I-123-Iododexetimide Preferentially Binds to the Muscarinic Receptor Subtype M-1 In Vivo

Geor Bakker*, Wilhelmina A. Vingerhoets, Jan-Peter van Wieringen, Kora de Bruin, Jos Eersels, Jan de Jong, Youssef Chahid, Bart P. Rutten, Susan DuBois, Megan Watson, Adrian J. Mogg, Hongling Xiao, Michael Crabtree, David A. Collier, Christian C. Felder, Vanessa N. Barth, Lisa M. Broad, Oswald J. Bloemen, Thersee A. van Amelsvoort, Jan Booij

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The muscarinic M-1 receptor (M1R) is highly involved in cognition, and selective M-1 agonists have procognitive properties. Loss of M1R has been found in postmortem brain tissue for several neuropsychiatric disorders and may be related to symptoms of cognitive dysfunction. I-123-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M1R-rich brain areas, I-123-iododexetimide may be an attractive radiopharmaceutical to image M1R. To date, the binding affinity and selectivity of I-123-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 I-127-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5'-[gamma-35S-thio] triphosphate [GTP gamma S-35] assay), were assessed on recombinant human M1R-M5R. Distributions of I-127-iododexetimide and I-123-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 I-127-iododexetimide and I-123-iododexetimide binding in M1R-rich brain areas by the M1R/M4R agonist xanomeline, or the antipsychotics olanzapine (M1R antagonist) and haloperidol (low M1R affinity), was assessed in rats ex vivo. Results: In vitro, I-127-iododexetimide displayed high affinity for M1R (pM range), with modest selectivity over other mAchRs. In bio-distribution studies on rats, ex vivo I-127-iododexetimide binding was much higher in M1R-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, I-127-iododexetimide binding was strongly reduced in the frontal cortex compared with wild-type mice. Finally, acute administration of both an M1R/M4R agonist xanomeline and the M1R antagonist olanzapine was able to inhibit I-123-iododexetimide ex vivo, and I-123-iododexetimide binding in M-1-rich brain areas in rats, whereas administration of haloperidol had no effect. Conclusion: The current results suggest that I-123-iododexetimide preferentially binds to M1R in vivo and can be displaced by M1R ligands. I-123-iododexetimide may therefore be a useful imaging tool as a way to further evaluate M1R changes in neuropsychiatric disorders, as a potential stratifying biomarker, or as a clinical target engagement biomarker to assess M1R.
Original languageEnglish
Pages (from-to)317-322
JournalJournal of Nuclear Medicine
Issue number2
Publication statusPublished - Feb 2015


  • dexetimide
  • muscarinic receptors
  • cognition
  • SPECT imaging
  • characterization

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