Abstract
BackgroundThe 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.MethodsThe 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.ConclusionsAll 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0113-3) contains supplementary material, which is available to authorized users.
Highlights
The norepinephrine transporter (NET) has been demonstrated to be relevant to a multitude of neurological, psychiatric and cardiovascular pathologies
We aimed at the preparation of a benzo[d]imidazolone derivative—[11C]Me@APPI as new NET positron emission tomography (PET) tracer [19]
The influence of basic catalysis was examined: tetrabutylammonium hydroxide 30-hydrate (TBAH) catalysis could not shift the reaction kinetics to favourable outcomes, as it did not result in any methylation of HAPTHI
Summary
The norepinephrine transporter (NET) has been demonstrated to be relevant to a multitude of neurological, psychiatric and cardiovascular pathologies. The noradrenergic system—and the presynaptic norepinephrine transporter (NET)—is proposed to be altered in a variety of neurological, neuropsychiatric and cardiovascular diseases. Previous studies have shown that the in vivo and in vitro behaviour of these reboxetine analogues, [11C]MeNER ([11C]MRB, ((S,S)-2-(α-(2[11C]methoxyphenoxy)benzyl)morpholine), [11C]MeNET and [18 F]FMeNER-D2 ((S,S)-2-(α-(2-[18 F]fluoro[2H2] methoxyphenoxy)benzyl) morpholine), is not favourable for viable imaging of the NET by PET. Limitations include their metabolic stability, late reaching of equilibrium, unexplainable striatal uptake and complexity of radiosynthesis [10, 15,16,17,18]. Despite its favourable properties and straightforward production, its affinity was not sufficient
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