Synthesis and Evaluation in Monkey of Two Sensitive ¹¹C-Labeled Aryloxyanilide Ligands for Imaging Brain Peripheral Benzodiazepine Receptors In Vivo

Abstract

We sought to develop (11)C-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 [ (11)C]iodomethane to provide [ (11)C] 3. The O-desmethyl analogue of 10 was converted into [ (11)C] 10 with [ (11)C]iodomethane. [ (11)C] 3 and [ (11)C] 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. [ (11)C] 3 and [ (11)C] 10 are effective for imaging PBR in monkey brain. [ (11)C] 10 especially warrants further evaluation in human subjects.

The immune response of the human brain to abdominal surgery

“…[30][31][32] The average radioactivity administered was 435 6 50MBq (mean 6 standard deviation [SD]), with a specific radioactivity of 229 6 82GBq/mmol and an injected mass of 0.77 6 0.38 mg. PET data were acquired for 63 minutes. Arterial blood was sampled using an automated system for the first 5 minutes.…”

Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors

“…PBR28 was labeled by 11 C-methylation of the O-desmethyl precursor, as described by Briard et al, (2005a).The specific activity of [ 11 C]PBR28 at time of injection was 101 ± 89 GBq/ μmol (Table 2), with these and subsequent data are expressed as mean ± SD.…”

“…We also synthesized aryloxyanilide-based PET ligands that have high affinity and selectivity for PBRs: [ 11 C]PBR01, [ 18 F]PBR06, and [ 11 C]PBR28 ( Fig. 1 and Table 1) (Briard et al, 2005a;Briard et al, 2005b). [ 11 C]PBR01 and [ 18 F]PBR06 showed similar kinetics of brain uptake and washout in rhesus monkey (Imaizumi et al, 2007a).…”

MicroPET/CT Imaging of [18F]-FEPPA in the Nonhuman Primate: A Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity

“…In their activated state, microglia undergo morphological changes, accumulate and proliferate at the site of neuronal damage, synthesize proinflammatory cytokines, and release toxic molecules and metabolites to eliminate damaged cells. Activation of microglia also may indicate that they are performing some protective functions such as releasing neurotrophic factors and protecting cells from damage [32,34,35]. Various studies have demonstrated that PBRs are involved in numerous nervous system disorders such as multiple sclerosis, cerebral ischemia and stroke, epilepsy, brain injury, neurotoxic brain damage, and neurodegenerative diseases [17,[34][35][36][37].…”