Phosphodiesterases (PDEs) are phosphohydrolytic enzymes responsible for degrading cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), two key second messengers involved in regulating cellular functions. The PDE superfamily can be subdivided into 11 families, with PDE7 playing a crucial role in the proinflammatory process, T-cell activation and proliferation. As such, PDE7 has emerged as a potential therapeutic target for treating inflammatory, immunological, and neurological disorders. To date, only a limited number of PDE7 PET ligands have been reported. These ligands often suffer from low in vivo stability or moderate binding affinity, underscoring the need for highly specific PET radioligands for imaging PDE7 in vivo. Here, we report the development of [18F]7 ([18F]P7-2302)-a highly potent (IC50 = 0.18 nM) and selective (>400 folds over other PDEs) PDE7 PET ligand. In vitro autoradiography studies using rat brain sections revealed high PDE7-specific binding for [18F]7. Notwithstanding these encouraging findings, PET imaging experiments in rats demonstrated low brain uptake of [18F]7, potentially owing to brain efflux mechanism. Indeed, in vivo studies with combined P-gp and BCRP inhibition substantially improved brain uptake and enabled us to demonstrate in vivo binding specificity of [18F]7 with PDE7-targeted blockade. Overall, [18F]7 ([18F]P7-2302) exhibits promising pharmacological properties and chemical scaffold which holds potential as a PDE7-specific PET radioligand, though further work is required to enhance blood-brain barrier permeability.

Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC50 = 18.6 nM and (S)-6, IC50 = 1.6 nM). In vitro autoradiography studies of [18F](R)-6 (codenamed [18F]MAGL-2304) and [18F](S)-6 (codenamed [18F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [18F](S)-6. Dynamic PET imaging studies revealed that [18F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [18F](S)-6 uptake in the brain, suggesting that [18F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.

Phosphodiesterase 4B (PDE4B) plays a critical role in cAMP hydrolysis and is highly expressed in brain regions associated with neuroinflammation and central nervous system (CNS) disorders. Selective PDE4B radioligands hold significant potential for elucidating disease mechanisms, such as those in Parkinson's disease and schizophrenia, and enabling target occupancy measurements. In this study, we developed [ 18 F]P4B-2412, a novel PDE4B-selective radioligand, and evaluated its utility for positron emission tomography imaging (PET). [ 18 F]P4B-2412 was synthesized in high radiochemical yield (27.2%), excellent radiochemical purity (99%), and favorable molar activity (66.2 ± 2.5 GBq/μmol. In vitro autoradiography and dynamic PET imaging demonstrated high specificity for PDE4B in rodent brain regions, with blocking studies confirming negligible interaction with PDE4D. [ 18 F]P4B-2412 also exhibited robust in vitro and in vivo metabolic stability. These results establish [ 18 F]P4B-2412 as a promising PET imaging agent for visualizing PDE4B activity, offering a valuable tool for investigating neuroinflammation and advancing CNS drug development.

Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 holds potential therapeutic benefits for various pathologies. Despite the current FDA approval of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) ligand is crucial for disease biology and target occupancy studies, aiding the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its 18F-isotopologue ([18F]5). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographical, and in vivo PET imaging in non-human primates, demonstrates the capacity of [18F]5 for specific binding to PARP1 and successful penetration of the BBB. These findings position [18F]5 as a viable molecular imaging tool, poised to facilitate the exploration of physiopathological changes of PARP1 across various diseases.

Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase family that regulates diverse biological processes including glucose metabolism, insulin activity and energy homeostasis. Dysregulation of GSK3 is implicated in the development of several diseases such as type 2 diabetes mellitus, Alzheimer's disease (AD), and various cancer types. In this study, we report the synthesis and evaluation of a novel positron emission tomography (PET) ligand compound 28 (codenamed [18F]GSK3-2209). The PET ligand [18F]28 was obtained via copper-mediated radiofluorination in more than 32% radiochemical yields, with high radiochemical purity and high molar activity. In vitro autoradiography studies in rodents demonstrated that this tracer exhibited a high specific binding to GSK3. Furthermore, PET imaging studies of [18F]28 revealed its ability to penetrate the blood-brain barrier (BBB).

Phosphodiesterases (PDEs) constitute a superfamily of phosphohydrolytic enzymes that regulate intracellular second messenger signaling by hydrolyzing cyclic adenosine monophosphate and cyclic guanosine monophosphate. Among the 11 subfamilies of PDEs, phosphodiesterase 1 (PDE1) stands out due to its broad implications in central and peripheral pathologies. There are three subtypes of PDE1: PDE1A, PDE1B, and PDE1C. While PDE1A and PDE1C are distributed in both the brain and peripheral organs, PDE1B is predominantly expressed in the brain, rendering it an attractive drug target for neurological and psychological disorders. Despite continuous efforts dedicated to the development of novel PDE1 inhibitors, a suitable PDE1 radioligand for human use is currently lacking. In this study, we present the identification and preclinical evaluation of [C-11]PF-04822163, a selective radioligand candidate for imaging PDE1 with positron emission tomography. PF-04822163 exhibits excellent potency toward PDE1 and demonstrates great target selectivity over other PDEs. Then, PF-04822163 was labeled with carbon-11 (half-life, 20 min) in favorable radiochemical yields (25 +/- 10%, decay-corrected) and high molar activities (106-194 GBq/mu mol). Further, in vitro and in vivo evaluations in rodents suggested that [C-11]PF-04822163 displayed good brain penetration and a rapid washout. Despite these promising performance characteristics of [C-11]PF-04822163, only marginal specific binding was observed in vivo. Further optimization of the scaffold is warranted to obtain favorable pharmacological and ADME properties.

