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

Journal of Nuclear Medicine

Hongling Xiao¹  Geor Bakker¹  Jan Booij¹  Jos Eersels¹  Megan Watson¹  Wilhelmina A. Vingerhoets¹  Susan DuBois¹  Oswald J. Bloemen¹  Michael Crabtree¹  Thérèse A. van Amelsvoort¹  Christian C. Felder¹  Lisa M. Broad¹  Jan–Peter van Wieringen¹  Youssef Chahid¹  Kora de Bruin¹  Adrian J. Mogg¹  Vanessa N. Barth¹  Bart P. Rutten¹  David A. Collier¹  Jan de Jong¹ 

关键词: dexetimide;    muscarinic receptors;    cognition;    SPECT imaging;    characterization;   

DOI  :  10.2967/jnumed.114.147488

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The muscarinic M1 receptor (M1R) is highly involved in cognition, and selective M1 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. 123I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M1R-rich brain areas, 123I-iododexetimide may be an attractive radiopharmaceutical to image M1R. To date, the binding affinity and selectivity of 123I-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 127I-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5′-[γ-35S-thio]triphosphate [GTPγ35S] assay), were assessed on recombinant human M1R–M5R. Distributions of 127I-iododexetimide and 123I-iododexetimide in the brain were evaluated using liquid chromatography–mass spectrometry and storage phosphor imaging, respectively, ex vivo in rats, wild-type mice, and M1–M5 knock-out (KO) mice. Inhibition of 127I-iododexetimide and 123I-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, 127I-iododexetimide displayed high affinity for M1R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo 127I-iododexetimide binding was much higher in M1R-rich brain areas, such as the cortex and striatum, than in cerebellum (devoid of M1Rs). In M1 KO mice, but not M2–M5 KO mice, 127I-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 123I-iododexetimide ex vivo, and 123I-iododexetimide binding in M1-rich brain areas in rats, whereas administration of haloperidol had no effect. Conclusion: The current results suggest that 123I-iododexetimide preferentially binds to M1R in vivo and can be displaced by M1R ligands. 123I-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.

【 授权许可】

Unknown