Positron Emission Tomography Ligand Research Articles

Radioligands for the dopamine receptor subtypes

The actions of the predominant neurotransmitter in the brain, dopamine, are mediated by the postsynaptic dopamine receptors. The five dopamine receptor subtypes and their regulation have been associated with a large variety of psychiatric diseases. Therefore, positron emission tomography (PET) imaging studies using suitable and selective (18) F-labeled and (11) C-labeled dopamine receptor radioligands could provide valuable knowledge on the impact of receptor density on the pathogenesis and evolvement of neuropsychiatric and neurological diseases. This special issue subchapter provides a summary of the most important (18) F-labeled and (11) C-labeled radioligands for PET imaging of the dopamine receptor subtypes, their radiochemistry, and characteristics from in vitro and in vivo applications, considering not only the already established PET ligands but also the recently published preclinical work.

Profiling of hepatic clearance pathways of Pittsburgh compound B and human liver cytochrome p450 phenotyping

Background11C-PiB has been developed as a positron-emission tomography (PET) ligand for evaluating fibrillar β-amyloid (Aβ) in the human brain. The ligand is rapidly metabolized, with approximately 10% of intact tracer remaining 30 min after injection. When 11C-PiB is used as a treatment endpoint in intervention studies for Alzheimer’s disease (AD), a concern is whether the clearance of the tracer changes from one scan to the next, increasing within subject variability in the PET signal. Subjects enrolled in AD trials may start or stop medications that inhibit or induce xenobiotic metabolizing enzymes such as the cytochrome P450 (CYP) isozymes.FindingsWe conducted CYP phenotyping in recombinantly expressed systems, and in human liver microsomes, to evaluate CYP isozyme contributions to the metabolism of PiB (carrier) and profiled microsomal and hepatocyte incubations for metabolites. The metabolism of PiB appears to be polyzymic, with direct conjugation via UDP-glucuronosyltransferases (UGTs) also occurring.ConclusionIt is unlikely that CYP inhibition or induction will significantly influence the clearance of 11C-PiB.

Connectivity-Based Functional Analysis of Dopamine Release in the Striatum Using Diffusion-Weighted MRI and Positron Emission Tomography

The striatum acts in conjunction with the cortex to control and execute functions that are impaired by abnormal dopamine neurotransmission in disorders such as Parkinson's and schizophrenia. To date, in vivo quantification of striatal dopamine has been restricted to structure-based striatal subdivisions. Here, we present a multimodal imaging approach that quantifies the endogenous dopamine release following the administration of d-amphetamine in the functional subdivisions of the striatum of healthy humans with [(11)C]PHNO and [(11)C]Raclopride positron emission tomography ligands. Using connectivity-based (CB) parcellation, we subdivided the striatum into functional subregions based on striato-cortical anatomical connectivity information derived from diffusion magnetic resonance imaging (MRI) and probabilistic tractography. Our parcellation showed that the functional organization of the striatum was spatially coherent across individuals, congruent with primate data and previous diffusion MRI studies, with distinctive and overlapping networks. d-amphetamine induced the highest dopamine release in the limbic followed by the sensory, motor, and executive areas. The data suggest that the relative regional proportions of D2-like receptors are unlikely to be responsible for this regional dopamine release pattern. Notably, the homogeneity of dopamine release was significantly higher within the CB functional subdivisions in comparison with the structural subdivisions. These results support an association between local levels of dopamine release and cortical connectivity fingerprints.

Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-HT4 receptor

BackgroundSerotonin 5-HT4 receptor (5-HT4-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-HT4-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-HT4-R agonist, was selected.Methods[11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its LogDoct,pH7.4 was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography.Results[11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its LogDoct,pH7.4 was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·g−1) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the role of the P-glycoprotein pump in the gut.Conclusion[11C]Prucalopride demonstrated low radioactivity levels in rat brain; a combination of reasons may include rapid metabolism in the rat in particular, low passive diffusion and potential P-glycoprotein substrate. In humans, further investigation of [11C]prucalopride for imaging the active state of 5-HT4-R is worthwhile, in view of the therapeutic applications of 5-HT4 agonists for treatment of gastrointestinal motility disorders.

