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

Emmanuelle Briard, Sami S. Zoghbi, Masao Imaizumi, Jonathan P. Gourley, H. Umesha Shetty, Jinsoo Hong, Vanessa Cropley, Masahiro Fujita, Robert B. Innis, Victor W. Pike

Research output: Contribution to journalArticle

142 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)17-30
Number of pages14
JournalJournal of Medicinal Chemistry
Volume51
Issue number1
DOIs
StatePublished - Jan 10 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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