2025
PET Mapping of Receptor Occupancy Using Joint Direct Parametric Reconstruction
Marin T, Belov V, Chemli Y, Ouyang J, Najmaoui Y, Fakhri G, Duvvuri S, Iredale P, Guehl N, Normandin M, Petibon Y. PET Mapping of Receptor Occupancy Using Joint Direct Parametric Reconstruction. IEEE Transactions On Biomedical Engineering 2025, 72: 1057-1066. PMID: 39446540, PMCID: PMC11875991, DOI: 10.1109/tbme.2024.3486191.Peer-Reviewed Original ResearchCentral nervous systemReceptor occupancyLow-binding regionsPET scansSimulation resultsPreclinical in vivo experimentsDynamic PET scansPairs of baselineEstimation of receptor occupancyEstimation frameworkPET neuroimagingReconstruction frameworkModulating drugsTime activity curvesParametric reconstructionDevelopment of drugs
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
2023
Investigating CNS distribution of PF‐05212377, a P‐glycoprotein substrate, by translation of 5‐HT6 receptor occupancy from non‐human primates to humans
Sawant‐Basak A, Chen L, Lockwood P, Boyden T, Doran A, Mancuso J, Zasadny K, McCarthy T, Morris E, Carson R, Esterlis I, Huang Y, Nabulsi N, Planeta B, Fullerton T. Investigating CNS distribution of PF‐05212377, a P‐glycoprotein substrate, by translation of 5‐HT6 receptor occupancy from non‐human primates to humans. Biopharmaceutics & Drug Disposition 2023, 44: 48-59. PMID: 36825693, DOI: 10.1002/bdd.2351.Peer-Reviewed Original ResearchConceptsNon-human primatesBrain penetrationPositron emission tomographyReceptor occupancyUnbound concentrationsPre-clinical evidenceVivo brain penetrationConcentration-dependent increaseP-glycoprotein substratesPlasma ECsP-gpAlzheimer's diseaseEmission tomographyRat BBBTarget engagementCumulative evidenceDependent increaseTransporter substratesCNS distributionBBBRatsDiseasePrimatesSpecies differencesHumans
2021
Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer 11C-TASP699
Naganawa M, Nabulsi NB, Matuskey D, Henry S, Ropchan J, Lin SF, Gao H, Pracitto R, Labaree D, Zhang MR, Suhara T, Nishino I, Sabia H, Ozaki S, Huang Y, Carson RE. Imaging Pituitary Vasopressin 1B Receptor in Humans with the PET Radiotracer 11C-TASP699. Journal Of Nuclear Medicine 2021, 63: 609-614. PMID: 34385336, DOI: 10.2967/jnumed.121.262430.Peer-Reviewed Original ResearchConceptsMultilinear analysis 1Test-retest variabilityPlasma concentrationsHealthy subjectsR occupancyR antagonistBrain regionsMetabolite-corrected arterial input functionAbsolute test-retest variabilityAdrenal axis activityNovel PET radiotracersSubstantial specific bindingDose-dependent fashionVasopressin 1b receptorTest-retest reproducibilityHalf maximal inhibitory concentrationAdverse eventsAxis activityOutcome measuresReceptor occupancyTime-activity curvesArginine vasopressinPosterior pituitaryDistribution volumeNeuropsychiatric disorders
2020
Joint Direct Parametric Reconstruction for Pet Receptor Occupancy Mapping
Marin T, Ouyang J, Fakhri G, Normandin M, Petibon Y. Joint Direct Parametric Reconstruction for Pet Receptor Occupancy Mapping. 2020, 00: 1-4. DOI: 10.1109/nss/mic42677.2020.9507742.Peer-Reviewed Original ResearchCentral nervous systemPositron emission tomographyVariable splitting techniqueReceptor occupancyBayesian reconstruction frameworkDenoising problemDose-occupancy relationshipReconstruction frameworkCentral nervous system drugsDevelopment of central nervous systemEstimation of receptor occupancyOptimization problemDrug brain penetrationLow precisionMeasure occupancyDrug AdministrationBrain penetrationRadiation exposureSplitting techniqueEmission tomographyDynamic dataTracer bindingNervous systemConventional approachesTarget engagementFirst-in-Human Assessment of 11C-LSN3172176, an M1 Muscarinic Acetylcholine Receptor PET Radiotracer
