SPE). This procedure is operationally simple, and provides high quality doses of [(11)C]PBR28 suitable for use in clinical PET imaging studies. Typical radiochemical yield using the optimized method is 3.6% yield (EOS, n=3), radiochemical and chemical purity are consistently >99%, and specific activities are 14,523Ci/mmol., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Radiolytic decomposition of high specific concentration radiopharmaceuticals is an undesired side-effect that can hamper development of novel PET tracers. This was particularly evident in a series of carbon-11 and fluorine-18 labeled mono- and dimethyl-substituted aryl amines, where rapid decomposition was observed in isolation and formulation steps. We tested a number of additives that inhibit radiolysis and can be safely added to the synthesis procedures (purification and isolation) and reformulation steps to provide suitable clinical formulations. Ethanol and sodium ascorbate are established anti-oxidant stabilizers that completely inhibit radiolytic decomposition and are amenable to human use. Herein, we also demonstrate for the first time that nitrones are non-toxic radical scavengers that are capable of inhibiting radiolysis.

4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (Kryptofix 2.2.2) is used in the routine preparation of [18F]-labeled tracers employed in positron emission tomography (PET) imaging. Confirming the absence of Kryptofix in radiopharmaceuticals is a quality control criterion required before they can be released for human use. Analysis of Kryptofix levels using the iodoplatinate spot-test can be complicated by false-positive results due to nitrogen containing tracers and/or false-negative results caused by added stabilizers. To overcome this issue, we have developed a universal TLC method for the rapid and reliable determination of Kryptofix levels in the wide range of fluorine-18 radiopharmaceuticals we prepare, including complex multi-component formulations.

The International Atomic Energy Agency (IAEA) held the 3rd International Symposium on Trends in Radiopharmaceuticals, (ISTR-2023) at IAEA Headquarters in Vienna, Austria, during the week of 16–21 April 2023. This procedural paper summarizes highlights from symposium presentations, posters, panel discussions and satellite meetings, and provides additional resources that may be useful to researchers working with diagnostic and therapeutic radiopharmaceuticals in the academic, government and industry setting amongst IAEA Member States and beyond. More than 550 participants in person from 88 Member States attended the ISTR-2023. Over 360 abstracts were presented from all over the world by a diverse group of global scientists working with radiopharmaceuticals. Given this group of international radiochemists is unique to ISTR (IAEA funding enabled many to attend), there was an invaluable wealth of knowledge on the global state of the radiopharmaceutical sciences present at the meeting. The intent of this Proceedings paper is to share this snapshot from our international colleagues with the broader radiopharmaceutical sciences community by highlighting presentations from the conference on the following topics: Isotope Production and Radiochemistry, Industrial Insights, Regional Trends, Training and Education, Women in the Radiopharmaceutical Sciences, and Future Perspectives and New Initiatives. The authors of this paper are employees of IAEA, members of the ISTR-2023 Organizing Committee and/or members of the EJNMMI Radiopharmacy and Chemistry Editorial Board who attended ISTR-2023. Overall, ISTR-2023 fostered the successful exchange of scientific ideas around every aspect of the radiopharmaceutical sciences. It was well attended by a diverse mix of radiopharmaceutical scientists from all over the world, and the oral and poster presentations provided a valuable update on the current state-of-the-art of the field amongst IAEA Member States. Presentations as well as networking amongst the attendees resulted in extensive knowledge transfer amongst the various stakeholders representing 88 IAEA Member States. This was considered particularly valuable for attendees from Member States where nuclear medicine and the radiopharmaceutical sciences are still relatively new. Since the goal is for the symposium series to be held every four years; the next one is anticipated to take place in 2027. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field, and include new PET-labelling methods for 11C and 18F, the importance of choosing the proper chelator for a given radioactive metal ion, implications of total body PET on use of radiopharmaceuticals, legislation issues and radionuclide therapy including the emerging role of 161Tb. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry. [ABSTRACT FROM AUTHOR]

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field. Results: This commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry. [ABSTRACT FROM AUTHOR]

In this paper, we describe the use of Cu‐mediated [18F]fluorodeboronation for the automated production of positron emission tomography radiotracers suitable for clinical use. Two recurrent issues with the method, low radiochemical conversion on automation and protoarene byproduct purification issues, have been successfully addressed. The new method was utilized to produce sterile injectable doses of [18F]‐(±)‐IPMICF17, a positron emission tomography radiotracer for tropomyosin receptor kinase B/C, using an automated synthesis module. The product was isolated in 1.9 ± 0.1% isolated radiochemical yield, excellent radiochemical purity (>99%), and high specific activity (5294 ± 1227 Ci/mmol). Quality control testing confirmed that doses were suitable for clinical use. [ABSTRACT FROM AUTHOR]