[11C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [11C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg路kg鈭?, intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15聽mg路kg鈭?, intravenously), as well as metabolite analysis (n=4).
The precursor for the radiosynthesis of [11C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41%overall yield. [11C]D617 was synthesized in 58%-77%decay-corrected yield with a radiochemical purity of 鈮?9%. The homogeneously distributed cerebral volume of distribution (VT) of [11C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment.
VT of [11C]D617 was comparable to that of (R)-[11C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[11C]verapamil and [11C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar.