Further characterization of a CNS adenosine A2a receptor ligand [11C]KF18446 with in vitro autoradiography and in vivo tissue uptake

PET assessment of the adenosine A(2a) receptors localized in the striatum offers us a potential new diagnostic tool for neurological disorders. In the present study, we carried out in vitro receptor autoradiography of a newly developed PET ligand [C-11]KF18446 ([7-methyl-C-11]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) with rat brain sections. [C-11] KF18446 showed a high striatum/cortex binding ratio (5.0) and low nonspecific binding (<10%), suggesting that [C-11] KF18446 has characteristics comparable or slightly superior to [H-3]CGS 21680 or [H-3]SCH 58261, which are currently available representative A(2a) receptor ligands. Scatchard analysis indicated a K-d Of 9.8 nM and a B-max of 170 fmol/mm(3) tissue in the striatum and a K-d of 16.4 nM and a B-max of 33 fmol/mm(3) tissue in the cortex. Seven xanthine-type and four nonxanthine-type adenosine receptor ligands with an affinity for the adenosine A(2a) receptors significantly reduced the in vitro binding of [C-11]KF18446 to the brain section. The blocking effects were much stronger in the striatum than in the cortex, but did not necessarily parallel their affinity. On the other hand, four xanthine-type ligands and one nonxanthine-type ligand (SCH 58261) of the 11 ligands studied reduced the in vivo uptake of [C-11]KF18446 in mice, but other ligands, including A(1)-selective and nonselective ligands and three nonxanthine-typeA(2a)-selective antagonists did not. We conclude that [C-11]KF18446 is a promising adenosine A(2a) receptor ligand for PET study.