title: 123I-iododexetimide preferentially binds to the muscarinic receptor subtype M1 in vivo.
abstract: 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. (123)I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M1R-rich brain areas, (123)I-iododexetimide may be an attractive radiopharmaceutical to image M1R. 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 M1R-M5R. 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 M1-M5 knock-out (KO) mice. Inhibition of (127)I-iododexetimide and (123)I-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, (127)I-iododexetimide displayed high affinity for M1R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo (127)I-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, (127)I-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 (123)I-iododexetimide ex vivo, and (123)I-iododexetimide binding in M1-rich brain areas in rats, whereas administration of haloperidol had no effect.
  
  
  CONCLUSIONS
  The current results suggest that (123)I-iododexetimide preferentially binds to M1R in vivo and can be displaced by M1R ligands. (123)I-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.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Geor.bakker@maastrichtuniversity.nl.
authors.forename: Geor
authors.initials: G
authors.lastname: Bakker
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wilhelmina A
authors.initials: WA
authors.lastname: Vingerhoets
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: van Wieringen
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Kora
authors.initials: K
authors.lastname: de Bruin
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Eersels
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Chahid
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Rutten
authors.affiliation: Eli Lilly and Co., Indianapolis, Indiana; and.
authors.forename: Susan
authors.initials: S
authors.lastname: DuBois
authors.affiliation: Eli Lilly and Co., Indianapolis, Indiana; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Watson
authors.affiliation: Lilly Research Centre, Eli Lilly and Co., Windlesham, Surrey, United Kingdom.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mogg
authors.affiliation: Eli Lilly and Co., Indianapolis, Indiana; and.
authors.forename: Hongling
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Lilly Research Centre, Eli Lilly and Co., Windlesham, Surrey, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Crabtree
authors.affiliation: Lilly Research Centre, Eli Lilly and Co., Windlesham, Surrey, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Collier
authors.affiliation: Eli Lilly and Co., Indianapolis, Indiana; and.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
authors.affiliation: Eli Lilly and Co., Indianapolis, Indiana; and.
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.affiliation: Lilly Research Centre, Eli Lilly and Co., Windlesham, Surrey, United Kingdom.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Broad
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Oswald J
authors.initials: OJ
authors.lastname: Bloemen
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Thérèse A
authors.initials: TA
authors.lastname: van Amelsvoort
authors.affiliation: Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Booij
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015415:Biomarkers; D002853:Chromatography, Liquid; D003071:Cognition; D003909:Dexetimide / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D015415:Biomarkers; C086088:CHRM1 protein, human; D007457:Iodine Radioisotopes; D008024:Ligands; C094599:N-methyl-4-iododexetimide; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D003909:Dexetimide
keywords: SPECT imaging; characterization; cognition; dexetimide; muscarinic receptors