Jensen SB, Di Santo R, Olsen AK, Pedersen K, Costi R, Cirilli R, Cumming PSynthesis and cerebral uptake of 1-(1-[(11)C]methyl-1H-pyrrol-2-yl)-2-phenyl-2-(1-pyrrolidinyl)ethanone, a novel tracer for positron emission tomography studies of monoamine oxidase type A. J Med Chem 51:1617-1622

PET Centre, Aarhus University Hospital, Nørrebrogade 44, Arhus C, Denmark.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2008; 51(6):1617-22. DOI: 10.1021/jm701378e
Source: PubMed


( R)-(-)- and ( S)-(+)-1-(1-[ (11)C]methyl-1 H-pyrrol-2-yl)-2-phenyl-2-(1-pyrrolidinyl)ethanone 4 and 5 were synthesized, and their properties as tracers for positron emission tomography (PET) studies of monoamine oxidase type A (MAO-A) in the brain of living pigs were tested. Parametric maps of the distribution volume ( V d) 4 in pig brain were qualitatively similar to those obtained with [ (11)C]harmine, with prominent binding in the ventral forebrain and mesencephalon. Its binding was highly vulnerable to MAO blockade, suggesting a binding potential as high as 2 for MAO-A sites. The slow plasma metabolism of 4 and 5 may present advantages over [ (11)C]harmine for routine PET studies of MAO-A.

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Available from: Roberto Di Santo, Apr 18, 2014
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    • "The irreversibly binding PET ligand [ 11 C]clorgyline had binding in white matter of human brain which was not entirely displaced by MAO-A inhibition (Fowler et al. 2001). Among the few reversibly-binding PET ligands described for MAO-A are [ 11 C]-ROMAO, which had a BP ND of unity in pig brain (Jensen et al. 2008), and [ 11 C]befloxatone, which had a BP ND of approximately five in baboon brain (Zanotti-Fregonara et al. 2013). The state of development of MAO ligands is the subject of a very recent review, which called for a concerted "
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    ABSTRACT: We investigated [18F]fluoroethyl-harmol ([18F]FEH) as a reversible and selective ligand for positron emission tomography (PET) studies of monoamine oxidase A (MAO-A). Binding of [18F]FEH in rat brain cryostat sections indicated high affinity (KD = 3 nM), and density (Bmax; 600 pmol/g). The plasma free fraction was 45%, and untransformed parent constituted only 13% of plasma radioactivity at ten minutes after injection. Compartmental analysis of PET recordings in pargyline-treated rats showed high permeability to brain (K1; 0.32 mL g−1 min−1) and slow washout (k2; 0.024 min−1), resulting in a uniformly high equilibrium distribution volume (VD; 20 mL g−1). Using this VD to estimate unbound ligand in brain of untreated rats, the binding potential (BPND) ranged from 4.2 in cerebellum to 7.2 in thalamus. We also calculated BPND maps of rats receiving [18F]FEH at a range of specific activities, and then estimated saturation binding parameters in living brain. In thalamus, striatum and frontal cortex KD was globally close to 300 nM and Bmax close to 1600 pmol/g; the 100-fold discrepancy in affinity suggests a very low free fraction for [18F]FEH in living brain. Based on a synthesis of findings, we calculate the endogenous dopamine concentration to be 0.4 μM in the striatal compartment containing MAO-A, thus unlikely to exert competition against [18F]FEH binding in vivo. In summary, [18F]FEH has good properties for the detection of MAO-A in rat brain by PET, and may present logistic advantages for clinical research at centres lacking a medical cyclotron.This article is protected by copyright. All rights reserved.
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    • "[ 11 C]-harmine showed favorable kinetics and showed sensitivity to pretreatment with selective MAO-A inhibitors. (R-(À) and (S)-( + )- 1-1[11C]methyl-1H-pyrrol-2-yl)-2-phenyl-2-(1-pyrro- lidinyl)ethanone were also synthetized and characterized in vivo (Jensen et al, 2008). They presented two obvious advantages over harmine: a simple radiosynthesis with high yield and a slower plasma metabolism. "
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    ABSTRACT: [(11)C]befloxatone is a high-affinity, reversible, and selective radioligand for the in vivo visualization of the monoamine oxidase A (MAO-A) binding sites using positron emission tomography (PET). The multi-injection approach was used to study in baboons the interactions between the MAO-A binding sites and [(11)C]befloxatone. The model included four compartments and seven parameters. The arterial plasma concentration, corrected for metabolites, was used as input function. The experimental protocol-three injections of labeled and/or unlabeled befloxatone-allowed the evaluation of all the model parameters from a single PET experiment. In particular, the brain regional concentrations of the MAO-A binding sites (B'(max)) and the apparent in vivo befloxatone affinity (K(d)) were estimated in vivo for the first time. A high binding site density was found in almost all the brain structures (170+/-39 and 194+/-26 pmol/mL in the frontal cortex and striata, respectively, n=5). The cerebellum presented the lowest binding site density (66+/-13 pmol/mL). Apparent affinity was found to be similar in all structures (K(d)V(R)=6.4+/-1.5 nmol/L). This study is the first PET-based estimation of the B(max) of an enzyme.
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    ABSTRACT: Since its discovery 50 years ago, brain dopamine has been implicated in the control of movement and cognition, and is concerned with diverse brain diseases such as Parkinson's disease, schizophrenia and drug addiction. This book is an illustrated biography of the dopamine molecule, from its synthesis in the brain to its signalling mechanisms and ultimately to its metabolic breakdown. Using colour illustrations of positron emission tomography (PET) scans, each chapter presents a specific stage in the biochemical pathway for dopamine. Writing for researchers and graduate students, Paul Cumming presents a compilation of all that has been learned about dopamine through molecular imaging, a technology which allows the measurement of formerly invisible processes in the living brain. He reviews current technical controversies in the interpretation of dopamine imaging, and presents key results illuminating brain dopamine in illness and health.
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