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Imaging of cholesterol use is possible with the

This report describes a method for the nucleophilic radiofluorination of (hetero)aryl chlorides, (hetero)aryl triflates, and nitroarenes using a combination of [(18)F]KF•K(2.2.2) and Me(4)N HCO(3) for the in situ formation of a strongly nucleophilic fluorinating reagent (proposed to be [(18)F]Me(4)NF). This method is applied to 24 substrates bearing diverse functional groups, and it generates [(18)F](hetero)aryl fluoride products in good to excellent radiochemical yields in the presence of ambient air/moisture. The reaction is applied to the preparation of (18)F-labeled HQ-415 for potential (pre)clinical use.

Imaging of misfolded proteins implicated in neurodegenerative disorders using positron emission tomography (PET) imaging has revolutionized dementia research. In this viewpoint, the development of radiotracers for tau PET is highlighted. We draw attention to key innovations that were essential to development of radiotracers for imaging tau, from early imaging agents, through the structure-activity relationship (SAR) studies required to minimize off-target binding of the newer probes in use today. We also highlight development of Tauvid, the first tau PET radiotracer approved by the US FDA for tau imaging in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease.

This article describes a sequential Ir/Cu-mediated process for the meta-selective C-H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp2)-H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [18F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a benchtop without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FXFN module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (Am), respectively.

Melatonin is a neurohormone that modulates several physiological functions in mammals through the activation of melatonin receptor type 1 and 2 (MT

A new method for the synthesis of the highly selective delta opioid receptor (DOR) antagonist radiotracer N1 '-([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%).

Radiolabeled guanidines such as meta-iodobenzylguanidine (MIBG) find utility in nuclear medicine as both diagnostic imaging agents and radiotherapeutics and, over the years, numerous methods for incorporating radionuclides into guanidines have been developed. In connection with a project developing new positron emission tomography (PET) radiotracers for cardiac sympathetic nerve density, we had cause to prepare [11C]3F-PHPOG. However, it quickly became apparent that radiolabeling of guanidine scaffolds with carbon-11 has remained challenging, and historical methods lack compatibility with modern automated radiochemistry synthesis platforms and current Good Manufacturing Practice (cGMP) requirements. To address this challenge, we report a new automated method for radiolabeling guanidines with carbon-11. The method was used to prepare a series of [11C]guanidines in good radiochemical yield (8-76% by radio-HPLC) and was found to have broad substrate scope and tolerance of unprotected OH and NH functional groups. The method was used to synthesize [11C]3F-PHPOG for preclinical imaging, and suitability of the radiotracer for preclinical use was demonstrated through preliminary cardiac PET in New Zealand white rabbits which revealed good cardiac uptake and expected retention in the heart.

The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([18F]InRAGER) and extracellular ([18F]RAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radiotracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration., Graphical abstract Image 1, Highlights • The implication of RAGE in numerous diseases make it a therapeutic target and an imaging biomarker. • [18F]RAGER and [18F]InRAGER are potential radiotracers for positron emission tomography (PET) imaging of RAGE. • Both radiotracers show good brain uptake but suffer from off target binding. • New radiotracers with more druglike properties and better selectivity for RAGE are needed.

PURPOSE: Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C-(18)F bonds. This minireview examines proof-of-concept, pre-clinical, and in-human imaging studies of new and established imaging agents containing aromatic C-(18)F bonds synthesized with CMRF. An exhaustive discussion of CMRF methods is not provided, although key developments that have enabled or improved upon the syntheses of fluorine-18 imaging agents are discussed. METHODS: A comprehensive literature search from April 2014 onwards of the Web of Science and PubMed library databases was performed to find reports that utilize CMRF for the synthesis of fluorine-18 radiopharmaceuticals, and these represent the primary body of research discussed in this minireview. Select conference proceedings, previous reports describing alternative methods for the synthesis of imaging agents, and preceding fluorine-19 methodologies have also been included for discussion. CONCLUSIONS: CMRF has significantly expanded the chemical space that is accessible to fluorine-18 radiolabeling with production methods that can meet the regulatory requirements for use in Nuclear Medicine. Furthermore, it has enabled novel and improved syntheses of radiopharmaceuticals and facilitated subsequent PET imaging studies. The rapid adoption of CMRF will undoubtedly continue to simplify the production of imaging agents and inspire the development of new radiofluorination methodologies.

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.

[(18)F]-labeled aryl fluorides are widely used as radiotracers for positron emission tomography (PET) imaging. Aryl halides (ArX) are particularly attractive precursors to these radiotracers, as they are readily available, inexpensive, and stable. However, to date, the direct preparation of [(18)F]-aryl fluorides from aryl halides remains limited to S(N)Ar reactions between highly activated ArX substrates and K(18)F. This report describes an aryl halide radiofluorination reaction in which the C(sp(2))–(18)F bond is formed via a copper-mediated pathway. Copper N-heterocyclic carbene complexes serve as mediators for this transformation, using aryl halide substrates with directing groups at the ortho position. This reaction is applied to the radiofluorination of electronically diverse aryl halide derivatives, including the bioactive molecules vismodegib and PH-089.

Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/μmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 μg (range, 0.16-8.27 μg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.

When utilizing [18F]tetrabutylammonium fluoride ([18F]TBAF) in the synthesis of 18F-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-[18F]fluoro-DOPA.

Mitochondrial complex I (MC-I) is an essential component of brain bioenergetics and can be quantified and studied using positron emission tomography (PET). A specific high affinity

Radiochemical conversion is an important term to be included in the "Consensus nomenclature rules for radiopharmaceutical chemistry". Radiochemical conversion should be used to define reaction efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation. (C) 2020 Elsevier Inc. All rights reserved.

Funder: Herchel Smith Fellowship programme, 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)-[11C]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 [18F]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)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]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)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]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)-[18F]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)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation.

This communication reports a method for the vinylogous radiofluorination of α-diazoacetates to generate [18F]-γ-fluoro-α,β-unsaturated esters and ketones in moderate to good radiochemical yields. The method uses no-carrier-added [18F]AgF and is compatible with aromatic and non-aromatic substrates and a number of different functional groups. The labeling method is showcased in the synthesis of a fluorinated cholest-5-en-3-one derivative as well as a difluorinated product pertinent to drug discovery.

For 45 years, efforts to prepare a fluorinated analogue of the scintiscanning/SPECT agent 6-(iodomethyl)-19-norcholest-5(10)-en-3-ol (NP-59) for development of a PET imaging agent have failed due to undesired elimination reactions and unexpected rearrangements observed­ while utilizing a wide variety of fluorinating conditions (e.g., cesium­ fluoride, silver fluoride, (2-chloro-1,1,2-trifluoroethyl)diethylamine (FAR), diethylaminosulfur trifluoride (DAST), and hexa­fluoro­propene diethylamine FPA). Herein, we report the full synthesis of NP-59, followed by the four-step synthesis of 6-(fluoromethyl)-19-norcholest-5(10)-en-3-ol (FNP-59) using a recently developed mild fluorinating reagent, less prone to producing elimination reactions in the preparation of primary fluorides, TBAF(pinacol)2, with an overall yield of 16% (four steps). Also included is an evaluation of the TBAF(pinacol)2 reagent on eight test substrates to investigate its scope.

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 11C-carbonylation chemistry toward novel high-affinity reversibly binding inhibitors.

A Cu-mediated ortho-C-H radiofluorination of aromatic carboxylic acids that are protected as 8-aminoquinoline benzamides is described. The method uses K18 F and is compatible with a wide range of functional groups. The reaction is showcased in the high specific activity automated synthesis of the RARβ2 agonist [18 F]AC261066.

This report describes a Pd-mediated C–H radiofluorination of 8-methylquinoline derivatives with no-carrier-added Ag[18F]F. To achieve this transformation, a new method was developed for the generation of Ag[18F]F using a sep-pak cartridge. The C–H radiofluorination was then optimized and applied to a series of substituted 8-methylquinoline derivatives. Finally, this method was fully automated using a radiochemistry synthesis module.

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.

This Article describes a sequential Ir/Cu-mediated process for the meta-selective C─H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp(2))─H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [(18)F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a bench-top without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FX(FN) module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [(18)F]1-fluoro-3,5-dimethoxybenzene and an (18)F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (A(m)), respectively.

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)-[11C]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 [18F]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)-[18F]GE387 and (R)-[18F]GE387. The specific binding of (S)-[18F]GE387 to TSPO was investigated by pre-treatment with (R)-PK11195. (S)-[18F]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)-[18F]GE387 and (R)-[18F]GE387 entered the brain in both rats and rhesus macaques. (R)-PK11195 blocked the uptake of (S)-[18F]GE387 in healthy olfactory bulb and peripheral tissues constitutively expressing TSPO. A 2.7-fold higher uptake of (S)-[18F]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)-[18F]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)-[18F]GE387 warrants further evaluation with studies on human subjects to assess its suitability as a TSPO PET radioligand for assessing neuroinflammation. Supplementary Information The online version contains supplementary material available at 10.1007/s00259-021-05495-w.

