Deuterated [¹⁸F]fluoroethyl tropane analogs as dopamine transporter probes: Synthesis and biological evaluation

The dopamine transporter (DAT) is vitally correlated with Parkinson's disease (PD) and other neurodegenerative diseases. Non-invasive imaging of DAT contributes to early diagnosis and monitoring of related diseases. Recently, we reported a deuterated [¹⁸F]fluoroethyl tropane analogue [¹⁸F]FECNT-d₄ as a potential DAT PET imaging agent. The objective of this work was to extend the investigation by comparing four deuterated [¹⁸F]fluoroethyl tropane derivatives ([¹⁸F]2a-d) to develop metabolically stable DAT radioligands.

Four fluoroethyl substituted phenyl-tropane compounds 1a-d and deuterated compounds 2a-d were synthesized and their IC₅₀ values to DAT were evaluated. The [¹⁸F]fluoroethyl ligands [¹⁸F]1a-d and [¹⁸F]2a-d were obtained from corresponding labeling precursors by one-step radio-labeling reactions and investigated in terms of lipophilicity and in vitro binding affinity studies. [¹⁸F]1d and [¹⁸F]2d were then selected for further evaluations by in vivo metabolism study, biodistribution, ex vivo autoradiography, and microPET imaging studies.

[¹⁸F]1a-d and [¹⁸F]2a-d were obtained in radiochemical yield of 11-32 % with molar activities of 28-54 GBq/μmol. The 1d and 2d exhibited relatively high affinity to DAT (IC₅₀: 1.9-2.1 nM). Ex vivo autoradiography and microPET studies showed that [¹⁸F]2d selectively localized on DAT-rich striatal regions and the specific signal could be blocked by DAT inhibitor. Biodistribution results showed that [¹⁸F]2d consistently exhibited a higher ratio of the target to non-target (striatum/cerebellum) than [¹⁸F]1d. Furthermore, metabolism study indicated that the in vivo metabolic stability of [¹⁸F]2d was superior to that of [¹⁸F]1d.

Our findings suggested that the deuterated compound [¹⁸F]2d might be a potential probe for DAT PET imaging in the brain.