Naganawa M, Nabulsi N, Henry S, Matuskey D, Lin SF, Slieker L, Schwarz AJ, Kant N, Jesudason C, Ruley K, Navarro A, Gao H, Ropchan J, Labaree D, Carson RE, Huang Y. First-in-Human Assessment of 11C-LSN3172176, an M1 Muscarinic Acetylcholine Receptor PET Radiotracer. Journal Of Nuclear Medicine 2020, 62: 553-560. PMID: 32859711, PMCID: PMC8049371, DOI: 10.2967/jnumed.120.246967.Peer-Reviewed Original ResearchConceptsSimplified reference tissue modelM1 receptorsHealthy subjectsMuscarinic acetylcholine receptor subtype M1Distribution volumePET radiotracersAbsolute test-retest variabilityExcellent test-retest reproducibilityReference tissue model 2Total distribution volumeSuitable reference regionTest-retest reproducibilityTest-retest variabilityReference regionTest-retest protocolNondisplaceable distribution volumeReference tissue modelTest-retest studySubtypes M1Preclinical studiesRegional time-activity curvesAcetylcholine concentrationHuman studiesReceptor occupancyTime-activity curves
2019
Development and In Vivo Evaluation of a κ-Opioid Receptor Agonist as a PET Radiotracer with Superior Imaging Characteristics
Li S, Zheng MQ, Naganawa M, Kim S, Gao H, Kapinos M, Labaree D, Huang Y. Development and In Vivo Evaluation of a κ-Opioid Receptor Agonist as a PET Radiotracer with Superior Imaging Characteristics. Journal Of Nuclear Medicine 2019, 60: 1023-1030. PMID: 30630942, PMCID: PMC6604690, DOI: 10.2967/jnumed.118.220517.Peer-Reviewed Original ResearchConceptsMultilinear analysis 1Κ-opioid receptor agonistCentral nervous system diseaseNervous system diseasesHigh specific bindingAgonist tracersGlobus pallidusReceptor abnormalitiesReceptor agonistFrontal cortexSystem diseasesPrimate brainReceptor occupancySuperior imaging characteristicsCingulate cortexAlzheimer's diseasePeak uptakeImaging characteristicsRhesus monkeysOptimal radiotracerPET studiesArterial input functionBlocking studiesPET radiotracersAnalysis 1
2018
T156. IN VIVO CHARACTERIZATION OF THE FIRST AGONIST DOPAMINE D1 RECEPTORS PET IMAGING TRACER [18F]MNI-968 IN HUMAN
Tamagnan G, Barret O, Alagille D, Carroll V, Madonia J, Constantinescu C, SanDiego C, Papin C, Morley T, Russell D, McCarthy T, Zhang L, Gray D, Villalobos A, Lee C, Chen J, Seibyl J, Marek K. T156. IN VIVO CHARACTERIZATION OF THE FIRST AGONIST DOPAMINE D1 RECEPTORS PET IMAGING TRACER [18F]MNI-968 IN HUMAN. Schizophrenia Bulletin 2018, 44: s176-s176. PMCID: PMC5888516, DOI: 10.1093/schbul/sby016.432.Peer-Reviewed Original ResearchLogan graphical analysisNon-human primatesRhesus monkeysD1 receptorsBlockade studiesPET studiesPET radiotracersD1 receptor occupancyWhole-brain uptakeNovel PET radiotracersInhibitory G proteinSame dose levelMin post injectionHealthy human volunteersTest-retest reproducibilityBrain PET studiesPET imaging tracerAgonist PET tracerClinical studiesStriatal regionsInjected dosePsychiatric disordersCerebellar cortexDose levelsReceptor occupancy
2017
Evaluation of (‐)‐[18F]Flubatine‐specific binding: Implications for reference region approaches
