2024
PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator
Belov V, Guehl N, Duvvuri S, Iredale P, Moon S, Dhaynaut M, Chakilam S, MacDonagh A, Rice P, Yokell D, Renger J, Fakhri G, Normandin M. PET imaging of M4 muscarinic acetylcholine receptors in rhesus macaques using [11C]MK-6884: Quantification with kinetic modeling and receptor occupancy by CVL-231 (emraclidine), a novel positive allosteric modulator. Cerebrovascular And Brain Metabolism Reviews 2024, 44: 1329-1342. PMID: 38477292, PMCID: PMC11342722, DOI: 10.1177/0271678x241238820.Peer-Reviewed Original ResearchConceptsPositive allosteric modulatorsReceptor occupancyNon-human primatesBinding potentialPositron emission tomographyMuscarinic acetylcholine receptorsAllosteric modulatorsNon-human primate brainM4 muscarinic acetylcholine receptorStriatal hyperdopaminergiaAcetylcholine receptorsBrain regionsCaudate nucleusTotal volume of distributionDose-dependent blockReference regionVolume of distributionPositron emission tomography imagingEmission tomographyReceptor levelsFunction of dosePET scansClinical trialsBlood-basedRhesus macaques
2022
Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP
Brugarolas P, Wilks M, Noel J, Kaiser J, Vesper D, Ramos-Torres K, Guehl N, Macdonald-Soccorso M, Sun Y, Rice P, Yokell D, Lim R, Normandin M, El Fakhri G. Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP. European Journal Of Nuclear Medicine And Molecular Imaging 2022, 50: 344-351. PMID: 36197499, PMCID: PMC9816249, DOI: 10.1007/s00259-022-05980-w.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDemyelinating DiseasesFemaleHumansMalePositron-Emission TomographyRadiometryRadiopharmaceuticalsTissue DistributionConceptsRadiation dosimetryTime-activity curvesAdverse eventsEffective doseMultiple bed positionsComprehensive metabolic panelNonhuman primatesHealthy human volunteersNo adverse eventsDynamic PET scansVoltage-gated potassiumAnimal models of neurological diseasesNonhuman primate studiesModels of neurological diseasesHuman biodistributionAverage effective doseMetabolic panelDosimetryOLINDA softwareHealthy volunteersUrinary bladderPET scansDemyelinating lesionsBed positionAnimal modelsDesign, Synthesis, and Characterization of [18F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2
Yuan G, Dhaynaut M, Guehl N, Afshar S, Huynh D, Moon S, Iyengar S, Jain M, Pickett J, Kang H, Ondrechen M, Fakhri G, Normandin M, Brownell A. Design, Synthesis, and Characterization of [18F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2. Journal Of Medicinal Chemistry 2022, 65: 9939-9954. PMID: 35802702, PMCID: PMC9434700, DOI: 10.1021/acs.jmedchem.2c00593.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainLigandsPositron-Emission TomographyRadiopharmaceuticalsRatsRats, Sprague-DawleyReceptors, Metabotropic GlutamateConceptsPositive allosteric modulatorsMetabotropic glutamate receptor 2Glutamate receptor 2Cu-mediated radiofluorinationPET imaging ligandsReceptor 2High molar activityExcellent radiochemical purityGloSensor assayPositron emission tomography radiotracersClasses of positive allosteric modulatorsNon-human primatesJNJ-46356479Radiochemical yieldBrain heterogeneityAllosteric modulatorsBrain uptakeMGluR2Molar activityLigandBrainBrain permeabilityImaging ligandsBinding kineticsMetabotropicSynthesis and Characterization of 5‑(2-Fluoro-4‑[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro‑2H‑pyrano[2,3‑b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2
