Synthesis and Preliminary Evaluation of an In Vivo Stable ¹³¹I‐Labeled Deuterated Tropane for Mapping Dopamine Transporter

Dopamine transporter (DAT) is closely associated with neurodegenerative diseases such as Parkinson's disease (PD). To develop an in vivo stable radioligand targeting DAT, we synthesized a novel iodine-131-labeled tropane analog [¹³¹I]1 with deuteration on both the N-fluoropropyl and 2β-carbomethoxy positions of the tropane scaffold and then biologically compared with the previously reported analog [¹³¹I]FP-CIT-d₆ with deuteration only on the N-fluoropropyl group. The radioligand [¹³¹I]1 was obtained via a radioiodine-destannylation reaction with a radiochemical yield of ~95%, a radiochemical purity of > 99% and a molar activity of 12.72 GBq/μmol. [¹³¹I]1 exhibited a high in vitro binding affinity for DAT with an IC₅₀ value of 2.2 nM. Metabolic stability studies demonstrated that [¹³¹I]1 displayed superior in vivo stability compared with [¹³¹I]FP-CIT-d₆. Biodistribution studies revealed that [¹³¹I]1 had better DAT affinity, specificity, and a higher target-to-background ratio than [¹³¹I]FP-CIT-d₆. Ex vivo autoradiography and blocking experiments validated the selective and reversible binding of [¹³¹I]1 to DAT and superiority to [¹³¹I]FP-CIT-d₆. These preliminary results suggest that deuterated radioligand [¹³¹I]1, with enhanced in vivo stability and higher target-to-background ratio, is a promising DAT probe, warranting the development and application of ¹²³I-labeled counterpart ([¹²³I]1) for SPECT imaging in DAT-related disorders.