Development of N-[4-[6-(Isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]methylbenzamide for Positron Emission Tomography Imaging of Metabotropic Glutamate 1 Receptor in Monkey Brain

Three novel 4-substituted benzamides have been synthesized as potential ligands for the positron emission tomography (PET) imaging of metabotropic glutamate 1 (mGlu1) receptor in the brain. Of these compounds, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N,4-dimethylbenzamide (4) exhibited the highest binding affinity (K(i) = 13.6 nM) for mGlu1 and was subsequently labeled with carbon-11. In vitro autoradiography using rat brain sections showed that [(11)C]4 binding was consistent with the distribution of mGlu1, with high specific binding in the cerebellum and thalamus. PET studies with [(11)C]4 in monkey showed a high brain uptake and a kinetic profile suitable for quantitative analysis. Pretreatment with a mGlu1-selective ligand 16 largely decreased the brain uptake, indicating high in vivo specific binding of [(11)C]4 to mGlu1. In metabolite analysis, only unchanged [(11)C]4 was found in the brain. [(11)C]4 is a useful PET ligand for the imaging and quantitative analysis of mGlu1 in monkey brain and merits further evaluation in humans.

Discovery of novel α1-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands

The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity α1A-adrenoceptor ligands with Ki values of 0.52 and 0.16nM, respectively, and with a >100-fold selectivity versus dopamine D2 receptors. Compound 3i showed almost equal affinity for α1B- (Ki=1.9nM) and α1D-adrenoceptors (Ki=2.5nM) as for α1A, as well as moderate affinity for 5-HT1B (Ki=13nM) and 5-HT6 (Ki=16nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands.

09 Biomarkers for Detection of Activated Macrophages in Atherosclerosis

Atherosclerosis is the pathogenic mechanism underlying the majority of strokes, heart attacks and peripheral vascular disease. These are the principal causes of morbidity and mortality in the developed nations. The atherosclerotic lesion (or plaque) is characterised by a build up of lipid and inflammatory cells in the artery wall. Arterial stenosis is the current clinical predictor for endarterectomy, although macrophage burden in the lesion correlates strongly with likelihood of rupture and could be a better proxy of plaque vulnerability. Activated macrophages have up-regulated expression of translocator protein (TSPO), which is readily quantified by the positron emission tomography (PET)-based ligands (1) such as [11C](R)-1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ([11C](R)-PK11195). Studies examining TSPO plaque biodistribution frequently use CD68, a pan-phenotype marker, for identification of macrophage presence. However, this biomarker demonstrates some inconsistencies in these analyses (1). We hypothesise that more specific macrophage phenotype markers may perform better as correlates for TSPO PET-ligand binding. In this study, we examined the expression of phenotype-restricted macrophage markers in endarterectomy tissue, and correlated these with the distribution of [3H](R)-PK11195 using autoradiographic, immunohistochemical and immunofluorescence techniques. Autoradiographic and immunohistochemical images were digitised and co-registered to provide more accurate correlation of expression. We identified several markers of activated macrophage phenotype which have better correlation with [3H](R)-PK11195 binding patterns compared with CD68. These data indicate that TSPO PET ligands bind principally to activated macrophage phenotypes, and the phenotype markers have the potential to more accurately identify PET-ligand binding macrophages in ex vivo analysis. 1) Bird JL et al. Atherosclerosis, (2010), 210(2): 388–91.

Systematic review of the body of evidence for the use of biomarkers in the diagnosis of dementia

BackgroundAlthough recent diagnostic criteria for Alzheimer's disease propose the use of biomarkers, validation of these biomarkers by diagnostic test accuracy studies is a necessary first step, followed by the synthesis of the evidence from these studies in systematic reviews and meta-analyses. The quality of the resulting evidence depends on the number and size of the primary studies, their quality, and the adequacy of their reporting. This systematic review assesses the weight and quality of the evidence available from primary diagnostic test accuracy studies. MethodsA MEDLINE search was performed in August 2011 to identify all potentially relevant publications relating to the biomarkers β-amyloid, tau, positron emission tomography (18F-fluorodeoxyglucose or ligands for amyloid), or magnetic resonance imaging (MRI). The reporting and methodology were assessed using the Standards for Reporting of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies assessment tools, respectively. Because clinical progression to dementia is the most commonly used reference standard, this review focuses on participants with objective cognitive impairment but no dementia at baseline. ResultsOf the 19,104 published references identified by the search, 142 longitudinal studies relating to the biomarkers of interest were identified, which included subjects who had objective cognitive impairment but no dementia at baseline. The highest number of studies (n = 70) and of participants (n = 4722) related to structural MRI. MRI also yielded the highest number of studies with extractable data for meta-analysis (n = 32 [46% of all structural MRI studies]), followed by cerebrospinal fluid tau (n = 24 [73%]). There were few studies on positron emission tomography ligands for amyloid having suitable data for meta-analysis (n = 4). There was considerable variation across studies in reporting outcomes, methods of blinding and selection, means of accounting for indeterminate or missing values, the interval between the test and assessments, and the determination of test thresholds. ConclusionsThe body of evidence for biomarkers is not large and is variable across the different types of biomarkers. Important information is missing from many study reports, highlighting the need for standardization of methodology and reporting to improve the rigor of biomarker validation.

