Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation

doi:10.1016/j.nucmedbio.2009.12.012

Nuclear Medicine and Biology

Volume 37, Issue 4, May 2010, Pages 509-516

https://doi.org/10.1016/j.nucmedbio.2009.12.012 Get rights and content

Abstract

Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, a specific inhibitor of phosphodiesterase (PDE) 10A with IC₅₀ values of 36 nM for PDE10A, 1,300 nM for PDE3A and 320 nM for PDE4D, has served as a useful pharmaceutical tool to study the physiological role of PDE10A. Here, we report the radiosynthesis of [¹¹C]papaverine and the in vitro and in vivo evaluation of [¹¹C]papaverine as a potential positron emission tomography (PET) radiotracer for imaging PDE10A in the central nervous system (CNS). The radiosynthesis of papaverine with ¹¹C was achieved by O-methylation of the corresponding des-methyl precursor with [¹¹C]methyl iodide. [¹¹C]papaverine was obtained with ∼70% radiochemical yield and a specific activity >10 Ci/μmol. In vitro autoradiography studies of rat and monkey brain sections revealed selective binding of [¹¹C]papaverine to PDE10A enriched regions: the striatum of rat brain and the caudate and putamen of rhesus monkey brain. The biodistribution of [¹¹C]papaverine in rats at 5 min demonstrated an initially higher accumulation in striatum than in other brain regions, however the washout was rapid. MicroPET imaging studies in rhesus macaques similarly displayed initial specific uptake in the striatum with very rapid clearance of [¹¹C]papaverine from brain. Our initial evaluation suggests that despite papaverine's utility for in vitro studies and as a pharmaceutical tool, [¹¹C]papaverine is not an ideal radioligand for clinical imaging of PDE10A in the CNS. Analogs of papaverine having a higher potency for inhibiting PDE10A and improved pharmacokinetic properties will be necessary for imaging this enzyme with PET.

Introduction

Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates. cAMP and cGMP function as intracellular second messengers regulating many intracellular processes particularly in neurons of the central nervous system (CNS). A major mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 11 known families of phosphodiesterases encoded by 21 different genes [1], [2], [3]. PDE10A is a dual specificity phosphodiesterase that can convert both cAMP to adenosine monophosphate (AMP) and cGMP to guanosine monophosphate; PDE10A is uniquely localized in mammals relative to other PDE families. PDE10A mRNA is reported to be highly expressed in the brain, particularly in striatal medial spinal neurons, with variable expression seen in the testes [1], [4]. In human brain, high expression of PDE10A was found in caudate nucleus and putamen of striatum. In other mammalian species PDE10A is enriched in the striatal complex including caudate nucleus, nucleus accumbens and olfactory tubercle [3], [5], [6], [7]. Outside the brain, PDE10A distribution is limited to a few kinds of tissue, such as the testis, epididymal sperm and enteric ganglia. PDE10A is primarily membrane-bound and it is most often associated with membranes in dendrites and spines of medium spiny neurons, which suggests that PDE10A enables the regulation of intracellular signaling from glutamatergic and dopaminergic input to these neurons [3].

Papaverine was identified as a specific inhibitor of PDE10A with an IC₅₀ value of 36 nM for PDE10A and IC₅₀ values of 1,300 nM for PDE3A and 320 nM for PDE4D [8]. Papaverine proved to be a useful pharmacological tool for investigations of the behavioral effects of PDE10A enzyme inhibition in rodents. Systemic administration of papaverine to genetically modified mice demonstrated inhibition of PDE10A activity and resulted in increased activation of the medial spinal neurons that led to suppression of behavioral responsiveness. The inhibition of PDE10A with papaverine increased the effectiveness of haloperidol-induced catalepsy in rats and inhibited conditioned avoidance responding in mice [8], [9]. Papaverine also inhibits the locomotor hyperactivity induced by stimulants [6]. Furthermore, papaverine displayed anti-schizophrenic activity and anti-psychotic activity in different animal models of neurological disorders [8]. As an inhibitor of PDE10A, papaverine not only helped define the physiological role of PDE10A, but it also provided evidence to support the hypothesis that the inhibition of PDE10A mediated cyclic nucleotide hydrolysis might be an effective new approach for the treatment of schizophrenia and other disorders of basal ganglia function.

