Arabian Journal of Chemistry (Nov 2023)
Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes
Abstract
Purpose: Dopamine transporter (DAT) is a promising target for positron emission tomography (PET) imaging of many neuropsychiatric diseases. 18F-labelled N-alkyl tropane analogues were reported to be useful PET radioligands for DAT. However, the drawback of 18F-labelled tropane analogues is that N-alkyl on tropane is easily metabolized in vivo, which interferes with brain imaging. To develop a more in vivo stable DAT-targeted PET radioligand with high DAT affinity and specificity, in this study, we synthesized and compared a series of 18F-labelled novel deuterated N-fluoropropyl tropane derivatives [18F]4a-e for DAT tracing. Procedures: Five deuterated N-fluoropropyl-d6 tropane derivatives (4a-e) and corresponding non-deuterated compounds (6a-e) were synthesized, and their semi-inhibitory concentrations (IC50) were measured by competitive binding assay. The radioligands [18F]4a-e and [18F]6a-e were obtained by two-step one-pot radio-labelling reactions. The selectivity and specificity of these radioligands were evaluated by cellular uptake and microPET in normal rats. [18F]4e was selected for further investigation with microPET of the PD model, autoradiography and biodistribution experiments and compared with its non-deuterated [18F]6e. Finally, in vivo metabolic stability was analyzed by radio-HPLC. Results: Ten tropane compounds had high DAT affinity (IC50 = 2–21 nM), in which FP-CIT-d6 (4e) had the lowest IC50 value of 2.7 nM. Radiolabelled [18F]4a-e and [18F]6a-e were obtained with radiochemical yields ranging from 10.6 ± 2.8% to 35.1 ± 5.4% with molar activities >20 GBq/μmol and the radiochemical purities >99%. [18F]4e showed the highest cell uptake (12%) and CFT inhibition efficacy (∼72%) among [18F]4a-e. MicroPET results showed [18F]4e has the highest target to non-target ratio (striatum/cerebellum). Therefore, [18F]4e was then selected for further biological evaluation. Ex vivo autoradiography experiment confirmed high specific binding of [18F]4e towards DAT. Biodistribution results indicated that [18F]4e has a higher striatum/cerebellum value than [18F]FP-CIT ([18F]6e) at 30–120 min. Furthermore, in vivo metabolism studies in rats revealed improved stability of [18F]4e as compared with that of [18F]6e. Conclusions: The new probe [18F]4e is a promising candidate with good DAT affinity, specificity and metabolic stability for PET imaging, and might provide reliable diagnosis, treatment and prognostic detection of DAT-related neuropsychiatric diseases.
