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.
Methods: 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.
Results: (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.
Conclusion: (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.