A new method for the synthesis of the highly selective delta opioid receptor (DOR) antagonist radiotracer N

When utilizing [

[Image: see text] Radiolabeled guanidines such as meta-iodobenzylguanidine (MIBG) find utility in nuclear medicine as both diagnostic imaging agents and radiotherapeutics and, over the years, numerous methods for incorporating radionuclides into guanidines have been developed. In connection with a project developing new positron emission tomography (PET) radiotracers for cardiac sympathetic nerve density, we had cause to prepare [(11)C]3F-PHPOG. However, it quickly became apparent that radiolabeling of guanidine scaffolds with carbon-11 has remained challenging, and historical methods lack compatibility with modern automated radiochemistry synthesis platforms and current Good Manufacturing Practice (cGMP) requirements. To address this challenge, we report a new automated method for radiolabeling guanidines with carbon-11. The method was used to prepare a series of [(11)C]guanidines in good radiochemical yield (8–76% by radio-HPLC) and was found to have broad substrate scope and tolerance of unprotected OH and NH functional groups. The method was used to synthesize [(11)C]3F-PHPOG for preclinical imaging, and suitability of the radiotracer for preclinical use was demonstrated through preliminary cardiac PET in New Zealand white rabbits which revealed good cardiac uptake and expected retention in the heart.

[Image: see text] The radiotracers [(11)C]COU and [(11)C]PHXY are potential PET imaging agents for in vivo studies of monoamine oxidases (MAOs), as previously shown in rodent and primate brain. One-pot, automated methods for the radiosynthesis of [(11)C]PHXY and [(11)C]COU were developed to provide reliable and improved radiochemical yields. Although derived from the structure of the neurotoxin MPTP, COU did not exhibit in vivo neurotoxicity to dopaminergic nerve terminals in the mouse brain as assayed by losses of VMAT2 radioligand binding. PET imaging studies in rats demonstrated that both [(11)C]COU and [(11)C]PHXY exhibit retention in cardiac tissues that can be blocked by pretreatment with the MAO inhibitors deprenyl (MAO-B) and pargyline (MAO-A and -B). In addition to prior neuroimaging applications, [(11)C]COU and [(11)C]PHXY are thus also of interest for studies of MAO enzymatic activity and imaging of sympathetic nerve density in heart.

This communication reports a method for the vinylogous radiofluorination of α-diazoacetates to generate γ-[(18)F]fluoro-α,β-unsaturated esters and ketones in moderate to good radiochemical yields. The method uses no-carrier-added [(18)F]AgF and is compatible with aromatic and non-aromatic substrates and a number of different functional groups. The labeling method is showcased in the synthesis of a fluorinated 5-cholesten-3-one derivative as well as a difluorinated product pertinent to drug discovery.

Advances in drug discovery and diverse radiochemical methodologies have led the discovery of novel positron emission tomography (PET) radiotracers to image the GABAergic system, and have been used to shape 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.

[Image: see text] PD-132301, an inhibitor of sterol O-acyltransferase 1 (SOAT1; also known as acyl-coenzyme A:cholesterol acyltransferase-1, ACAT1), is under clinical investigation for numerous adrenal disorders. Radiolabeled SOAT1 inhibitors could support drug discovery and help diagnose SOAT1-related disorders, such as atherosclerosis. We synthesized two radiolabeled SOAT1 inhibitors, [(11)C]PD-132301 and fluorine analogue [(18)F]1. Rat biodistribution studies were conducted with both agents and, as the most selective tracer, [(11)C]PD-132301 was advanced to preclinical positron emission tomography studies in (atherosclerotic) ApoE(–/–) mice. The uptake of [(11)C]PD-132301 in SOAT1-rich tissue warrants further investigation into the compound as an atherosclerosis and adrenal imaging agent.

This report describes a Pd-mediated C-H radiofluorination of 8-methylquinoline derivatives with no-carrier-added Ag[(18)F]F. To achieve this transformation, a new method was developed for the generation of Ag[(18)F]F using a sep-pak cartridge. The C–H radiofluorination was then optimized and applied to a series of substituted 8-methylquinoline derivatives. Finally, this method was fully automated using a radiochemistry synthesis module.

Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer’s disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [(18)F]N-methyl lansoprazole ([(18)F]NML). Herein we report validation of the synthesis of [(18)F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers, and confirmed that it can be readily implemented at multiple production facilities to provide [(18)F]NML in good non-corrected radiochemical yield (3.4 ± 1.5 GBq, 4.6 ± 2.6%) and molar activity (120.1 ± 186.3 GBq/μmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [(18)F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [(18)F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mild cognitively impaired (MCI) / AD patients (n = 6) received [(18)F]NML (tau), [(18)F]AV1451 (tau) and [(18)F]florbetaben or [(18)F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [(18)F]NML and [(18)F]AV1451 PET scans. [(18)F]NML showed good brain uptake, reasonable pharmacokinetics and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [(18)F/(19)F]NML was 2.01 ± 2.17 μg (range, 0.16 – 8.27 μg) and the mean administered activity was 350 ± 62 MBq (range, 199 – 403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [(18)F]NML as a tau PET imaging agent is not warranted at this time.