Yuan G, Dhaynaut M, Lan Y, Guehl N, Huynh D, Iyengar S, Afshar S, Jain M, Pickett J, Kang H, Wang H, Moon S, Ondrechen M, Wang C, Shoup T, Fakhri G, Normandin M, Brownell A. Synthesis and Characterization of 5‑(2-Fluoro-4‑[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro‑2H‑pyrano[2,3‑b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2. Journal Of Medicinal Chemistry 2022, 65: 2593-2609. PMID: 35089713, PMCID: PMC9434702, DOI: 10.1021/acs.jmedchem.1c02004.Peer-Reviewed Original ResearchConceptsNegative allosteric modulatorsMetabotropic glutamate receptor 2Positron emission tomographyGlutamate receptor 2MGluR2 functionNeuropsychiatric disordersDrug effectsBrain heterogeneityReceptor 2Allosteric modulatorsMGluR2Nonhuman primatesBrain imagingPositron emission tomography imagingPositron emission tomography imaging ligandsHigh molar activityEmission tomographyExcellent radiochemical purityImaging ligandsBlocking agentsPET imagingMolar activityTherapeutic targetMetabotropicDisorders
2021
Synthesis and Characterization of [18F]JNJ-46356479 as the First 18F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2
Yuan G, Guehl N, Zheng B, Qu X, Moon S, Dhaynaut M, Shoup T, Afshar S, Kang H, Zhang Z, El Fakhri G, Normandin M, Brownell A. Synthesis and Characterization of [18F]JNJ-46356479 as the First 18F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2. Molecular Imaging And Biology 2021, 23: 527-536. PMID: 33559035, PMCID: PMC8277681, DOI: 10.1007/s11307-021-01586-0.Peer-Reviewed Original ResearchConceptsNon-human primatesIn vivo PET imaging studiesNucleus accumbensGlutamate receptor 2PET imaging ligandsImaging ligandsParietal cortexBrain regionsPET imaging studiesPET radioligandIn vivo PET imaging experimentsVolume of distributionMGluR2C57BL/6 J micePET imaging experimentsPET studiesBrainSprague-Dawley ratsAlzheimer's diseaseBrain permeabilityPre-treatment studyImaging studiesDisordersRat studiesReversible kinetics
2020
Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques
Guehl N, Ramos-Torres K, Linnman C, Moon S, Dhaynaut M, Wilks M, Han P, Ma C, Neelamegam R, Zhou Y, Popko B, Correia J, Reich D, Fakhri G, Herscovitch P, Normandin M, Brugarolas P. Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques. Cerebrovascular And Brain Metabolism Reviews 2020, 41: 1721-1733. PMID: 33090071, PMCID: PMC8221756, DOI: 10.1177/0271678x20963404.Peer-Reviewed Original ResearchConceptsFocal brain injuryMyelin repair therapyContributions of demyelinationDrivers of disabilityImaging demyelinationBrain injuryMeasurements of molecular changesTool's sensitivity to changesLower myelin contentDemyelinating lesionsNeuronal conductionImpaired conductionDemyelinationBrain penetrationGold standardRhesus macaquesInjured areaMultiple sclerosisMolecular changesMyelin sheathNeurological diseasesHigh metabolic stabilityMRI methodsMRIInjuryPET imaging of neurotransmission using direct parametric reconstruction
Petibon Y, Alpert N, Ouyang J, Pizzagalli D, Cusin C, Fava M, Fakhri G, Normandin M. PET imaging of neurotransmission using direct parametric reconstruction. NeuroImage 2020, 221: 117154. PMID: 32679252, PMCID: PMC7800040, DOI: 10.1016/j.neuroimage.2020.117154.Peer-Reviewed Original ResearchMeSH KeywordsBrainComputer SimulationHumansNeuroimagingPositron-Emission TomographyRadiopharmaceuticalsSynaptic TransmissionConceptsSignal-to-noise ratioImage reconstructionPositron emission tomography image reconstructionLow signal-to-noise ratioPoisson log-likelihood functionScattered coincidencesDetector sensitivityPET sinogramsStatistical fluctuationsEstimate parametric imagesGradient-based optimizationParametric reconstructionLog-likelihood functionEffects of head movementVoxel scalePositron emission tomographySimplified reference region modelActivity concentration dataDependence of fluorodeoxyglucose (FDG) uptake on cell cycle and dry mass: a single-cell study using a multi-modal radiography platform
