Synthesis and Biological Evaluation of [F]FECNT-d 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-[F]-fluoroethyl)nortropane ([F]FECNT), an 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 [F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [F]FECNT-d, and to make a preliminary investigation of its properties as a DAT tracer in vivo.

PROCEDURES

The ligand [F]FECNT-d was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [F]FECNT-d were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [F]FECNT-d was estimated by radio-HPLC.

RESULTS

[F]FECNT-d 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). [F]FECNT-d displayed a high binding affinity for DAT comparable to that of [F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [F]FECNT-d 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 [F]FECNT-d vs [F]FECNT). MicroPET imaging studies of [F]FECNT-d 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 [F]FECNT-d remained ~4.02 in the striatum between 5 and 20 min, whereas that of [F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [F]FECNT-d than [F]FECNT.

CONCLUSION

The deuterated compound [F]FECNT-d may serve as a promising PET imaging agent to assess DAT-related disorders.