Synthesis and Evaluation of Novel 18F Labeled 2-Pyridinylbenzoxazole and 2-Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β-Amyloid Plaques

A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for (18)F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [(18)F]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([(18)F]32) (K(i) = 8.0 ± 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [(18)F]32 to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [(18)F]32 is a promising Aβ imaging agent for PET and merits further evaluation in human subjects.

HaloTag® Platform: From Proteomics to Cellular Analysis and Animal Imaging

HaloTag® Platform: From Proteomics to Cellular Analysis and Animal Imaging

Feedback-Controlled Bolus plus Infusion (FC-B/I) Method for Quantitative Drug Assessment in Living Brain with PET

We have developed a feedback-controlled bolus plus infusion (FC-B/I) method for monitoring the interaction between positron emission tomography (PET) ligands and their specific target molecules with PET. The usefulness of the FC-B/I method was evaluated by the direct interaction between [11C]raclopride, a dopamine D2 receptor (D2R) ligand, and cold raclopride (10 and 100 μg/kg) in the brains of conscious monkeys. The present results demonstrated that the FC-B/I method could achieve the equilibrium state of [11C]raclopride in the striatum of monkey brain, and also that the cold raclopride-induced reduction of [11C]raclopride binding to D2R was observed in a dose-dependent manner. Good correlations of distribution volume ratio of the striatum to cerebellum between the conventional bolus plus infusion (B/I) method and the FC-B/I method as well as between the conventional bolus injection method and the FC-B/I method were observed. These results indicated that the system could be a useful tool for the evaluation of interaction between drug candidates and their target molecules like enzymes, receptors, and transporters by using of their specific PET ligands.

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

The most recently discovered serotonin (5-HT) receptor subtype, 5-HT(7), is considered to be associated with several CNS disorders. Noninvasive in vivo positron emission tomography (PET) studies of cerebral 5-HT(7) receptors could provide a significant advance in the understanding of the neurobiology and eventual dysfunctions of the 5-HT(7) receptor. To date, no appropriate 5-HT(7) receptor PET ligand has been developed. Here, we modified known 5-HT(7) selective phenylpiperazinyl-butyloxindole derivatives so that they may be labeled either with carbon-11 or fluorine-18. A set of potential 5-HT(7) ligands for PET molecular imaging was successfully synthesized. Two compounds (10 and 14) were tested against a range of targets. Both compounds display a promising in vitro profile with respect to PET imaging of the 5-HT(7) receptor in thalamic regions.

Detection of ischemic neuronal damage with [18F]BMS‐747158‐02, a mitochondrial complex‐1 positron emission tomography ligand: Small animal PET study in rat brain

The acute and subacute ischemic neuronal damage in rat brain caused by photochemically induced thrombosis (PIT) was imaged using [¹⁸F]BMS-747158-02 ([¹⁸F]BMS) for mitochondrial complex-1 (MC-1) and [¹¹C](R)-PK11195 ([¹¹C](R)-PK) for peripheral benzodiazepine receptor [PBR; translocator protein] at preischemic "Normal," 1 (day 1), and 7 days (day 7) after ischemic insult. When [¹⁸F]BMS was intravenously injected into "Normal" rat, it was rapidly taken up into the brain, in which it showed a homogeneous distribution, and the uptake was suppressed by rotenone, a specific MC-1 inhibitor. The specificity of [¹⁸F]BMS binding to MC-1 was also confirmed by living brain slice imaging. At day 1, [¹⁸F]BMS uptake was low in infarct and peri-infarct regions where neuronal damage was detected by 2,3,5-triphenyltetrazolium chloride (TTC) staining. At day 7, the damaged areas determined using [¹⁸F]BMS revealed some discrepancy from those detected by TTC staining, suggesting that TTC stained not only surviving cells but also activated microglial cells in the peri-infarct region. This was also confirmed by [¹¹C](R)-PK imaging and immunohistochemical assessment with Iba1 antibody. In contrast, the uptake pattern of [¹⁸F]BMS was consistent with immunohistochemical assessment with NeuN antibody at both days 1 and 7. These results demonstrated that [¹⁸F]BMS could be a promising positron emission tomography ligand to assess the neuronal damage induced by ischemic insult in both acute and subacute phases.

