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

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.