2025
[18F]MK-6240 Radioligand Delivery Indices as Surrogates of Cerebral Perfusion: Bias and Correlation Against [15O]Water.
Fu J, Juttukonda M, Garimella A, Salvatore A, Lois C, Ranasinghe A, Efthimiou N, Sari H, Aye W, Guehl N, El Fakhri G, Johnson K, Dickerson B, Izquierdo-Garcia D, Catana C, Price J. [18F]MK-6240 Radioligand Delivery Indices as Surrogates of Cerebral Perfusion: Bias and Correlation Against [15O]Water. Journal Of Nuclear Medicine 2025, 66: 410-417. PMID: 39947916, PMCID: PMC11876731, DOI: 10.2967/jnumed.124.268701.Peer-Reviewed Original ResearchIn Vivo Head-to-Head Comparison of [18F]GTP1 with [18F]MK-6240 and [18F]PI-2620 in Alzheimer Disease
Olafson E, Tonietto M, Klein G, Teng E, Stephens A, Russell D, Pickthorn K, Bohorquez S. In Vivo Head-to-Head Comparison of [18F]GTP1 with [18F]MK-6240 and [18F]PI-2620 in Alzheimer Disease. Journal Of Nuclear Medicine 2025, 66: jnumed.124.268623. PMID: 39746756, PMCID: PMC11800736, DOI: 10.2967/jnumed.124.268623.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseAccumulation of tau neurofibrillary tanglesTau neurofibrillary tanglesOff-target regionsNeurofibrillary tanglesTau pathologyTau-PET signalTau PET tracersBinding profilesTau-PETMild ADNormal cognitionBraak regionsHead-to-head studiesAD patientsTauMagnitude of uptakeTracer bindingAlzheimerTarget region
2024
Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases
Aguero C, Dhaynaut M, Amaral A, Moon S, Neelamegam R, Scapellato M, Carazo-Casas C, Kumar S, El Fakhri G, Johnson K, Frosch M, Normandin M, Gómez-Isla T. Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases. Acta Neuropathologica 2024, 147: 25. PMID: 38280071, PMCID: PMC10822013, DOI: 10.1007/s00401-023-02672-z.Peer-Reviewed Original ResearchConceptsNon-AD tauopathiesTau aggregationTau PET tracersDNA-binding proteinsBinds to neurofibrillary tanglesSecond-generation tau tracersTransactive response DNA-binding proteinSpectrum of neurodegenerative diseasesNeurofibrillary tanglesTau lesionsMelanin-containing cellsTDP-43Binding signalTauopathiesBinding targetsCerebral amyloid angiopathyOff-target bindingB-amyloidBinding patternsNeurodegenerative diseasesTau tracersTauBinding to areasBinding profilesBinding
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
Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions
Kaunzner UW, Kang Y, Zhang S, Morris E, Yao Y, Pandya S, Rua S, Park C, Gillen KM, Nguyen TD, Wang Y, Pitt D, Gauthier SA. Quantitative susceptibility mapping identifies inflammation in a subset of chronic multiple sclerosis lesions. Brain 2018, 142: 133-145. PMID: 30561514, PMCID: PMC6308309, DOI: 10.1093/brain/awy296.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntigens, CDAntigens, Differentiation, MyelomonocyticBrainCarbon RadioisotopesChronic DiseaseCross-Sectional StudiesFemaleHumansInflammationIronIsoquinolinesMacrophagesMagnetic Resonance ImagingMaleMicrogliaMiddle AgedMultiple SclerosisPositron-Emission TomographyRetrospective StudiesYoung AdultConceptsChronic active lesionsMultiple sclerosisChronic lesionsActive lesionsMultiple sclerosis lesionsHyperintense rimQuantitative susceptibility mappingChronic active multiple sclerosis lesionsSclerosis lesionsChronic multiple sclerosis lesionsActive multiple sclerosis lesionsPersistent inflammatory activityProgressive multiple sclerosisMicroglia/macrophagesInnate immune activationEarly disease stagesTranslocator proteinGreater tissue damagePost-mortem studiesProgressive patientsActivated microgliaInflammatory activityPersistent inflammationImmune activationDisease stageDuvelisib, an oral dual PI3K‐δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study
