Synthesis 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.
ABSTRACT ( 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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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.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 11/2009; 30(4):792-800. · 5.46 Impact Factor
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ABSTRACT: Biologically important processes in normal brain function and brain disease involve the action of various protein-based receptors, ion channels, transporters and enzymes. The ability to interrogate the location, abundance and activity of these entities in vivo using non-invasive molecular imaging can provide unprecedented information about the spatio-temporal dynamics of brain function. Indeed, positron emission tomography (PET) imaging is transforming our understanding of the central nervous system and brain disease. Great emphasis has historically been placed on developing radioligands for the non-invasive detection of neuroreceptors. In contrast, relatively few enzymes have been amenable to examination by PET imaging procedures based upon trapping or accumulation of enzymatic products, because only a subset of enzymes have sufficient catalytic rate to produce measureable accumulation within the practical time-limit of PET recordings. However, high affinity inhibitors are now serving as tracers for enzymes, particularly for measuring the abundance of enzymes mediating intracellular signal transduction in the brain, which offer a rich diversity of potential targets for drug discovery. The purpose of this review is to summarize well-known radiotracers for brain enzymes, and draw attention to recent developments in PET radiotracers for imaging signal transduction pathways in the brain. The review is organized by target class and focuses on structural chemistry of the best-established radiotracers identified in each class.American journal of nuclear medicine and molecular imaging. 01/2013; 3(3):194-216.