Positron emission tomography (PET) imaging with appropriate tracers is a highly sensitive non-invasive imaging modality that can measure the densities of neuronal receptors in CNS and thus provide neurological information regarding molecular and cellular function in living subjects. Up to now, no suitable PET tracer for imaging PDE10A enzyme activity has been reported, thus the measurement of PDE10A activity is currently limited to the use of ex vivo immunohistochemistry techniques in tissue. Although radioactive [³H]papaverine [10] and [¹⁴C]papaverine [11] have been made for pharmacologic studies, the radiosynthesis of [¹¹C]papaverine and the evaluation of [¹¹C]papaverine as a PET tracer for imaging PDE10A have not yet been reported. Here, we report the radiosynthesis of [¹¹C]papaverine and the initial in vitro and in vivo evaluation of [¹¹C]papaverine as a PET tracer for imaging PDE10A. Papaverine possesses four O-methyl groups that can be readily labeled with carbon-11 via O-alkylation of the des-methyl precursors. We chose 1-(4-(benzyloxy)-3-methoxybenzyl)-6,7-dimethoxyisoquinoline, 4, as precursor for radiosynthesis of [¹¹C]papaverine, which is based on this position is easy to be metabolized. Metabolic demethylation from this labeling position will result that the metabolite lose the radioactivity carbon-11, which can avoid the formation of radiolabeled metabolites that might cross the blood brain barrier and interrupt measurement of [¹¹C]papaverine in the brain. In this paper, we report the synthesis of precursor 4 and the radiolabeling conditions used to prepare [¹¹C]papaverine via O-alkylation of 4 with [¹¹C]methyl iodide. In vitro autoradiographic studies on both rat and macaque brain sections were conducted with [¹¹C]papaverine; the biodistribution and regional brain uptake studies of [¹¹C]papaverine was evaluated in mature male Sprague–Dawley rats. MicroPET brain imaging was carried out using male rhesus macaques. The metabolite studies were performed on rat blood and rat brain post injection of [¹¹C]papaverine. The results of these studies indicated that although [¹¹C]papaverine binds to PDE10A-rich regions of the brain in vitro, the rapid washout of the tracer limits its utility as PET radiopharmaceutical for in vivo measurements of PDE10A.

Section snippets

General

All analytical grade chemicals and reagents were purchased from Sigma-Aldrich (Milwaukee, WI, USA) and were used without further purification unless otherwise stated. Flash column chromatography was conducted using Scientific Adsorbents, Inc. silica gel, 60a, “40 Micron Flash” (32–63 μm). ¹H NMR spectra were recorded at 300 MHz on a Varian Mercury-VX spectrometer. All chemical shift values are reported in ppm (δ).

2-(4-(benzyloxy)-3-methoxyphenyl)-N-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-acetamide (2)

A mixture of 2-(4-(benzyloxy)-3-methoxyphenyl)acetic acid, 1 (0.5 g, 1.83 mmol) in

Chemistry

Papaverine, 1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, possesses four methoxy groups which provide positions that facilitate radiosynthesis of [¹¹C]papaverine using an O-desmethylated phenol analogue as precursor reacted with [¹¹C]CH₃I. We choose 4-desmethylpapaverine, 4, as the precursor for making [¹¹C]papaverine by O-alkylation with [¹¹C]CH₃I using aqueous NaOH solution as base. The synthesis of 4-desmethylpapaverine was accomplished according to Scheme 2 following general methods

Conclusions

We have successfully prepared [¹¹C]papaverine which has high affinity for PDE10A and moderate selectivity of PDE10A versus PDE3A. This C-11 labeled radiotracer binds in vitro predominantly to PDE10A enriched areas of rat and monkey brain. In vivo evaluation with biodistribution and regional brain uptake studies in rats and microPET brain imaging studies in rhesus macaques demonstrated that [¹¹C]papaverine was able to enter the brain and initially accumulated in PDE-rich regions of the brain.

Acknowledgments

This research was supported by the National Institutes of Health grants: DA 16181 and NS48056.We would like to thank Dr. Joel S. Perlmutter and his staff for their assistance with the nonhuman primate microPET imaging process.

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There are more references available in the full text version of this article.

