N-(5-fluoro-2-phenoxyphenyl)-N-(2-[131I]iodo-5-methoxybenzyl)acetamide:: A potent iodinated radioligand for the peripheral-type benzodiazepine receptor in brain

To image the peripheral-type benzodiazepine receptor (PBR) in vivo, we previously developed two positron emission tomography (PET) ligands, N-(2-[C-11],5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([C-11]1a) and its [F-18]fluoroethyl analogue ([F-18]1b), for the investigation of PBR in the living human brain. This time, using 1a as a leading compound, we designed two novel iodinated analogues, N-(5-fluoro-2-phenoxyphenyl)-N-(2-iodo-5-methoxybenzyl)acetamide (3a) and N-(2,5-dimethoxybenzyl)-N-(5-iodo-2-phenoxyphenyl)acetamide (3b) for the PBR imaging. Ligands 3 were synthesized by the iodination of tributystannyl precursors 10. Radiolabeling for 3 with I-131 was carried out by the reaction of 10 with [I-131]NaI using H2O2 as an oxidizing agent. In vitro competition experiments determined that 3a exhibited both high affinity and selectivity for PBR (IC50: 7.8 nM) vs CBR (> 1 mu M). Biodistribution study in mice determined that [I-131]3a had a high radioactivity level (1.69% dose/g) in the brain, and its distribution pattern in the brain was consistent with the known distribution of PBR in rodents. Ex vivo autoradiography of the rat brain gave visual evidence that [I-131]3a was a potent and specific radioligand for PBR.