Synthesis and biological evaluation of 18F-labelled deuterated tropane derivatives as dopamine transporter probes

Purpose: Dopamine transporter (DAT) is a promising target for positron emission tomography (PET) imaging of many neuropsychiatric diseases. F-18-labelled N-alkyl tropane analogues were reported to be useful PET radioligands for DAT. However, the drawback of F-18-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 F-18-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 [F-18]4a-e and [F-18]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. [F-18]4e was selected for further investigation with microPET of the PD model, autoradiography and biodistribution experiments and compared with its non-deuterated [F-18]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-d(6) (4e) had the lowest IC50 value of 2.7 nM. Radiolabelled [F-18]4a-e and [F-18]6a-e were obtained with radiochemical yields ranging from 10.6 +/- 2.8% to 35.1 +/- 5.4% with molar activities >20 GBq/ lmol and the radiochemical purities >99%. [F-18]4e showed the highest cell uptake (12%) and CFT inhibition efficacy (similar to 72%) among [F-18]4a-e. MicroPET results showed [F-18]4e has the highest target to non-target ratio (striatum/cerebellum). Therefore, [F-18]4e was then selected for further biological evaluation. Ex vivo autoradiography experiment confirmed high specific binding of [F-18]4e towards DAT. Biodistribution results indicated that [F-18]4e has a higher striatum/cerebellum value than [F-18]FP-CIT ([F-18]6e) at 30-120 min. Furthermore, in vivo metabolism studies in rats revealed improved stability of [F-18]4e as compared with that of [F-18]6e. Conclusions: The new probe [F-18]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. (c) 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).