Development of 18F-Labeled Deuterated Tropane Derivatives with High Metabolic Stability for PET Imaging of the Dopamine Transporter.

Purpose: Dopamine transporter (DAT) in the central nervous system is an attractive biomarker for the diagnosis and study of various neurodegenerative diseases. To develop in vivo metabolically stable positron emission tomography (PET) probes for DAT imaging with a high target/background ratio, two ¹⁸F-labeled tropane derivatives with deuteration on both the N-fluoropropyl and 2β-carbomethoxy groups of the tropane scaffold were synthesized and evaluated.

Methods: Radioligands [¹⁸F]6 and [¹⁸F]10 were synthesized from anhydroecgonine and radiolabeled with ¹⁸F through a "two-step one-pot" method. Lipophilicity, in vitro binding assay and microPET imaging in rats were performed. [¹⁸F]10 showed a higher standardized uptake value ratio (SUVr) and was selected for further evaluations by in vivo metabolism and biodistribution.

Results: The radioligands [¹⁸F]6 and [¹⁸F]10 were obtained in radiochemical purities > 98% and molar activity of about 30 GBq/μmol. [¹⁸F]6 or [¹⁸F]10 demonstrated high specificity and binding affinity to DAT in vitro, with IC₅₀ values between 2 ~ 3 nM. MicroPET imaging in wild type Sprague-Dawley rats revealed that [¹⁸F]10 has a higher SUVr than [¹⁸F]6. Blocking experiments demonstrated the selectivity and reversibility of [¹⁸F]10 for DAT binding in microPET imaging. The diagnostic efficacy of [¹⁸F]10 for DAT-related disorders was verified in semi-PD model rats with microPET. In vivo metabolic studies in rats indicated that [¹⁸F]10 exhibited enhanced stability. Biodistribution experiments further confirmed that [¹⁸F]10 accumulated in the DAT-rich region of the striatum.

Conclusion: [¹⁸F]10 is a highly promising metabolically stable ¹⁸F-labeled PET probe for DAT imaging, with potential clinical applications in detecting and monitoring DAT-related neurological disorders.