Theacetylcholineneurotransmittersystemplaysanimportantroleinthemaintenanceofnormalphysiology suchasmemoryfunction,anditsdysregulation/dysfunctionhasbeenimplicatedinavarietyofneurologicaland psychiatric disease, especially in cognitive impairments associated with Alzheimer?s disease (AD) and schizophrenia.Themuscarinicacetylcholinereceptors(mAChRs)areimportanttargetsfordrugdevelopmentin AD and schizophrenia. Agonists at the orthosteric or allosteric sites of the M1 subtype receptor are currently underdevelopmentasdrugsforthetreatmentofcognitivedeficits.PositronEmissionTomography(PET)isa non-invasiveimagingtechniquethatallowstheinvivoinvestigationofneuroreceptorsinthelivingbodyandin receptor occupancy studies of emerging drugs. The availability of PET imaging agents selective for the M1 AChR will provide a non-invasive biomarker to interrogate this receptor subtype in vivo in humans and gain insights into its function and dysfunction in diseases. Further, PET imaging with an M1 AChR selective radiotracercanbeusedasaninvivobiomarkertoassesstargetengagementandcorrelatetargetoccupancy, doseexposureandtherapeuticresponseofemergingM1AChR-targetingdrugsinclinicaltrials,thusaidingthe developmentofnoveltherapeuticagents. Therehavebeennopriorreportsofvalidated,selectivePETradiotracersforuseinhumanstoimageM1 AChR.WearethefirsttocarryouttheradiosynthesisofaselectiveM1AChRradiotracer,11C-EMO,and evaluateditinnon-humanprimates.FurtherwehaveperformedpreliminarycharacterizationofthisnovelPET radiotracerinhumansanddemonstrateditsusefulnesstoimageandquantifyM1AChRavailabilityinthe brain.Inthisapplication,weproposetofullyvalidate11C-EMOfortheimagingandquantificationofM1AChR inhumansandfordetectionofchangesinsynapticacetylcholineconcentrations.Ourultimategoalisto providethebiomedicalimagingcommunitywithanoptimal,selectivePETradiotracerforinvivoimagingofM1 AChRinhumans.ThedevelopmentandsuccessfuldeploymentofasuitablePETimagingagentforM1AChR willenable,forthefirsttime,theinvivoinvestigationofthisreceptorsubtypeinpsychiatricandneurological diseases,anddrugoccupancystudiesofemergingM1AChRtargetingtherapeuticagents.
This project proposes to develop a positron emission tomography (PET) agent for imaging the M1 subtype of muscarinic acetylcholine receptors (AChR) in humans. Availability of a suitable PET imaging agent for M1 AChR will provide the biomedical research community with a non-invasive, quantitative method to investigate the expression and functionality of this receptor subtype in the brain, as well as its possible dysfunction in patients with schizophrenia and Alzheimer's disease. Its application in receptor occupancy studies will also assist in the development of new drugs targeting the M1 AChR for treatment of cognitive impairments associated with these diseases.
| An, Joon-Yong; Lin, Kevin; Zhu, Lingxue et al. (2018) Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362: |