Bhatt S, Hillmer AT, Nabulsi N, Matuskey D, Lim K, Lin S, Esterlis I, Carson RE, Huang Y, Cosgrove KP. Evaluation of (‐)‐[18F]Flubatine‐specific binding: Implications for reference region approaches. Synapse 2017, 72 PMID: 29105121, PMCID: PMC6547815, DOI: 10.1002/syn.22016.Peer-Reviewed Original ResearchConceptsNicotinic acetylcholine receptorsPositron emission tomographyCorpus callosumAcetylcholine receptorsGreater receptor occupancyReference regionRegion-based quantificationMin bolusTobacco smokersFrontal cortexTobacco cigarettesReceptor occupancyConstant infusionDistribution volumeEmission tomographyCallosumSpecific bindingBrainReceptorsSmokersSmokingPutamenInfusionBolusCortex18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials
Wang Y, Ayres KL, Goldman DA, Dickler MN, Bardia A, Mayer IA, Winer E, Fredrickson J, Arteaga CL, Baselga J, Manning HC, Mahmood U, Ulaner GA. 18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials. Clinical Cancer Research 2017, 23: 3053-3060. PMID: 28011460, PMCID: PMC5474190, DOI: 10.1158/1078-0432.ccr-16-2197.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedBiomarkers, PharmacologicalBreast NeoplasmsCinnamatesDose-Response Relationship, DrugEstradiolEstrogen Receptor alphaFemaleFulvestrantHumansIndazolesMiddle AgedMolecular ImagingMolecular Targeted TherapyPositron Emission Tomography Computed TomographyReceptors, EstrogenTamoxifenConceptsFES-PET/CTPET/CTClinical trialsER-positive metastatic breast cancerPhase IPhase I clinical trialEstrogen receptor occupancyPhase II trialMetastatic breast cancerSubsequent clinical trialsClin Cancer ResER downregulationFulvestrant therapyAntagonist/Escalation trialII trialTarget lesionsBreast cancerER occupancyUseful biomarkerPatientsReceptor occupancyDay 3Uptake valueDrug dosageUse of Electronic Cigarettes Leads to Significant Beta2-Nicotinic Acetylcholine Receptor Occupancy: Evidence From a PET Imaging Study
Baldassarri SR, Hillmer AT, Anderson JM, Jatlow P, Nabulsi N, Labaree D, Cosgrove KP, O’Malley S, Eissenberg T, Krishnan-Sarin S, Esterlis I. Use of Electronic Cigarettes Leads to Significant Beta2-Nicotinic Acetylcholine Receptor Occupancy: Evidence From a PET Imaging Study. Nicotine & Tobacco Research 2017, 20: 425-433. PMID: 28460123, PMCID: PMC5896427, DOI: 10.1093/ntr/ntx091.Peer-Reviewed Original ResearchConceptsBlood nicotine levelsAlternative nicotine delivery systemsNicotinic acetylcholine receptorsElectronic cigarettesNicotine delivery systemsCigarette smokersCigarette smokingTobacco cigarettesReceptor occupancyAbuse liabilityAcetylcholine receptorsNicotine levelsEC challengeCigarette smoking groupPositron emission tomography studyTobacco cigarette smokingEmission tomography studiesPET imaging studiesSmoking groupNeurologic effectsNicotine challengeNicotine addictionNicotine usersNovel radiotracersImaging studies
2016
Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [11C]-(+)-PHNO
