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?

Abstract

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 (M₁ receptor₎ plays a critical role. Blocking the M₁ receptor gives rise to profound cognitive deficits, while the administration of M₁ agonist drugs improves cognitive functioning. In this research highlight we will outline supporting data that the radiotracer ¹²³I-iododexetimide preferentially binds to the M₁ receptor in-vivo and can be used to assess changes in M₁ receptor expression in-vivo associated with cognitive decline. These findings come from a previously published paper extensively examining binding characteristics of ^123/127I-iododexetimide to muscarinic receptors. Results of biodistribution studies also has shown that acute administration of the M₁/₄ receptor agonist xanomeline could inhibit ¹²⁷I-iododexetimide binding in M₁-rich brain areas in rats, suggesting that ¹²³I-iododexetimide may also be used to evaluate the occupancy of M₁ receptors by M₁ agonists in-vivo. This may be of clinical relevance considering the efficacy of M₁ 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 ¹²³I-iododexetimide may be a useful radiotracer to evaluate the M₁ receptor occupancy by M₁ agonists in-vivo. Contrary to our expectations, no significant change in ¹²³I-iododexetimide ex-vivo binding was observed after acute administration of xanomeline in M₁ receptor-rich brain areas, whereas significantly decreased ¹²³I-iododexetimide binding was found after chronic treatment with xanomeline. ¹²³I-iododexetimide single photon emission computed tomography (SPECT) may therefore be a useful imaging tool to further evaluate M₁ receptor changes in neuropsychiatric disorders, as a potential stratifying biomarker, to assess the occupancy of M₁ receptors after M₁ antagonist treatment, or after chronic treatment with M₁ agonists, although it may be less suited to evaluate the M₁ receptor occupancy after acute treatment with M₁ agonists. Future studies should concentrate efforts towards finding also an M₁ agonist radiotracer for positron emission tomography (PET) or SPECT to assess the working mechanism of M₁ agonists.