Sung Y, Tetrault M, Takahashi K, Ouyang J, Pratx G, Fakhri G, Normandin M. Dependence of fluorodeoxyglucose (FDG) uptake on cell cycle and dry mass: a single-cell study using a multi-modal radiography platform. Scientific Reports 2020, 10: 4280. PMID: 32152343, PMCID: PMC7062696, DOI: 10.1038/s41598-020-59515-0.Peer-Reviewed Original ResearchMeSH KeywordsCell CycleCell DivisionCell ProliferationFluorodeoxyglucose F18HeLa CellsHumansPositron-Emission TomographyRadiopharmaceuticalsSingle-Cell AnalysisConceptsCell divisionHeLa cellsDry massM phaseCell dry massCancer compared to normal tissuesCell cycle phasesHouse-keeping proteinsSingle-cell studiesSingle-cell levelIncreased dry massProliferation indexCell cycleG1 phaseProportion of cellsHigher glucose uptakeFluorodeoxyglucose uptakeGlucose uptakeHeLaUptake rateA Radio-Nano-Platform for T1/T2 Dual-Mode PET-MR Imaging
Gholami Y, Yuan H, Wilks M, Maschmeyer R, Normandin M, Josephson L, Fakhri G, Kuncic Z. A Radio-Nano-Platform for T1/T2 Dual-Mode PET-MR Imaging. International Journal Of Nanomedicine 2020, 15: 1253-1266. PMID: 32161456, PMCID: PMC7049573, DOI: 10.2147/ijn.s241971.Peer-Reviewed Original ResearchConceptsLine spread functionPET-MR imagingSignal-to-noise ratioFull-width half-maximum (FWHMPET-MRHalf-maximum (FWHMSpatial resolutionTransmission electron microscopyImage quality gainSimultaneous positron emission tomographyContrast-enhanced diagnostic imagingAtom adsorptionPhantom imagesPositron emission tomographySpatial resolution of MRHybrid PET-MRRadio-isotopesSpread functionMulti-modal imaging techniquesSensitivity of positron emission tomographyMagnetic resonanceCo-registeredTransmission electron microscopy analysisSuper paramagnetic iron oxide nanoparticlesContrast agentsPreclinical Validation of a Single-Scan Rest/Stress Imaging Technique for 13N-Ammonia Positron Emission Tomography Cardiac Perfusion Studies
Guehl N, Pelletier-Galarneau M, Wooten D, Guerrero J, Kas A, Normandin M, Fakhri G, Alpert N. Preclinical Validation of a Single-Scan Rest/Stress Imaging Technique for 13N-Ammonia Positron Emission Tomography Cardiac Perfusion Studies. Circulation Cardiovascular Imaging 2020, 13: e009407. PMID: 31959009, PMCID: PMC7205554, DOI: 10.1161/circimaging.119.009407.Peer-Reviewed Original ResearchConceptsMyocardial blood flowPerfusion imagingMyocardial perfusion imaging proceduresSCAN-ALeft anterior descending arteryDose of adenosineAbsolute myocardial blood flowStress perfusion imagingAnterior descending arteryCardiac perfusion studiesMyocardial blood flow measurementsBland-Altman analysisNonstationary kinetic modelPositron emission tomographyMeasurement of restMyocardial blood flow valuesPharmacological stressorDescending arteryPreclinical validationMyocardial blood flow estimatesSingle-scan acquisitionPerfusion studiesVariable dosesImaging sessionMicrosphere MBF measurementsA Chelate-Free Nano-Platform for Incorporation of Diagnostic and Therapeutic Isotopes
Gholami Y, Josephson L, Akam E, Caravan P, Wilks M, Pan X, Maschmeyer R, Kolnick A, Fakhri G, Normandin M, Kuncic Z, Yuan H. A Chelate-Free Nano-Platform for Incorporation of Diagnostic and Therapeutic Isotopes. International Journal Of Nanomedicine 2020, 15: 31-47. PMID: 32021163, PMCID: PMC6954846, DOI: 10.2147/ijn.s227931.Peer-Reviewed Original ResearchConceptsDynamic light scatteringRadiochemical yieldSize exclusion chromatographyThin-layer chromatographyEmpty d orbitalsF-orbital electronsD-orbitalsICP-MSRelaxation spectrometryRadioactive isotopologuesMass spectrometryInductively coupled plasma mass spectrometryChelate-freeNonradioactive metalsPositive chargePlasma mass spectrometryFh NPsNanoparticlesReaction timeLight scatteringMetalExclusion chromatographySpectrometryApproved drugsReaction
2019
Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects
