Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R)-[11C]verapamil

Objectives: (R)-[C-11]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood-brain barrier in man. A disadvantage of (R)-[C-11]verapamil is the fact that its main metabolite, [C-11]D617, also enters the brain. For quantitative analysis of (R)-[C-11]verapamil data, it has been assumed that the cerebral kinetics of (R)-[C-11]verapamil and [C-11]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[C-11]verapamil and [C-11]D617 are indeed similar and, if so, whether [C-11]D617 itself could serve as an alternative PET tracer for P-gp. Methods: [C-11]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [C-11]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg-kg(-1), intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15 mg-kg(-1), intravenously), as well as metabolite analysis (n=4). Results: The precursor for the radiosynthesis of [C-11]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41% overall yield. [C-11]D617 was synthesized in 58%-77% decay-corrected yield with a radiochemical purity of >= 99%. The homogeneously distributed cerebral volume of distribution (V-T) of[C-11]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment. Conclusion: V-T of [C-11]D617 was comparable to that of (R)-[C-11]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[C-11]verapamil and [C-11]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar. (C) 2012 Elsevier Inc. All rights reserved.