钙通道拮抗剂[11C]伊拉地平的实用放射性合成及临床前神经成像

Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist.

作者信息

Rotstein Benjamin H, Liang Steven H, Belov Vasily V, Livni Eli, Levine Dylan B, Bonab Ali A, Papisov Mikhail I, Perlis Roy H, Vasdev Neil

机构信息

Department of Radiology, Harvard Medical School, Division of Nuclear Medicine and Molecular Imaging and Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.

Department of Research, Shriners Hospitals for Children-Boston, 51 Blossom Street, Boston, MA 02114, USA.

出版信息

Molecules. 2015 May 26;20(6):9550-9. doi: 10.3390/molecules20069550.

DOI:10.3390/molecules20069550

PMID:26016546

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4870226/

Abstract

In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15-60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg-1, i.p.), whole brain radioactivity uptake was diminished by 25%-40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.

摘要

为了开发用于钙通道神经成像的体内正电子发射断层扫描（PET）探针，我们制备了二氢吡啶类钙通道拮抗剂伊拉地平的碳-11同位素类似物。去甲基伊拉地平（4-(苯并[c][1,2,5]恶二唑-4-基)-5-(异丙氧基羰基)-2,6-二甲基-1,4-二氢吡啶-3-羧酸）在四丁基氢氧化铵存在下于N,N-二甲基甲酰胺（DMF）中在高效液相色谱进样环中与[11C]CH3I反应，以良好的产率（未校正放射化学产率为6±3%）和高比活度（合成结束时为143±90 GBq·µmol-1）产生放射性示踪剂。正常大鼠的PET成像显示在基线时脑摄取迅速（峰值时为0.37±0.08% ID/cc（每立方厘米注射剂量的百分比），15 - 60秒），随后快速清除。用伊拉地平（2 mg·kg-1，腹腔注射）预处理后，全脑放射性摄取减少了25% - 40%。这项初步研究证实[11C]伊拉地平可常规合成用于研究，且具有脑渗透性。计划对钙通道放射性示踪剂的开发进行进一步研究。