Synthesis and preliminary evaluation of a carbon-11-labeled adenosine transporter blocker [(11)C]KF21562 .

We prepared an (11)C-labeled adenosine transporter blocker, [1-methyl-(11)C]-3-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H, 3H)-quinazolinedione ([(11)C]KF21652) and examined its potential as a positron emission tomography (PET) ligand for mapping adenosine transporters in the brain and peripheral organs. The log P(7.4) value of KF21652 was 3.14, and the K(i) value was 13 nM for adenosine transporters using [(3)H]nitrobenzylthioinosine as a radioligand. In mice, the highest initial uptake was found in the liver, followed by the kidney and small intestine. The brain uptake was very low. The radioactivity level slightly increased with time in the liver and small intestine, but decreased in the other organs. Coinjection of carrier KF21652 slightly decreased the uptake of [(11)C]KF21562 only in the liver, but not in any other organs. Ex vivo autoradiography of the rat brain showed that [(11)C]KF21652 was scarcely incorporated into the brain. On the other hand, in vitro autoradiography showed the binding of [(11)C]KF21562 to adenosine transporters with high nonspecific binding. These results show that the compound is not a suitable PET ligand for mapping adenosine transporters.

Evaluation of carbon-11 labeled KF15372 and its ethyl and methyl derivatives as a potential CNS adenosine A1 receptor ligand.

We prepared [11C]KF15372 ([1-propyl-11C]8-dicyclopropylmethyl-1,3-dipropylxanthine, refs 10, 13) as well as its 11C-ethyl and 11C-methyl derivatives ([11C]EPDX and [11C]MPDX), and examined the potential of the three compounds as PET ligands for CNS adenosine A1 receptors. The three compounds had high affinity for the A1 receptors in vitro in the following order; [11C]EPDX > [11C]KF15372 > [11C]MPDX. In mice, the highest initial brain uptake was found in [11C]MPDX followed by [11C]EPDX and [11C]KF15372, but the level of [11C]MPDX decreased faster than those of the other two compounds. The uptake of each compound was decreased by carrier KF15372, but not by an A2A antagonist, indicating the selective affinity for the A1 receptors. Autoradiography with [11C]MPDX ex vivo demonstrated decreased A1 receptor binding in the superior colliculus of rats deprived of retino-collicular fibers by contralateral eye enucleation. These results show that three compounds have potential as PET ligands for CNS adenosine A1 receptors.