Metabotropic glutamate receptor 7 (mGlu7) is a G protein-coupled receptor that is preferentially found in the active zone of neurotransmitter release in the central nervous system (CNS). mGlu7 plays a vital role in memory, learning, and neuronal development, rendering it a potential target for treating epilepsy, depression, and anxiety. The development of noninvasive imaging ligands targeting mGlu7 could help elucidate the functional significance of mGlu7 and accelerate drug discovery for neurological and psychiatric disorders. In this report, a novel carbon-11 labeled positron emission tomography (PET) tracer designated [11C]18 (codenamed MG7-2109) was synthesized via 11C-methylation in 23% decay-corrected radiochemical yield (RCY). In vitro serum stability, serum protein binding, in vitro autoradiography and ex vivo biodistribution studies of [11C]18 were conducted. Preliminary PET imaging results revealed a homogeneous distribution of [11C]18 and rapid clearance in rodent brains. This study provides valuable insights into the development of mGlu7-targeted PET tracer based on an isoxazolo(5,4-c)pyridine scaffold.

The histamine subtype 3 (H3) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H3 receptor. In this study, we synthesized and evaluated the binding effects of [18F]H3-2404 and [18F]H3-2405 by modifying the structure of AZD5213, a selective H3 antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [18F]H3-2404 and [18F]H3-2405 are unsuitable as PET tracers for brain imaging of the H3 receptor, this study provides a valuable attempt for optimizing 18F labeled radiotracers based on AZD5213.

The synthesis of a promising brain imaging agent 4-[F-18]fluoro-4-deoxy-N-acetyl-1,3,6-tri-O-acetylglucosamine, 2, was successfully accomplished from commercially available N-acetyl glucosamine in 5 steps. The non-decay corrected radiochemical yield and purity were found to be 31% ± 4% (n = 3) and >98% respectively. The total reaction time for radio labelling step was 50 min.

As a subclass of ionotropic glutamate receptors (iGluRs), α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in various neurological disorders and neurodegenerative diseases. To further our understanding of AMPA receptor-related disorders in the central nervous system (CNS), it is important to be able to image and quantify AMPA receptors in vivo. In this study, we identified a novel F-containing AMPA positive allosteric modulator (PAM) 6 as a potential lead compound. Molecular docking studies and CNS PET multi-parameter optimization (MPO) analysis were used to predict the absorption, distribution, metabolism, and excretion (ADME) characteristics of 6 as a PET probe. The resulting PET probe, [18F]6 (codename [18F]AMPA-2109), was successfully radiolabeled and demonstrated excellent blood-brain barrier (BBB) permeability and high brain uptake in rodents and non-human primates. However, [18F]6 did not show substantial specific binding in the rodent or non-human primate brain. Further medicinal chemistry efforts are necessary to improve specific binding, and our work may serve as a starting point for the design of novel 18F-labeled AMPA receptor-targeted PET radioligands aimed for clinical translation.

AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP gamma-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable in vivo visualization of TARP gamma-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel (18) F-labeled TARP gamma-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [(18) F]TARP-2204 and [(18) F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity. In vitro autoradiography demonstrates high level of specific binding of [(18) F]TARP-2205 to TARP gamma-8 in both rat and nonhuman primate brain tissues. However, unexpected radiodefluorination in PET imaging studies of rodents emphasizes the need for further structural refinement. This work serves as an excellent starting point for the development of future (18) F-labeled TARP gamma-8 PET tracers, offering valuable insights into medicinal chemistry design, radiosynthesis and subsequent PET evaluation.

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds 1 (K i = 3.6 nM) and 2 (K i = 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [11C]1 and [11C]2. PET imaging in rat brains indicated that the low brain uptake of [11C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.

Cholinergic receptors represent a promising class of diagnostic and therapeutic targets due to their significant involvement in cognitive decline associated with neurological disorders and neurodegenerative diseases as well as cardiovascular impairment. Positron emission tomography (PET) is a noninvasive molecular imaging tool that has helped to shed light on the roles these receptors play in disease development and their diverse functions throughout the central nervous system (CNS). In recent years, there has been a notable advancement in the development of PET probes targeting cholinergic receptors. The purpose of this review is to provide a comprehensive overview of the recent progress in the development of these PET probes for cholinergic receptors with a specific focus on ligand structure, radiochemistry, and pharmacology as well as in vivo performance and applications in neuroimaging. The review covers the structural design, pharmacological properties, radiosynthesis approaches, and preclinical and clinical evaluations of current state-of-the-art PET probes for cholinergic receptors.

The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this regard, much work remains to address this ongoing crisis effectively. Favipiravir is an antiviral drug initially developed for the treatment of influenza and has received approval for emergency use for COVID-19 in many countries. A better understanding of the biodistribution and pharmacokinetics of Favipiravir in vivo would facilitate the development and translation of clinical antiviral drugs for COVID-19. Herein, we report the evaluation of [18F]Favipiravir in naive mice, transgenic mice models of Alzheimer’s disease, and nonhuman primates (NHP) with positron emission tomography (PET). The [18F]Favipiravir was obtained in an overall decay-corrected radiochemical yield of 29% with a molar activity of 25 GBq/µmol at the end of synthesis (EOS). PET imaging in naive mice, transgenic mice models of Alzheimer’s disease, and nonhuman primates revealed a low initial brain uptake, followed by a slow washout of [18F]Favipiravir in vivo. The [18F]Favipiravir was eliminated by a combination of hepatobiliary and urinary excretion. The low brain uptake was probably attributed to the low lipophilicity and low passive permeability of the drug. We hope this proof-of-concept study will provide a unique feature to study antiviral drugs using their corresponding isotopologues by PET.