Chiral amide 1 (MK-0364, taranabant) is a potent, selective,
and orally bioavailable cannabinoid-1 receptor (CB-1R) inverse
agonist indicated for the treatment of obesity. An asymmetric
synthesis featuring a dynamic kinetic resolution via hydrogenation for the preparation of the bromo alcohol 5 is disclosed.
Conversion of the alcohol intermediate to the chiral amide 1 is
accomplished in good overall yield.
The discovery of a structurally distinct cannabinoid-1 receptor (CB1R) positron emission tomography tracer is described. Starting from an acyclic amide CB1R inverse agonist (1) as the lead compound, an efficient route to introduce 18F to the molecule was developed. Further optimization focused on reducing the lipophilicity and increasing the CB1R affinity. These efforts led to the identification of [18F]-16 that exhibited good brain uptake and an excellent signal-to-noise ratio in rhesus monkeys.
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