Radiosynthesis and first preclinical evaluation of the novel norepinephrine transporter pet-ligand [ ¹¹C]ME@HAPTHI

Background: The norepinephrine transporter (NET) has been demonstrated to be relevant to a multitude of neurological, psychiatric and cardiovascular pathologies. Due to the wide range of possible applications for PET imaging of the NET together with the limitations of currently available radioligands, novel PET tracers for imaging of the cerebral NET with improved pharmacological and pharmacodynamic properties are needed. Methods: The present study addresses the radiosynthesis and first preclinical evaluation of the novel NET PET tracer [ ¹¹C]Me@HAPTHI by describing its affinity, selectivity, metabolic stability, plasma free fraction, blood–brain barrier (BBB) penetration and binding behaviour in in vitro autoradiography. Results: [ ¹¹C]Me@HAPTHI was prepared and displayed outstanding affinity and selectivity as well as excellent in vitro metabolic stability, and it is likely to penetrate the BBB. Moreover, selective NET binding in in vitro autoradiography was observed in human brain and rat heart tissue samples. Conclusions: All preclinical results and radiosynthetic key-parameters indicate that the novel benzothiadiazole dioxide-based PET tracer [ ¹¹C]Me@HAPTHI is a feasible and improved NET radioligand and might prospectively facilitate clinical NET imaging.