Synthesis and evaluation of a C-11 labeled reboxetine analog as a norepinephrine transporter imaging agent

Abstract

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Objectives: The norepinephrine transporter (NET), a specific marker of noradrenergic neurons, has been recognized in the involvement of several neurological and psychiatric disorders and is an established molecular target for the treatment of depression, ADHD, and anxiety disorder. (S,S)-reboxetine, a potent and selective NET ligand, has recently become the model compound for the development of NET imaging agents. As part of an ongoing research project in our laboratories to develop NET imaging agents, we developed a novel reboxetine analog, (S,S)-2-[α-(2-methylphenoxy)benzyl]morpholine ((S,S)-MENET). We report here the asymmetric synthesis, C-11 labeling, and evaluation of its potential as a PET tracer for NET.

Methods: (S,S)-MENET was synthesized stereospecifically in eight linear steps starting from commercially available (S)-3-amino-1,2-propanediol. In vitro competition assays of (S,S)-MENET were performed in cells expressing human NET, SERT and DAT. Radiolabeling of (S,S)-[¹¹C]MENET was accomplished by palladium catalyzed cross coupling of N-t-Boc-protected aryl-stannane precursor with ¹¹CH₃I followed by deprotection with trifluoroacetic acid and HPLC purification. In vivo regional brain uptake of (S,S)-[¹¹C]MENET was determined in rhesus monkeys with a Concorde microPET P4.

Results: (S,S)-MENET exhibited high affinity and selectivity for the NET (Ki = 3.55 nM) over the SERT (Ki = 113.95 nM) and the DAT (Ki = 327.5 nM). (S,S)-[¹¹C]MENET was obtained in 31% decay-corrected radiochemical yield with a radiochemical purity of >98%, and a log P_7.4 of 2.04. The microPET images showed (S,S)-[¹¹C]MENET displayed regional specificity, with high uptake in thalamus, cerebellum, midbrain, and pons and little uptake in striatum, consistent with the known NET distribution. A significant blocking effect was observed in NET-rich regions such as thalamus and cerebellum with the desipramine pretreatment.

Conclusions: These results suggest that (S,S)-[¹¹C]MENET could be a potential agent for mapping the human NET by PET.