Guehl N, Wooten D, Yokell D, Moon S, Dhaynaut M, Katz S, Moody K, Gharagouzloo C, Kas A, Johnson K, El Fakhri G, Normandin M. Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects. European Journal Of Nuclear Medicine And Molecular Imaging 2019, 46: 2099-2111. PMID: 31332496, PMCID: PMC6709592, DOI: 10.1007/s00259-019-04419-z.Peer-Reviewed Original ResearchConceptsReference tissue methodDistribution volume ratioTissue methodIn vivo quantificationPharmacokinetic modeling strategiesArterial plasma input functionMultilinear reference tissue methodsTwo-tissue compartment modelBlood:plasma ratioTissue-to-plasmaPlasma input functionPlasma concentration time courseBlood-based methodMethodsThirty-five subjectsSUV ratioBlood-based analysesData setsArterial input functionPET scansControl subjectsMild cognitive impairmentPlasma ratioRadiometabolite analysisHealthy controlsConcentration time courseAutoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue
Aguero C, Dhaynaut M, Normandin M, Amaral A, Guehl N, Neelamegam R, Marquie M, Johnson K, El Fakhri G, Frosch M, Gomez-Isla T. Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue. Acta Neuropathologica Communications 2019, 7: 37. PMID: 30857558, PMCID: PMC6410510, DOI: 10.1186/s40478-019-0686-6.Peer-Reviewed Original ResearchConceptsIn vivo detection of neurofibrillary tanglesNeurofibrillary tanglesDetection of neurofibrillary tanglesAlzheimer's diseaseTDP-43Binds to neurofibrillary tanglesFrontotemporal lobar degeneration-tauOff-target bindingDNA-binding protein 43Binding patternsNon-Alzheimer tauopathiesHuman postmortem brain tissueTau aggregationPostmortem brain tissueBinding signalBinding targetsCerebral amyloid angiopathyIn vivo detectionB-amyloidNeurodegenerative diseasesHuman brain tissueTauTau positron emission tomographyBindingMK-6240
2018
Heat-induced radiolabeling and fluorescence labeling of Feraheme nanoparticles for PET/SPECT imaging and flow cytometry
Yuan H, Wilks M, Normandin M, El Fakhri G, Kaittanis C, Josephson L. Heat-induced radiolabeling and fluorescence labeling of Feraheme nanoparticles for PET/SPECT imaging and flow cytometry. Nature Protocols 2018, 13: 392-412. PMID: 29370158, PMCID: PMC5966297, DOI: 10.1038/nprot.2017.133.Peer-Reviewed Original Research
2017
Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case
Marquié M, Verwer E, Meltzer A, Kim S, Agüero C, Gonzalez J, Makaretz S, Siao Tick Chong M, Ramanan P, Amaral A, Normandin M, Vanderburg C, Gomperts S, Johnson K, Frosch M, Gómez-Isla T. Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson’s case. Acta Neuropathologica Communications 2017, 5: 75. PMID: 29047416, PMCID: PMC5648451, DOI: 10.1186/s40478-017-0482-0.Peer-Reviewed Original ResearchConceptsPositron emission tomographyBasal gangliaBinding to neuromelaninPositron emission tomography studiesDementia of AD typeInferior temporal cortexParkinson's diseaseTau pathologyPositron emission tomography scanAlzheimer's diseaseMild cognitive impairmentTemporal cortexAutoradiographic bindingBrain regionsNeurofibrillary tau pathologyOccipital cortexPositron emission tomography signalCognitive impairmentPostmortem materialEntorhinal cortexSubstantia nigraParenchymal hemorrhagePD diagnosisAutoradiography experimentsChoroid plexus[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging
Marquié M, Siao Tick Chong M, Antón-Fernández A, Verwer E, Sáez-Calveras N, Meltzer A, Ramanan P, Amaral A, Gonzalez J, Normandin M, Frosch M, Gómez-Isla T. [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging. Acta Neuropathologica 2017, 134: 619-628. PMID: 28612291, PMCID: PMC5772971, DOI: 10.1007/s00401-017-1740-8.Peer-Reviewed Original ResearchConceptsNeurofibrillary tanglesNeurofibrillary tau pathologyTau burdenBraak stageStaging of neurofibrillary tanglesBrain regionsAccurate diagnosis of Alzheimer's diseaseTau pathologyPhospho-tauStereotyped spatiotemporal patternBraak NFT stageNeurofibrillary tangle Braak stagePhosphor-screen autoradiographyAlzheimer's diseaseMild cognitive impairmentTau measuresNFT stageCognitively normal controlsObserved patternBraakCognitive impairmentWestern blottingBindingDiagnosis of Alzheimer's diseaseBraak staging of neurofibrillary tangles
2016
