PET study of the M(1)-agonists [C-11]xanomeline and [C-11]butylthio-TZTP in monkey and man

Xanomeline, a substituted TZTP, is a new M(1) selective muscarinic agonist in clinical trials for Alzheimer's disease. The brain uptake of [C-11]xanomeline and the analog [C-11]butylthio-TZTP was examined by positron emission tomography (PET), Radioactivity accumulated most markedly in the neocortex and the striatum. Pharmacological characterization in vitro and in cynomolgus monkeys in vivo by PET indicated specific [C-11]butylthio-TZTP binding to muscarinic receptors and to sigma-1 recognition sites, More than 5% of the radioactivity was in the human brain 5 min after i.v. injection of [C-11]xanomeline or [C-11]butylthio-TZTP. This high brain uptake may be clinically advantageous in the sense that substituted TZTP may induce central muscarinic agonist effects at a dose level for which there is a low risk of peripheral side-effects.