Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo

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Title: Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo
Author(s): Briard, Emmanuelle; Zoghbi, Sami S.; Imaizumi, Masao; Gourley, Jonathan P.; Shetty, H. Umesha; Hong, Jinsoo; Cropley, Vanessa; Fujita, Masahiro; Innis, Robert B.; Pike, Victor W.
Abstract: We sought to develop 11C-labeled ligands for sensitive imaging of brain peripheral benzodiazepine receptors (PBR) in vivo. Two aryloxyanilides with high affinity for PBR were identified and synthesized, namely, N-acetyl-N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline (3, PBR01) and N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide (10, PBR28). 3 was hydrolyzed to 4, which was esterified with [11C]iodomethane to provide [11C]3. The O-desmethyl analogue of 10 was converted into [11C]10 with [11C]iodomethane. [11C]3 and [11C]10 were each injected into monkey to assess their brain kinetics with positron emission tomography (PET). After administration of either radioligand there was moderately high brain uptake of radioactivity. Receptor blocking and displacement experiments showed that a high proportion of this radioactivity was bound specifically to PBR. In monkey and rat, 3 and 10 were rapidly metabolized by ester hydrolysis and N-debenzylation, respectively, each to a single polar radiometabolite. [11C]3 and [11C]10 are effective for imaging PBR in monkey brain. [11C]10 especially warrants further evaluation in human subjects.
Publication type: Journal article
Source: Journal of Medicinal Chemistry, Vol. 51, no. 1 (Jan 2008), pp. 17-30
Publication year: 2008
FOR Code(s): 0304 Medicinal and Biomolecular Chemistry; 1115 Pharmacology and Pharmaceutical Sciences
Keyword(s): Aryloxyanilides; Brains; Imaging; In vivo; Monkeys; PBR; Peripheral benzodiazepine receptor
Publisher: American Chemical Society
ISSN: 0022-2623
Publisher URL: http://dx.doi.org/10.1021/jm0707370
Additional information: This study was supported by the Intramural Research Program of the National Institutes of Health, specifically the National Institute of Mental Health.
Peer reviewed