18F-FEAC and 18F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

Abstract

We evaluated two (18)F-labeled PET ligands, N-benzyl-N-ethyl-2-[7,8-dihydro-7-(2-(18)F-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ((18)F-FEAC) and N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-(18)F-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ((18)F-FEDAC), by investigating their kinetics in the monkey brain and by performing in vitro and in vivo imaging of translocator protein (18 kDa) (TSPO) in the infarcted rat brain. Dissection was used to determine the distribution of (18)F-FEAC and (18)F-FEDAC in mice, whereas PET was used for a monkey. With each (18)F-ligand, in vitro autoradiography and small-animal PET were performed on infarcted rat brains. (18)F-FEAC and (18)F-FEDAC had a high uptake of radioactivity in the heart, lung, and other TSPO-rich organs of mice. In vitro autoradiography showed that the binding of each (18)F-ligand significantly increased on the ipsilateral side of rat brains, compared with the contralateral side. In a small-animal PET study, PET summation images showed the contrast of radioactivity between ipsilateral and contralateral sides. Pretreatment with TSPO ligands N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide (AC-5216) or (R)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195) diminished the difference in uptake between the 2 sides. The PET study showed that each (18)F-ligand had uptake and distribution patterns in the monkey brain similar to those of (11)C-AC-5216. After injection into the monkey during PET, the uptake of each (18)F-ligand in the brain decreased over time whereas (11)C-AC-5216 did not. In the brain homogenate of mice, the percentage of the fraction corresponding to intact (18)F-FEAC and (18)F-FEDAC was 68% and 75% at 30 min after injection. In monkey plasma, each (18)F-ligand was scarcely metabolized until the end of the PET scan. (18)F-FEAC and (18)F-FEDAC produced in vitro and in vivo signals allowing visualization of the increase in TSPO expression in the infarcted rat brain. The kinetics of both (18)F-ligands in the monkey brain and tolerance for in vivo metabolism suggested their usefulness for imaging studies of TSPO in primates.