کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2154143 | 1090219 | 2012 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R)-[11C]verapamil Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R)-[11C]verapamil](/preview/png/2154143.png)
Objectives(R)-[11C]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)-[11C]verapamil is the fact that its main metabolite, [11C]D617, also enters the brain. For quantitative analysis of (R)-[11C]verapamil data, it has been assumed that the cerebral kinetics of (R)-[11C]verapamil and [11C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[11C]verapamil and [11C]D617 are indeed similar and, if so, whether [11C]D617 itself could serve as an alternative PET tracer for P-gp.Methods[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·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).ResultsThe 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 ≥99%. The homogeneously distributed cerebral volume of distribution (VT) of [11C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment.ConclusionVT 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.
Journal: Nuclear Medicine and Biology - Volume 39, Issue 4, May 2012, Pages 530–539