Cholinergic Deficit and Response to Donepezil Therapy in Parkinson’s Disease with Dementia

Background: Although donepezil, an acetylcholinesterase inhibitor, has been proved to be effective in ameliorating cognitive impairment in Parkinson’s disease with dementia (PDD), the responsiveness of patients to donepezil therapy varies. [5-¹¹C-methoxy]donepezil, the radiolabeled form of donepezil, is a ligand for positron emission tomography (PET), which can be exploited for the quantitative analysis of donepezil binding to acetylcholinesterase and for cholinergic imaging. Objectives: To investigate the deficits of the cholinergic system in the brain in PDD and its association with response to donepezil therapy. Methods: Twelve patients with PDD and 13 normal control subjects underwent [5-¹¹C-methoxy]donepezil-PET imaging. For patients with PDD, daily administration of donepezil was started after [5-¹¹C-methoxy]donepezil-PET imaging and continued for 3 months. Results: In the PDD group, the mean total distribution volume of the cerebral cortices was 22.7% lower than that of the normal control group. The mean total distribution volume of the patients with PDD was significantly correlated with improvement of visuoperceptual function after 3 months of donepezil therapy. Conclusion: The results suggest that donepezil therapy is more effective in patients with less decrease in acetylcholinesterase, a binding site of donepezil, at least in the specific cognitive domain.

Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study

Inflammatory mechanisms, like microglial activation, could be involved in the pathogenesis of Alzheimer's disease (AD). (R)-[11C]PK11195 (1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide), a positron emission tomography (PET) ligand, can be used to quantify microglial activation in vivo. The purpose of this study was to assess whether increased (R)-[11C]PK11195 binding is present in AD and mild cognitive impairment (MCI), currently also known as “prodromal AD.” MethodsNineteen patients with probable AD, 10 patients with prodromal AD (MCI), and 21 healthy control subjects were analyzed. Parametric images of binding potential (BPND) of (R)-[11C]PK11195 scans were generated using receptor parametric mapping (RPM) with supervised cluster analysis. Differences between subject groups were tested using mixed model analysis, and associations between BPND and cognition were evaluated using Pearson correlation coefficients. ResultsVoxel-wise statistical parametric mapping (SPM) analysis showed small clusters of significantly increased (R)-[11C]PK11195 BPND in occipital lobe in AD dementia patients compared with healthy control subjects. Regions of interest (ROI)-based analyses showed no differences, with large overlap between groups. There were no differences in (R)-[11C]PK11195 BPND between clinically stable prodromal AD patients and those who progressed to dementia, and BPND did not correlate with cognitive function. ConclusionMicroglial activation is a subtle phenomenon occurring in AD.

Synthesis and evaluation of [11C]Cimbi-806 as a potential PET ligand for 5-HT7 receptor imaging

2-(2′,6′-Dimethoxy-[1,1′-biphenyl]-3-yl)-N,N-dimethylethanamine has been identified as a potent ligand for the serotonin 7 (5-HT7) receptor. In this study, we describe the synthesis, radiolabeling and in vivo evaluation of [11C]2-(2′,6′-dimethoxy-[1,1′-biphenyl]-3-yl)-N,N-dimethylethanamine ([11C]Cimbi-806) as a radioligand for imaging brain 5-HT7 receptors with positron emission tomography (PET). Precursor and reference compound was synthesized and subsequent 11C-labelling with [11C]methyltriflate produced [11C]Cimbi-806 in specific activities ranging from 50 to 300GBq/μmol. Following intravenous injection, brain uptake and distribution of [11C]Cimbi-806 was assessed with PET in Danish Landrace pigs. The time–activity curves revealed high brain uptake in thalamic and striatal regions (SUV ∼2.5) and kinetic modeling resulted in distribution volumes (VT) ranging from 6mL/cm3 in the cerebellum to 12mL/cm3 in the thalamus. Pretreatment with the 5-HT7 receptor antagonist SB-269970 did not result in any significant changes in [11C]Cimbi-806 binding in any of the analyzed regions. Despite the high brain uptake and relevant distribution pattern, the absence of appropriate in vivo blocking with a 5-HT7 receptor selective compounds renders the conclusion that [11C]Cimbi-806 is not an appropriate PET radioligand for imaging the 5-HT7 receptor in vivo.

