¹²³I-Iododexetimide Preferentially Binds to the Muscarinic Receptor Subtype M₁ In Vivo

Abstract

The muscarinic M 1 receptor (M 1 R) is highly involved in cognition, and selective M 1 agonists have procognitive properties. Loss of M 1 R has been found in postmortem brain tissue for several neuropsychiatric disorders and may be related to symptoms of cognitive dysfunction. 123 I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M 1 R-rich brain areas, 123 I-iododexetimide may be an attractive radiopharmaceutical to image M 1 R. To date, the binding affinity and selectivity of 123 I-iododexetimide for the mAchR subtypes has not been characterized, nor has its brain distribution been studied intensively. Therefore, this study aimed to address these topics. Methods: The in vitro affinity and selectivity of 127 I-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5′-[γ-35 S-thio]triphosphate [GTPγ 35 S] assay), were assessed on recombinant human M 1 R-M 5 R. Distributions of 127 I-iododexetimide and 123 I-iododexetimide in the brain were evaluated using liquid chromatography-mass spectrometry and storage phosphor imaging, respectively, ex vivo in rats, wild-type mice, and M 1 -M 5 knock-out (KO) mice. Inhibition of 127 I-iododexetimide and 123 I-iododexetimide binding in M 1 R-rich brain areas by the M 1 R/ M 4 R agonist xanomeline, or the antipsychotics olanzapine (M 1 R antagonist) and haloperidol (low M 1 R affinity), was assessed in rats ex vivo. Results: In vitro, 127 I-iododexetimide displayed high affinity for M 1 R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo 127 I-iododexetimide binding was much higher in M 1 R-rich brain areas, such as the cortex and striatum, than in cerebellum (devoid of M 1 Rs). In M 1 KO mice, but not M 2 -M 5 KO mice, 127 I-iododexetimide binding was strongly reduced in the frontal cortex compared with wild-type mice. Finally, acute administration of both an M 1 R/M 4 R agonist xanomeline and the M 1 R antagonist olanzapine was able to inhibit 123 I-iododexetimide ex vivo, and 123 I-iododexetimide binding in M 1 -rich brain areas in rats, whereas administration of haloperidol had no effect. Conclusion: The current results suggest that 123 I-iododexetimide preferentially binds to M 1 R in vivo and can be displaced by M 1 R ligands. 123 I-iododexetimide may therefore be a useful imaging tool as a way to further evaluate M 1 R changes in neuropsychiatric disorders, as a potential stratifying biomarker, or as a clinical target engagement biomarker to assess M 1 R.

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

“…While we cannot entirely exclude a contribution by other subtypes of this class when interpreting data using selective M 1 R antagonists, our data using M 1 R-deficient mice, overexpression of GFP-M 1 R, and the M 1 R-specific antagonist MT7 indicate that this receptor subtype mediates cholinergic constraint of the AMPK/PGC-1α axis, mitochondrial function, and neurite outgrowth. A role for endogenous ACh in regulating this pathway is supported by our measurement of secreted ACh detected in the culture medium, approximately 16 nmoles/ml (16 μM), which far exceeds estimations of the ACh K D of 0.2-0.4 nM for the M 1 R taken from studies with rat brain neurons (46,47). These data also correspond well with extracellular levels of ACh in the range of 0.1 to 0.6 nM detected using microdialysis in human and rat skin (48,49).…”

In Vitro Pharmacological Characterization and In Vivo Validation of LSN3172176 a Novel M1 Selective Muscarinic Receptor Agonist Tracer Molecule for Positron Emission Tomography

“…In vitro, IDEX is a nonselective mAChR antagonist, but in vivo it measures, primarily, M1 receptor occupancy owing to the high expression of M1 mAChRs relative to other subtypes in the hippocampus and cortex. (Bakker et al, 2015). This in vivo selectivity in rodent brain probably reflects in part the high expression of M1 relative to other mAChRs in hippocampus and cortex (Oki et al, 2005), and this binding distribution is mirrored in clinical studies with 123 I-IDEX (Wilson et al, 1989;Müller-Gärtner et al, 1992;Boundy et al, 1995).…”

Development and Design of Next-Generation Head-Mounted Ambulatory Microdose Positron-Emission Tomography (AM-PET) System

“…However, the PET-Hat imager has not yet been tested on humans. A recently developed imager (Helmet-Chin PET) developed by Yamaya and colleagues is designed for upright human brain imaging, has outstanding brain coverage and sensitivity, and provides high-quality imaging data of brain phantoms, but at the expense of detector bulkiness and the system not being truly “wearable” [10]. …”