Cited by (46)

New PET radiopharmaceuticals for imaging CNS diseases
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4
Positron emission tomography (PET) radiopharmaceuticals for central nervous system (CNS) diseases must fulfil prerequisites and pass clinical evaluations before they enter widespread use in humans. This article aims to give an overview on CNS PET ligands that after pre-clinical development have been applied in humans in recent years. The selected tracers have shown to provide reliable in vivo quantification of the respective molecular target and have been evaluated in at least one group of patients. The first target is the synaptic vesicle protein 2 A (SV2A), a marker for in vivo measurement of synaptic density, which can provide novel insights in the pathology of CNS disorders. Changes of synaptic density have been shown in several neurologic disorders and psychiatric conditions using the SV2A radioligand [¹¹C]UCB-J. The second group of radioligands include second-generation tracers for imaging tau aggregates (e.g., [¹⁸F]MK-6240 and [¹⁸F]PI-2620). These tau tracers display lower off-target binding and improved imaging properties allowing simplified acquisition protocols. PET radioligands for SV2A and tau aggregates are potential imaging markers for clinical trials and can also become part of routine patient care in the future. Furthermore, radioligands targeting phosphodiesterase 10A (e.g., [¹⁸F]MNI-659) have shown to provide reliable assessment of striatal pathology in Huntington's disease gene expansion carries, already at pre-manifest stages. Beyond these, new radioligands for the evaluation of mitochondrial activity ([¹⁸F]BCPP-EF), activated astroglia ([¹¹C]BU99008), and the purinoceptor P2X₇R as marker of neuroinflammation (e.g., [¹¹C]JNJ-717) have emerged. First evaluations of patients with neurodegenerative diseases yielded encouraging results, though non-invasive and simplified quantification methods might not be feasible or need confirmation in larger samples and more patient groups.
Medicinal chemistry strategies for the development of phosphodiesterase 10A (PDE10A) inhibitors - An update of recent progress
2021, European Journal of Medicinal Chemistry
Citation Excerpt :
However, [11C]papaverine (288) demonstrated quick clearance from CNS after 10 min of tracer injection leading to low retention of the radioactivity in the striatum. These initial data did not provide enough evidence for use of [11C]papaverine (288) as a non-invasive clinical imaging agent for PDE10A imaging in CNS [153]. Researches at GlaxoSmithKline synthesized [11C] labelled MP-10 and evaluated for its kinetics and specific binding in porcine and primate brains.
Phosphodiesterase 10A is a member of Phosphodiesterase (PDE)-superfamily of the enzyme which is responsible for hydrolysis of cAMP and cGMP to their inactive forms 5′-AMP and 5′-GMP, respectively. PDE10A is highly expressed in the brain, particularly in the putamen and caudate nucleus. PDE10A plays an important role in the regulation of localization, duration, and amplitude of the cyclic nucleotide signalling within the subcellular domain of these regions, and thereby modulation of PDE10A enzyme can give rise to a new therapeutic approach in the treatment of schizophrenia and other neurodegenerative disorders. Limitation of the conventional therapy of schizophrenia forced the pharmaceutical industry to move their efforts to develop a novel treatment approach with reduced side effects. In the past decade, considerable developments have been made in pursuit of PDE10A centric antipsychotic agents by several pharmaceutical industries due to the distribution of PDE10A in the brain and the ability of PDE10A inhibitors to mimic the effect of D2 antagonists and D1 agonists. However, no selective PDE10A inhibitor is currently available in the market for the treatment of schizophrenia. The present compilation concisely describes the role of PDE10A inhibitors in the therapy of neurodegenerative disorders mainly in psychosis, the structure of PDE10A enzyme, key interaction of different PDE10A inhibitors with human PDE10A enzyme and recent medicinal chemistry developments in designing of safe and effective PDE10A inhibitors for the treatment of schizophrenia. The present compilation also provides useful information and future direction to bring further improvements in the discovery of PDE10A inhibitors.
Attenuation of neurobehavioural abnormalities by papaverine in prenatal valproic acid rat model of ASD
2021, European Journal of Pharmacology
Citation Excerpt :
The effects of papaverine on DCX and synapsin-IIa in an animal model has never been studied directly, reports suggest that levels of DCX show positive correlation with levels of pCREB i.e. compounds such as phosphodiesterase inhibitors that increase the levels of cAMP accordingly increase the levels of DCX. However, in our study we have found a minor effect in the cerebellum but not in other areas, this could be attributed to the amount of papaverine available, few studies have pointed towards differential availability and activity of papaverine between brain region (Conway and Weiss, 1980; Dedeurwaerdere et al., 2011; Tu et al., 2010). Thus, maintaining neuronal integrity and function in the PDE10A rich bundle of neurons in the brain (Hsu et al., 2011; Siuciak et al., 2006; Torremans et al., 2010).
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase-10A (PDE10A) inhibition has shown to provide benefits in various brain conditions. We investigated the role of a PDE10A inhibitor, papaverine on core phenotypes in prenatal-valproic acid (Pre-VPA) model of ASD. In order to identify probable mechanisms involved, the effects on several protein markers of neuronal function such as, neurogenesis-DCX, neuronal survival-BDNF, synaptic transmission-synapsin-IIa, neuronal transcription factor-pCREB, neuronal inflammation (IL-6, IL-10 and TNF-α) and neuronal oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, hippocampus and striatum. Pre-VPA induced impairments in social behaviour, presence of repetitive behaviour, hyper-locomotion, anxiety, and diminished nociception were studied in male Albino Wistar rats. Administration of papaverine to Pre-VPA animals resulted in improvements of social behaviour, corrected repetitive behaviour, anxiety, locomotor, and nociceptive changes. Also, papaverine resulted in a significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB, IL-10 and GSH along with significant decrease in TNF-α, IL-6 and TBARS in different brain areas of Pre-VPA group. Finally, high association between behavioural parameters and biochemical parameters was observed upon Pearson's correlation analysis. Papaverine, administration rectified core behavioural phenotype of ASD, possibly by altering protein markers associated with neuronal survival, neurogenesis, neuronal transcription factor, neuronal transmission, neuronal inflammation, and neuronal oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ASD phenotypes.
Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates
2018, Nuclear Medicine and Biology
Citation Excerpt :
As an imaging technique and translational tool, positron emission tomography (PET) would allow in vivo quantification of PDE10A levels, providing information regarding target occupancy by potential drugs, distribution and density of PDE10A in tissues, and the specificity of the drug molecule [9]. In recent years, several PET radioligands for PDE10A, such as [11C]papaverine, [11C]MP-10, [18F]MNI654, [18F]MNI659, [18F]JNJ42259152, [18F]JNJ41510417, [11C]LuAE92686, and [11C]AMG7980, have been reported [10–14]. However, some of them suffer from limitations — for example, formation of lipophilic radiometabolites complicating image analysis or unsuitable kinetic properties, making them less-than-optimal for routine applications [11,12,15].
Phosphodiesterase 10A (PDE10A) is a member of the PDE enzyme family that degrades cyclic adenosine and guanosine monophosphates (cAMP and cGMP). Based on the successful development of [¹¹C]T-773 as PDE10A positron emission tomography (PET) radioligand, in this study our aim was to develop and evaluate fluorine-18 analogs of [¹¹C]T-773.
[¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄ were synthesized from the same precursor used for ¹¹C-labeling of T-773 in a two-step approach via ¹⁸F-fluoromethylation and ¹⁸F-fluoroethylation, respectively, using corresponding deuterated synthons. A total of 12 PET measurements were performed in seven non-human primates. First, baseline PET measurements were performed using High Resolution Research Tomograph system with both [¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄; the uptake in whole brain and separate brain regions, as well as the specific binding and tissue ratio between putamen and cerebellum, was examined. Second, baseline and pretreatment PET measurements using MP-10 as the blocker were performed for [¹⁸F]FM-T-773-d₂ including arterial blood sampling with radiometabolite analysis in four NHPs.
Both [¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄ were successfully radiolabeled with an average molar activity of 293 ± 114 GBq/μmol (n = 8) for [¹⁸F]FM-T-773-d₂ and 209 ± 26 GBq/μmol (n = 4) for [¹⁸F]FE-T-773-d₄, and a radiochemical yield of 10% (EOB, n = 12, range 3%–16%). Both radioligands displayed high brain uptake (~ 5.5% of injected radioactivity for [¹⁸F]FM-T-773-d₂ and ~ 3.5% for [¹⁸F]FE-T-773-d₄ at the peak) and a fast washout. Specific binding reached maximum within 30 min for [¹⁸F]FM-T-773-d₂ and after approximately 45 min for [¹⁸F]FE-T-773-d₄. [¹⁸F]FM-T-773-d₂ data fitted well with kinetic compartment models. BP_ND values obtained indirectly through compartment models were correlated well with those obtained by SRTM. BP_ND calculated with SRTM was 1.0–1.7 in the putamen. The occupancy with 1.8 mg/kg of MP-10 was approximately 60%.
[¹⁸F]FM-T-773-d₂ and [¹⁸F]FE-T-773-d₄ were developed as fluorine-18 PET radioligands for PDE10A, with the [¹⁸F]FM-T-773-d₂ being the more promising PET radioligand warranting further evaluation.
Comparison between [18F]fluorination and [18F]fluoroethylation reactions for the synthesis of the PDE10A PET radiotracer [18F]MNI-659
2017, Nuclear Medicine and Biology
2-(2-(3-(4-(2-[¹⁸F]Fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([¹⁸F]MNI-659, [¹⁸F]1) is a useful PET radiotracer for imaging phosphodiesterase 10A (PDE10A) in human brain. [¹⁸F]1 has been previously prepared by direct [¹⁸F]fluorination of a tosylate precursor 2 with [¹⁸F]F⁻. The aim of this study was to determine the conditions for the [¹⁸F]fluorination reaction to obtain [¹⁸F]1 of high quality and with sufficient radioactivity for clinical use in our institute. Moreover, we synthesized [¹⁸F]1 by [¹⁸F]fluoroethylation of a phenol precursor 3 with [¹⁸F]fluoroethyl bromide ([¹⁸F]FEtBr), and the outcomes of [¹⁸F]fluorination and [¹⁸F]fluoroethylation were compared.
We performed the automated synthesis of [¹⁸F]1 by [¹⁸F]fluorination and [¹⁸F]fluoroethylation using a multi-purpose synthesizer. We determined the amounts of tosylate precursor 2 and potassium carbonate as well as the reaction temperature for direct [¹⁸F]fluorination.
The efficiency of the [¹⁸F]fluorination reaction was strongly affected by the amount of 2 and potassium carbonate. Under the determined reaction conditions, [¹⁸F]1 with 0.82 ± 0.2 GBq was obtained in 13.6% ± 3.3% radiochemical yield (n = 8, decay-corrected to EOB and based on [¹⁸F]F⁻) at EOS, starting from 11.5 ± 0.4 GBq of cyclotron-produced [¹⁸F]F⁻. On the other hand, the [¹⁸F]fluoroethylation of 3 with [¹⁸F]FEtBr produced [¹⁸F]1 with 1.0 ± 0.2 GBq and in 22.5 ± 2.5 % radiochemical yields (n = 7, decay-corrected to EOB and based on [¹⁸F]F⁻) at EOS, starting from 7.4 GBq of cyclotron-produced [¹⁸F]F⁻. Clearly, [¹⁸F]fluoroethylation resulted in a higher radiochemical yield of [¹⁸F]1 than [¹⁸F]fluorination.
[¹⁸F]1 of high quality and with sufficient radioactivity was successfully radiosynthesized by two methods. [¹⁸F]1 synthesized by direct [¹⁸F]fluorination has been approved and will be provided for clinical use in our institute.
A human [11C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor
2016, NeuroImage
Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington’s disease. In this study, the brain kinetics of [¹¹C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [¹¹C]T-773.
Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [¹¹C]T-773: two baseline PETs and one postdose PET (3 hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3 hours and 23 hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (V_T), which was calculated as the V_T of the putamen minus the V_T of the cerebellum.
Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean V_T was 5.5 ± 0.7 in the putamen and 2.3 ± 0.5 in the cerebellum in the baseline PET. Absolute V_T variability between the two baseline scans was less than 7%. Reproducibility of V_T was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3 hours after a single administration of 3 to 1000 mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23 hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100 mg of TAK-063. In conclusion, [¹¹C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.