Girgis RR, Slifstein M, D’Souza D, Lee Y, Periclou A, Ghahramani P, Laszlovszky I, Durgam S, Adham N, Nabulsi N, Huang Y, Carson RE, Kiss B, Kapás M, Abi-Dargham A, Rakhit A. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [11C]-(+)-PHNO. Psychopharmacology 2016, 233: 3503-3512. PMID: 27525990, PMCID: PMC5035321, DOI: 10.1007/s00213-016-4382-y.Peer-Reviewed Original ResearchConceptsDopamine D3 receptorD2 receptorsD3 receptorsReceptor occupancyPartial agonistPositive symptomsD2 receptor partial agonistNegative symptomsPositron emission tomography scanDose-occupancy relationshipD2 receptor occupancyWeeks of dosingEmission tomography scanWeeks of treatmentExposure-response analysisReceptor partial agonistCerebrospinal fluid samplesDopamine D2 receptorsReward-related behaviorsD2 receptor ligandsTomography scanD2 antagonismPatientsDay 1Low dosesQuantitative projection of human brain penetration of the H3 antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy
Sawant-Basak A, Chen L, Shaffer CL, Palumbo D, Schmidt A, Tseng E, Spracklin DK, Gallezot JD, Labaree D, Nabulsi N, Huang Y, Carson RE, McCarthy T. Quantitative projection of human brain penetration of the H3 antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy. Xenobiotica 2016, 47: 119-126. PMID: 27353353, DOI: 10.3109/00498254.2016.1166531.Peer-Reviewed Original Research
2015
Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050
Naganawa M, Dickinson GL, Zheng MQ, Henry S, Vandenhende F, Witcher J, Bell R, Nabulsi N, Lin SF, Ropchan J, Neumeister A, Ranganathan M, Tauscher J, Huang Y, Carson RE. Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050. Journal Of Pharmacology And Experimental Therapeutics 2015, 356: 260-266. PMID: 26628406, PMCID: PMC4727157, DOI: 10.1124/jpet.115.229278.Peer-Reviewed Original ResearchConceptsHours postdosePositron emission tomographyReceptor occupancyEmission tomographySerious adverse eventsSingle oral dosesImportant therapeutic roleΚ-opioid receptorsSubstance abuse disordersFurther clinical testingHealthy human subjectsMultilinear analysis-1 (MA1) methodAntagonist radiotracersAdverse eventsOral dosesBrain penetrationTherapeutic rolePlasma concentrationsAbuse disordersEthanol consumptionLY2456302Clinical testingNovel radiotracersAlcohol dependenceDistribution volumeCombination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo. The Journal Of Immunology 2015, 194: 950-959. PMID: 25539810, PMCID: PMC4380504, DOI: 10.4049/jimmunol.1401686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, SurfaceAntineoplastic Combined Chemotherapy ProtocolsCTLA-4 AntigenCytokinesGene Expression ProfilingGene Expression Regulation, NeoplasticHumansImmunophenotypingIpilimumabLymphocytes, Tumor-InfiltratingNeoplasmsNivolumabProgrammed Cell Death 1 ReceptorSignal TransductionT-Lymphocyte SubsetsConceptsPD-1T cellsCTLA-4Checkpoint blockadeCombination therapyReceptor occupancyCombination immune checkpoint blockadeCTLA-4 immune checkpointsPD-1 receptor occupancyTransitional memory T cellsAnti-PD-1 therapyAnti CTLA-4Immune-based combinationsPD-1 blockadeSoluble IL-2RImmune checkpoint blockadeNK cell functionMemory T cellsTherapy-induced changesT cell activationTumor T cellsHuman T cellsRemarkable antitumor effectImmunologic changesImmunologic effects
2014
Adenosine 2A Receptor Occupancy by Tozadenant and Preladenant in Rhesus Monkeys
Barret O, Hannestad J, Alagille D, Vala C, Tavares A, Papin C, Morley T, Fowles K, Lee H, Seibyl J, Tytgat D, Laruelle M, Tamagnan G. Adenosine 2A Receptor Occupancy by Tozadenant and Preladenant in Rhesus Monkeys. Journal Of Nuclear Medicine 2014, 55: 1712-1718. PMID: 25082853, DOI: 10.2967/jnumed.114.142067.Peer-Reviewed Original ResearchConceptsParkinson's diseaseReceptor occupancyNonhuman primatesPhase 2 clinical trialPET radiotracersRadiation dosimetry estimatesDose-dependent blockingAdult rhesus macaquesAdenosine 2A receptorMotor symptomsSubstantia nigraPlasma levelsClinical trialsHuman pharmacokinetic parametersMotor functionDopamine inputPharmacokinetic parametersReceptor distributionRegional uptakeTozadenantReceptor functionRhesus monkeysWhole-body PET imagesDosimetry estimatesPharmacokinetic modeling
