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

• Published in: Synapse (New York, N.Y.) N.Y.), 2009-11, Vol.63 (11), p.961-971
• Main Authors: Yanamoto, Kazuhiko, Yamasaki, Tomoteru, Kumata, Katsushi, Yui, Joji, Odawara, Chika, Kawamura, Kazunori, Hatori, Akiko, Inoue, Osamu, Yamaguchi, Masatoshi, Suzuki, Kazutoshi, Zhang, Ming-Rong
• Format: Article
• Language: English
• Subjects: [11C]DAC; Animals; autoradiography; biomarker; Brain Injuries - diagnostic imaging; brain injury; Carbon Radioisotopes - chemistry; Carbon Radioisotopes - metabolism; Carbon Radioisotopes - pharmacology; Chromatography, High Pressure Liquid; Excitatory Amino Acid Agonists - toxicity; Kainic Acid - toxicity; Ligands; Male; Mice; PBR; Positron-Emission Tomography; Purines - chemistry; Purines - metabolism; Purines - pharmacology; Radioligand Assay; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, GABA - chemistry; Receptors, GABA - metabolism; small-animal PET; Tissue Distribution; TSPO
• ISSN: 0887-4476; 1098-2396; 1098-2396
• DOI: 10.1002/syn.20678

The aim of this study was to evaluate N‐benzyl‐N‐[11C]methyl‐2‐(7‐methyl‐8‐oxo‐2‐phenyl‐7,8‐dihydro‐9H‐purin‐9‐yl)acetamide ([11C]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 [11C]DAC was in agreement with TSPO distribution in rodents. No radioactive metabolite of [11C]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 [11C]DAC for TSPO in KA‐lesioned rats. [11C]DAC and [11C]AC‐5216 exhibited similar brain uptake in the lesioned and nonlesioned striatum, respectively. The binding of [11C]DAC to TSPO was increased significantly in the lesioned striatum, and [11C]DAC showed good contrast between the lesioned and nonlesioned striatum (the maximum ratio was about threefold). In displacement experiments, the uptake of [11C]DAC in the lesioned striatum was eventually blocked using an excess of either unlabeled DAC or PK11195 injected. [11C]DAC had high in vivo specific binding to TSPO in the injured rat brain. Therefore, [11C]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. © 2009 Wiley‐Liss, Inc.