Radiosynthesis and biological evaluation of the M1 muscarinic acetylcholine receptor agonist ligand [11C]AF150(S)

Purpose M1 muscarinic acetylcholine receptor (M1ACh-R) agonists are potential therapeutics for cognitive disorders. The aim of this study was to develop an orthosteric agonist positron emission tomography (PET) ligand for the M1ACh-R that would provide a tool to explore the active G-protein coupled receptor. To that extend, the radiosynthesis, receptor binding in vitro, and brain uptake of [11C]AF150(S), a selective M1ACh-R agonist, were investigated. Procedures [11C]AF150(S) was synthesized, its binding properties were investigated using autoradiography on rat brain sections, and brain uptake was determined in biodistribution studies ex vivo in rats. Metabolites in brain and blood were measured using high-performance liquid chromatography. Results Yield of the [11C]AF150(S) radiosynthesis was 69 ± 9% with radiochemical purity >99%. The logDoct,7.4 was 0.05. Autoradiography showed binding in M1ACh-R rich brain areas and selective inhibition by muscarinic agents in conditions promoting agonist binding. Biodistribution studies revealed rapid and high brain uptake, to levels exceeding five times the blood level. In M1ACh-R rich areas, specific uptake versus cerebellum was apparent, remaining constant over 60 min in spite of rapid decline of radioactivity from the brain and rapid peripheral metabolism. Brain uptake of [11C]AF150(S) may involve facilitated transport. Conclusion [11C]AF150(S) was successfully synthesized, showed M1ACh-R agonist binding properties, and high brain uptake. It provides an interesting lead for the development of an M1ACh-R agonist PET ligand meant to explore the active receptor state. Copyright © 2012 John Wiley & Sons, Ltd.

Amyloid deposition after cerebral hypoperfusion: Evidenced on [18F]AV-45 positron emission tomography

Animal studies have shown that cerebral hypoperfusion may be associated with amyloid plaque accumulation. Amyloid plaque is known to be associated with dementia and [18F]AV-45 is a positron emission tomography (PET) ligand that binds to extracelluar plaques. We hypothesized that demented patients with cerebral hypoperfusion may have increased [18F]AV-45 uptake.Five demented patients with cerebral hypoperfusion due to unilateral carotid artery stenosis (CAS) were examined with [18F]AV-45 PET, and the results were compared with six elderly controls. The standard uptake value ratio (SUVR) of each region of interest (ROI) was created using whole cerebellum as the reference region. All subjects underwent magnetic resonance imaging (MRI) for obtaining structural information.Patients with dementia and unilateral CAS had a higher global [18F]AV-45 SUVR (1.34±0.06) as compared with controls (1.10±0.04, p=0.0043), especially over the frontal, temporal, precuneus, anterior cingulate and occipital regions. The statistical distribution maps revealed a significantly increased [18F]AV-45 SUVR in the medial frontal, caudate, thalamus, posterior cingulate, occipital and middle and superior temporal regions ipsilateral to the side of CAS (p<0.01).The present study found that cerebral [18F]AV-45 binding is increased in demented patients with CAS, and its distribution is lateralized to the CAS side, suggesting that amyloid‐related dementia may occur under cerebral hypoperfusion.

Recent Advances in Positron Emission Tomography (PET) Radiotracers for Imaging Phosphodiesterases

Phosphodiesterases (PDEs) are a family of enzymes that metabolically inactivate the second messengers 3',5'- cyclic adenosine monophosphate (cAMP) and/or 3',5'-cyclic guanosine monophosphate (cGMP). These two messengers regulate the extracellular signal from the plasma membrane G protein-coupled receptors (GPCRs) to the intracellular effector proteins, hence modulating a wide variety of biological processes both in the central nervous system (CNS) and peripheral tissues. Although there are many radiotracers available for positron emission tomography (PET) studies of different receptors, there are just a few tracers available for imaging studies of second messenger systems. The first reported PDE PET ligands were the 11C-labeled versions of the PDE4 inhibitors rolipram and Ro 20-1724, and, to date, PET imaging studies in human subjects have only been reported with [11C]rolipram. As a consequence of the growing interest in identifying selective PDE inhibitors as potential new therapeutic agents, new PET radiotracers for imaging specific PDEs have been described in literature as well. This article highlights these efforts on the design and evaluation of novel PET radioligands for in vivo imaging of PDEs.

The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15-4513 positron emission tomography study

GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [11C]Ro15-4513 to measure α1 and α5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high-functioning ASD compared with three healthy matched volunteers. We found significantly lower [11C]Ro15-4513 binding throughout the brain of participants with ASD (p < 0.0001) compared with controls. Planned region of interest analyses also revealed significant reductions in two limbic brain regions, namely the amygdala and nucleus accumbens bilaterally. Further analysis suggested that these results were driven by lower levels of the GABAA α5 subtype. These results provide initial evidence of a GABAA α5 deficit in ASD and support further investigations of the GABA system in this disorder.This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.