2013
Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI
Sander C, Hooker J, Catana C, Normandin M, Alpert N, Knudsen G, Vanduffel W, Rosen B, Mandeville J. Neurovascular coupling to D2/D3 dopamine receptor occupancy using simultaneous PET/functional MRI. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 11169-11174. PMID: 23723346, PMCID: PMC3703969, DOI: 10.1073/pnas.1220512110.Peer-Reviewed Original ResearchConceptsFunctional magnetic resonance imagingDopamine receptor occupancyReceptor occupancyPositron emission tomographyFunctional magnetic resonance imaging measuresDose of racloprideBasal dopamine levelsDopamine-rich striatumInvestigation of neurovascular couplingDomains of spaceAnesthetized nonhuman primatesSimultaneous PET/fMRIDopamine levelsBrain activitySimultaneous neuroimagingBinding potentialBasal gangliaReceptor systemNonhuman primatesPositron emission tomography tracersMagnetic resonance imagingLiterature differencesEmission tomographyMap associationsNeurovascular couplingA receptor-based model for dopamine-induced fMRI signal
Mandeville J, Sander C, Jenkins B, Hooker J, Catana C, Vanduffel W, Alpert N, Rosen B, Normandin M. A receptor-based model for dopamine-induced fMRI signal. NeuroImage 2013, 75: 46-57. PMID: 23466936, PMCID: PMC3683121, DOI: 10.1016/j.neuroimage.2013.02.036.Peer-Reviewed Original ResearchConceptsDopamine releaseFMRI dataNon-human primatesLevels of dopamine releaseD2-like receptor familyElevated synaptic dopamineSynaptic dopamineAmphetamine stimulationDopaminergic stimulationFMRINeuroimaging techniquesDopamine effectsFMRI modelFMRI signalsDopamineReceptor densityReceptor occupancyBasal gangliaLow dosesHigh dosesPre-clinical dataNeuroadaptationsRacloprideAmphetamineFunction excitation
2011
P4‐253: Receptor occupancy of the 5‐HT6 receptor antagonist SAM‐760 in non‐human primates and healthy human volunteers
Comery T, Zasadny K, Morris E, Antinew J, Bell J, Billing B, Boyden T, Esterlis I, Huang Y, Kupiec J, Kuszpit K, Leil T, Nabulsi N, Planeta‐Wilson B, Plotka A, Skaddan M, Vandal G, Carson R, Katz E, McCarthy T. P4‐253: Receptor occupancy of the 5‐HT6 receptor antagonist SAM‐760 in non‐human primates and healthy human volunteers. Alzheimer's & Dementia 2011, 7: s794-s795. DOI: 10.1016/j.jalz.2011.05.2278.Peer-Reviewed Original ResearchP3‐431: Translational receptor occupancy for the 5‐HT4 partial agonist PF‐04995274 in rats, non‐human primates and healthy volunteers
Grimwood S, Drummond E, Zasadny K, Skaddan M, Brodney M, Coffman K, Nicholas T, Duvvuri S, Raunig D, Leurent C, Rowinski C, Park Y, Ogden A, Sawant A, Miller E, Rapp T, Wang Y, Planeta‐Wilson B, Ropchan J, Carson R, Morris E, Ding Y, Katz E. P3‐431: Translational receptor occupancy for the 5‐HT4 partial agonist PF‐04995274 in rats, non‐human primates and healthy volunteers. Alzheimer's & Dementia 2011, 7: s653-s653. DOI: 10.1016/j.jalz.2011.05.1875.Peer-Reviewed Original Research
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