Evaluation of N-Benzyl-N-[11C]Methyl-2-(7-Methyl-8-oxo-2-Phenyl-7,8-Dihydro-9H-Purin-9-yl)Acetamide ([11C]DAC) as a Novel Translocator Protein (18 kDa) Radioligand in Kainic Acid-Lesioned Rat

The aim of this study was to evaluate N-benzyl-N-[C-11]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([C-11]DAC) as a new translocator protein (18 kDa) [TSPO, formerly known as the peripheral-type benzodiazepine receptor (PBR)] positron emission tomography (PET) ligand in normal mice and unilateral kainic acid (KA)-lesioned rats. DAC is a derivative of AC-5216, which is a potent and selective PET ligand for the clinical investigation of TSPO. The binding affinity and selectivity of DAC for TSPO were similar to those of AC-5216, and DAC was less lipophilic than AC-5216. The distribution pattern of [C-11]DAC was in agreement with TSPO distribution in rodents. No radioactive metabolite of [C-11]DAC was found in the mouse brain, although it was metabolized rapidly in mouse plasma. Using small-animal PET, we examined the in vivo binding of [C-11]DAC for TSPO in KA-lesioned rats. [C-11]DAC and [C-11]AC-5216 exhibited similar brain uptake in the lesioned and nonlesioned striatum, respectively. The binding of [C-11]DAC to TSPO was increased significantly in the lesioned striatum, and [C-11]DAC showed good contrast between the lesioned and nonlesioned striatum (the maximum ratio was about threefold). In displacement experiments, the uptake of [C-11]DAC in the lesioned striatum was eventually blocked using an excess of either unlabeled DAC or PK11195 injected. [C-11]DAC had high in vivo specific binding to TSPO in the injured rat brain. Therefore, [C-11]DAC is a useful PET ligand for TSPO imaging, and its specific binding to TSPO is suitable as a new biomarker for brain injury. Synapse 63:961-971, 2009. (c) 2009 Wiley-Liss, Inc.