The antagonist SPECT tracer 123I-iododexetimide binds preferentially to the muscarinic M1 receptor in-vivo, but is it also a potential tool to assess the occupancy of muscarinic M1 receptors by agonists?

Cognitive deterioration in neuropsychiatric disorders is associated with high attrition rates giving an urgent need to develop better pharmaceutical therapies. The underlying mechanisms of cognitive impairments are unclear but research has shown that the muscarinic receptor subtype 1 (M 1 receptor ) plays a critical role. Blocking the M 1 receptor gives rise to profound cognitive deficits, while the administration of M 1 agonist drugs improves cognitive functioning. In this research highlight we will outline supporting data that the radiotracer 123 I-iododexetimide preferentially binds to the M 1 receptor in-vivo and can be used to assess changes in M 1 receptor expression in-vivo associated with cognitive decline. These findings come from a previously published paper extensively examining binding characteristics of 123/127 I-iododexetimide to muscarinic receptors. Results of biodistribution studies also has shown that acute administration of the M 1 / 4 receptor agonist xanomeline could inhibit 127 I-iododexetimide binding in M 1 -rich brain areas in rats, suggesting that 123 I-iododexetimide may also be used to evaluate the occupancy of M 1 receptors by M 1 agonists in-vivo. This may be of clinical relevance considering the efficacy of M 1 agonist drugs in the treatment of cognitive deficits. Here we show the results from new biodistribution experiments in rats conducted to test the hypothesis that 123 I-iododexetimide may be a useful radiotracer to evaluate the M 1 receptor occupancy by M 1 agonists in-vivo. Contrary to our expectations, no significant change in 123 I-iododexetimide ex-vivo binding was observed after acute administration of xanomeline in M 1 receptor-rich brain areas, whereas significantly decreased 123 I-iododexetimide binding was found after chronic treatment with xanomeline. 123 I-iododexetimide single photon emission computed tomography (SPECT) may therefore be a useful imaging tool to further evaluate M 1 receptor changes in neuropsychiatric disorders, as a potential stratifying biomarker, to assess the occupancy of M 1 receptors after M 1 antagonist treatment, or after chronic treatment with M 1 agonists, although it may be less suited to evaluate the M 1 receptor occupancy after acute treatment with M 1 agonists. Future studies should concentrate efforts towards finding also an M 1 agonist radiotracer for positron emission tomography (PET) or SPECT to assess the working mechanism of M 1 agonists.