放射性碘化邻碘反式十氢化萘vesamicol的两种光学异构体用作囊泡型乙酰胆碱转运体放射性配体的体内差异

In Vivo Differences between Two Optical Isomers of Radioiodinated o-iodo-trans-decalinvesamicol for Use as a Radioligand for the Vesicular Acetylcholine Transporter.

作者信息

Uno Izumi, Kozaka Takashi, Miwa Daisuke, Kitamura Yoji, Azim Mohammad Anwar-Ul, Ogawa Kazuma, Taki Junichi, Kinuya Seigo, Shiba Kazuhiro

机构信息

Division of Tracer Kinetics, Advanced Science Research Center, Kanazawa University, Ishikawa, 920-8640, Japan.

Clinical Laboratory, Kanazawa University Hospital, Kanazawa, Ishikawa, 920-8640, Japan.

出版信息

PLoS One. 2016 Jan 11;11(1):e0146719. doi: 10.1371/journal.pone.0146719. eCollection 2016.

DOI:10.1371/journal.pone.0146719

PMID:26752172

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4713475/

Abstract

PURPOSE

To develop a superior VAChT imaging probe for SPECT, radiolabeled (-)-OIDV and (+)-OIDV were isolated and investigated for differences in their binding affinity and selectivity to VAChT, as well as their in vivo activities.

PROCEDURES

Radioiodinated o-iodo-trans-decalinvesamicol ([125I]OIDV) has a high binding affinity for vesicular acetylcholine transporter (VAChT) both in vitro and in vivo. Racemic [125I]OIDV was separated into its two optical isomers (-)-[125I]OIDV and (+)-[125I]OIDV by HPLC. To investigate VAChT binding affinity (Ki) of two OIDV isomers, in vitro binding assays were performed. In vivo biodistribution study of each [125I]OIDV isomer in blood, brain regions and major organs of rats was performed at 2,30 and 60 min post-injection. In vivo blocking study were performed to reveal the binding selectivity of two [125I]OIDV isomers to VAChT in vivo. Ex vivo autoradiography were performed to reveal the regional brain distribution of two [125I]OIDV isomers and (-)-[123I]OIDV for SPECT at 60 min postinjection.

RESULTS

VAChT binding affinity (Ki) of (-)-[125I]OIDV and (+)-[125I]OIDV was 22.1 nM and 79.0 nM, respectively. At 2 min post-injection, accumulation of (-)-[125I]OIDV was the same as that of (+)-[125I]OIDV. However, (+)-[125I]OIDV clearance from the brain was faster than (-)-[125I]OIDV. At 30 min post-injection, accumulation of (-)-[125I]OIDV (0.62 ± 0.10%ID/g) was higher than (+)-[125I]OIDV (0.46 ± 0.07%ID/g) in the cortex. Inhibition of OIDV binding showed that (-)-[125I]OIDV was selectively accumulated in regions known to express VAChT in the rat brain, and ex vivo autoradiography further confirmed these results showing similar accumulation of (-)-[125I]OIDV in these regions. Furthermore, (-)-[123I]OIDV for SPECT showed the same regional brain distribution as (-)-[125I]OIDV.

CONCLUSION

These results suggest that radioiodinated (-)-OIDV may be a potentially useful tool for studying presynaptic cholinergic neurons in the brain.

摘要

目的

为开发一种用于单光子发射计算机断层扫描（SPECT）的更优质的囊泡乙酰胆碱转运体（VAChT）成像探针，分离出放射性标记的（-）-OIDV和（+）-OIDV，并研究它们对VAChT的结合亲和力、选择性以及体内活性的差异。

程序

放射性碘化邻碘反式十氢化萘维司米可（[125I]OIDV）在体外和体内对囊泡乙酰胆碱转运体（VAChT）均具有高结合亲和力。通过高效液相色谱法（HPLC）将外消旋[125I]OIDV分离为其两种旋光异构体（-）-[125I]OIDV和（+）-[125I]OIDV。为研究两种OIDV异构体对VAChT的结合亲和力（Ki），进行了体外结合试验。在注射后2、30和60分钟对每种[125I]OIDV异构体在大鼠血液、脑区和主要器官中的体内生物分布进行了研究。进行体内阻断研究以揭示两种[125I]OIDV异构体在体内对VAChT的结合选择性。在注射后60分钟进行离体放射自显影以揭示两种[125I]OIDV异构体和（-）-[123I]OIDV在SPECT下的脑区分布。

结果

（-）-[1二十五I]OIDV和（+）-[125I]OIDV对VAChT的结合亲和力（Ki）分别为22.1 nM和79.0 nM。注射后2分钟，（-）-[125I]OIDV的蓄积与（+）-[125I]OIDV相同。然而，（+）-[125I]OIDV从脑中的清除比（-）-[125I]OIDV快。注射后30分钟，（-）-[125I]OIDV在皮质中的蓄积（0.62±0.10%ID/g）高于（+）-[125I]OIDV（0.46±0.07%ID/g）。OIDV结合的抑制表明，（-）-[125I]OIDV选择性蓄积在大鼠脑中已知表达VAChT的区域，离体放射自显影进一步证实了这些结果，显示（-）-[125I]OIDV在这些区域有相似的蓄积。此外，用于SPECT的（-）-[123I]OIDV显示出与（-）-[125I]OIDV相同的脑区分布。