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Nuclear Medicine and Biology

Abstract

Introduction

Section snippets

General

2-(4-(benzyloxy)-3-methoxyphenyl)-N-(2-(3,4-dimethoxyphenyl)-2-hydroxyethyl)-acetamide (2)

Chemistry

Conclusions

Acknowledgments

References (17)

Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)

J Biol Chem

Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase

Neuroscience

Immunohistochemical localization of PDE10A in the rat brain

Brain Res

Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis

Neuropharmacology

Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function

Neuropharmacology

The excretion of 3H-papaverine in the rat

Biochem Pharmacol

Opium alkaloids. VII. Isolation of a new benzylisoquinoline alkaloid. Synthesis and NMR studies of papaveroline trimethyl ethers

J Pharm Sci

The potential therapeutic use of phosphodiesterase 10 inhibitors

Expert Opin Ther Pat

Cited by (46)

New PET radiopharmaceuticals for imaging CNS diseases

Medicinal chemistry strategies for the development of phosphodiesterase 10A (PDE10A) inhibitors - An update of recent progress

Attenuation of neurobehavioural abnormalities by papaverine in prenatal valproic acid rat model of ASD

Development of two fluorine-18 labeled PET radioligands targeting PDE10A and in vivo PET evaluation in nonhuman primates

Comparison between [<sup>18</sup>F]fluorination and [<sup>18</sup>F]fluoroethylation reactions for the synthesis of the PDE10A PET radiotracer [<sup>18</sup>F]MNI-659

A human [<sup>11</sup>C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor