Synthesis and Biological Evaluation of [F-18]FECNT-d(4) as a Novel PET Agent for Dopamine Transporter Imaging
Synthesis and Biological Evaluation of [F-18]FECNT-d(4) as a Novel PET Agent for Dopamine Transporter Imaging
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[F-18]FECNT-d(4) 作为多巴胺转运蛋白成像新型 PET 试剂的合成和生物学评价
DOI：
10.1007/s11307-021-01603-2
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发表时间：
2021
影响因子：
3.1
通讯作者：
Chen Zhengping
中科院分区：
文献类型：
--
作者：
Cao Shanshan;Tang Jie;Liu Chunyi;Fang Yi;Ji Linyang;Xu Yingjiao;Chen Zhengping
PurposeThe dopamine transporter (DAT) is a marker of the occurrence and development of Parkinson’s disease (PD) and other diseases with nigrostriatal degeneration. 2β-Carbomethoxy-3β-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)nortropane ([18F]FECNT), an18F-labelled tropane derivative, was reported to be a useful positron-emitting probe for DAT. However, the rapid formation of brain-penetrating radioactive metabolites is an impediment to the proper quantitation of DAT in PET studies with [18F]FECNT. Deuterium-substituted analogues have presented betterin vivostability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracerin vivo.ProceduresThe ligand [18F]FECNT-d4was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4were estimated byin vitrobinding assay, biodistribution, and microPET imaging in rats.In vivostability of [18F]FECNT-d4was estimated by radio-HPLC.Results[18F]FECNT-d4was synthesized at an average activity yield of 46 ± 17 % (n= 15) and the molar activity was 67 ± 12 GBq/μmol. The deuterated tracer showed suitable lipophilicity and the ability to penetrate the blood-brain barrier (brain uptake of 1.72 % ID at 5 min). [18F]FECNT-d4displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4exhibited a higher ratio of the target to non-target (striatum/cerebellum) at 15 min post administration (5.00 ± 0.44 vs 3.84 ± 0.24 for [18F]FECNT-d4vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4in normal rats showed that the ligand selectively localized to DAT-rich striatal regions and the accumulation could be blocked with DAT inhibitor. Furthermore, in the unilateral PD model rat, a significant reduction of the signal was found in the lesioned side relative to the unlesioned side. Striatal standardized uptake value of [18F]FECNT-d4remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated betterin vivostability of [18F]FECNT-d4than [18F]FECNT.ConclusionThe deuterated compound [18F]FECNT-d4may serve as a promising PET imaging agent to assess DAT-related disorders.