Pharmacokinetic Evaluation of the Tau PET Radiotracer 18F-T807 (18F-AV-1451) in Human Subjects
Wooten D, Guehl N, Verwer E, Shoup T, Yokell D, Zubcevik N, Vasdev N, Zafonte R, Johnson K, Fakhri G, Normandin M. Pharmacokinetic Evaluation of the Tau PET Radiotracer 18F-T807 (18F-AV-1451) in Human Subjects. Journal Of Nuclear Medicine 2016, 58: 484-491. PMID: 27660144, PMCID: PMC5334185, DOI: 10.2967/jnumed.115.170910.Peer-Reviewed Original ResearchConceptsDistribution volume ratioTraumatic brain injuryMetabolite-corrected arterial input functionPET imagingPlasma radioactivity concentrationsTemporal cortexDynamic PET imagesTotal volume of distributionVolume of distributionTraumatic brain injury subjectsMesial temporal cortexArterial blood samplesPosterior cingulate gyrusFocal uptakeSUV ratioHuman subjectsArterial input functionPosterior corpus callosumBolus injectionPharmacokinetic evaluation
2015
Validating novel tau positron emission tomography tracer [F‐18]‐AV‐1451 (T807) on postmortem brain tissue
Marquié M, Normandin M, Vanderburg C, Costantino I, Bien E, Rycyna L, Klunk W, Mathis C, Ikonomovic M, Debnath M, Vasdev N, Dickerson B, Gomperts S, Growdon J, Johnson K, Frosch M, Hyman B, Gómez-Isla T. Validating novel tau positron emission tomography tracer [F‐18]‐AV‐1451 (T807) on postmortem brain tissue. Annals Of Neurology 2015, 78: 787-800. PMID: 26344059, PMCID: PMC4900162, DOI: 10.1002/ana.24517.Peer-Reviewed Original ResearchConceptsTau filamentsAlzheimer brainsTDP-43Paired helical filamentsDNA-binding proteinsIn vitro binding assaysFrontotemporal lobar degeneration-tauBinding to tau lesionsDNA-binding protein 43Tauopathy brainsHelical filamentsBrain tau pathologyTau pathologyTau lesionsSubstrate-specificBinding proteinPostmortem brain tissueCerebral amyloid angiopathyPhosphor-screen autoradiographyOff-target bindingB-amyloidAlzheimer's diseaseBinding assaysTauProtein 43Heat‐Induced Radiolabeling of Nanoparticles for Monocyte Tracking by PET
Normandin M, Yuan H, Wilks M, Chen H, Kinsella J, Cho H, Guehl N, Absi‐Halabi N, Hosseini S, Fakhri G, Sosnovik D, Josephson L. Heat‐Induced Radiolabeling of Nanoparticles for Monocyte Tracking by PET. Angewandte Chemie International Edition 2015, 54: 13002-13006. PMID: 26368132, PMCID: PMC4754124, DOI: 10.1002/anie.201505525.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsHot TemperatureMetal NanoparticlesMiceMonocytesPositron-Emission TomographyRadioisotopesRadiopharmaceuticalsTissue DistributionZirconiumConceptsPositron emission tomographyRadiolabelling of nanoparticlesStandardized uptake valueNP pharmacokineticsSlow uptake processUptake valueLymph nodesCirculating monocytesMonocyte traffickingIV injectionImmune responseBlood clearanceEmission tomographyHepatic uptakeMonocytesPharmacokineticsLymphUptake processCytometryImaging the Cannabinoid CB1 Receptor in Humans with [11C] OMAR: Assessment of Kinetic Analysis Methods, Test–Retest Reproducibility, and Gender Differences
Normandin MD, Zheng MQ, Lin KS, Mason NS, Lin SF, Ropchan J, Labaree D, Henry S, Williams WA, Carson RE, Neumeister A, Huang Y. Imaging the Cannabinoid CB1 Receptor in Humans with [11C] OMAR: Assessment of Kinetic Analysis Methods, Test–Retest Reproducibility, and Gender Differences. Cerebrovascular And Brain Metabolism Reviews 2015, 35: 1313-1322. PMID: 25833345, PMCID: PMC4528005, DOI: 10.1038/jcbfm.2015.46.Peer-Reviewed Original ResearchConceptsTest-retest reliabilityCannabinoid type 1 receptorType 1 receptorCannabinoid CB1 receptorsPositron emission tomography (PET) imagingTest-retest reproducibilityEmission Tomography ImagingGender differencesTwo-tissue compartment modelCerebral uptakePresent studyCB1 receptorsCB1R availabilityInjected doseVascular componentBody weightReceptor availabilityNeuropsychiatric disordersMultilinear analysis methodRegional volumesReceptor bindingTomography imagingParent fractionOne-tissueHuman subjects