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

Synapse. 2009 Nov;63(11):961-71. doi: 10.1002/syn.20678.

Abstract

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 [(11)C]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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries / diagnostic imaging*
  • Carbon Radioisotopes / chemistry
  • Carbon Radioisotopes / metabolism
  • Carbon Radioisotopes / pharmacology
  • Chromatography, High Pressure Liquid
  • Excitatory Amino Acid Agonists / toxicity
  • Kainic Acid / toxicity
  • Ligands
  • Male
  • Mice
  • 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*
  • Tissue Distribution

Substances

  • Carbon Radioisotopes
  • Excitatory Amino Acid Agonists
  • Ligands
  • N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide
  • Purines
  • Radiopharmaceuticals
  • Receptors, GABA
  • TSPO protein, human
  • Kainic Acid