Synthesis and Biological Evaluation of [18F]FECNT-d4 as a Novel PET Agent for Dopamine Transporter Imaging

Purpose The 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-[ 18 F]-fluoroethyl)nortropane ([ 18 F]FECNT), an 18 F-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 [ 18 F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [ 18 F]FECNT- d 4 , and to make a preliminary investigation of its properties as a DAT tracer in vivo . Procedures The ligand [ 18 F]FECNT- d 4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [ 18 F]FECNT- d 4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [ 18 F]FECNT- d 4 was estimated by radio-HPLC. Results [ 18 F]FECNT- d 4 was 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). [ 18 F]FECNT- d 4 displayed a high binding affinity for DAT comparable to that of [ 18 F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [ 18 F]FECNT- d 4 exhibited 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 [ 18 F]FECNT- d 4 vs [ 18 F]FECNT). MicroPET imaging studies of [ 18 F]FECNT- d 4 in 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 [ 18 F]FECNT- d 4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [ 18 F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [ 18 F]FECNT- d 4 than [ 18 F]FECNT. Conclusion The deuterated compound [ 18 F]FECNT- d 4 may serve as a promising PET imaging agent to assess DAT-related disorders.