O'Brien S, Patel M, Kahl BS, Horwitz SM, Foss FM, Porcu P, Jones J, Burger J, Jain N, Allen K, Faia K, Douglas M, Stern HM, Sweeney J, Kelly P, Kelly V, Flinn I. Duvelisib, an oral dual PI3K‐δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study. American Journal Of Hematology 2018, 93: 1318-1326. PMID: 30094870, PMCID: PMC8260004, DOI: 10.1002/ajh.25243.Peer-Reviewed Original ResearchConceptsChronic lymphocytic leukemiaPhase 1 studyTN patientsRR patientsLymphocytic lymphomaLymphocytic leukemiaRefractory chronic lymphocytic leukemiaMedian response durationAdvanced hematologic malignanciesPhase 3 studyOverall response rateCLL/SLLSmall lymphocytic lymphomaPatient's diarrheaExpansion cohortTransaminase elevationHematologic malignanciesPharmacodynamic activityResponse durationPatientsResponse rateΓ inhibitorDuvelisibDual inhibitorLymphomaDuvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical activity in indolent non‐Hodgkin lymphoma in a phase 1 study
Flinn IW, Patel M, Oki Y, Horwitz S, Foss FF, Allen K, Douglas M, Stern H, Sweeney J, Kharidia J, Kelly P, Kelly VM, Kahl B. Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical activity in indolent non‐Hodgkin lymphoma in a phase 1 study. American Journal Of Hematology 2018, 93: 1311-1317. PMID: 30033575, PMCID: PMC6220789, DOI: 10.1002/ajh.25228.Peer-Reviewed Original ResearchConceptsIndolent non-Hodgkin lymphomaDose-limiting toxicityNon-Hodgkin lymphomaClinical activityINHL patientsHematologic malignanciesClinical developmentGrade 3 transaminase elevationMedian progression-free survivalOral dual inhibitorAcute respiratory failureE. coli sepsisElevated liver enzymesOpen-label studyAcceptable safety profileAdvanced hematologic malignanciesDose-escalation phaseGrade 3 rashProgression-free survivalSevere adverse eventsPhase 1 studyDuration of responseFavorable clinical activityFurther clinical developmentBID cohortPharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers
Kaullen JD, Owen JS, Brouwer KLR, Heerdt PM, Lien CA, Savarese JJ, Schmith VD. Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers. Anesthesiology 2018, 128: 1107-1116. PMID: 29494403, PMCID: PMC5953789, DOI: 10.1097/aln.0000000000002157.Peer-Reviewed Original ResearchConceptsNeuromuscular blocking agentsBlocking agentRapid onsetPharmacodynamic modelDifferent dose cohortsMuscle twitch heightOffset of effectSingle ascending dosePharmacokinetic/Pharmacodynamic ModelArterial plasma concentrationsIntermediate durationPlasma drug concentration dataSigmoid Emax modelDose-response studyDrug concentration dataConcentration-time dataLow interindividual variabilityDose cohortsED95 dosesAscending dosePredictable pharmacokineticsSevoflurane anesthesiaPopulation pharmacokineticsSingle dosesTwitch height
2017
Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma
Horwitz SM, Koch R, Porcu P, Oki Y, Moskowitz A, Perez M, Myskowski P, Officer A, Jaffe JD, Morrow SN, Allen K, Douglas M, Stern H, Sweeney J, Kelly P, Kelly V, Aster JC, Weaver D, Foss FM, Weinstock DM. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood 2017, 131: 888-898. PMID: 29233821, PMCID: PMC5824337, DOI: 10.1182/blood-2017-08-802470.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAged, 80 and overClass I Phosphatidylinositol 3-KinasesClass Ib Phosphatidylinositol 3-KinaseFemaleHumansIsoquinolinesLymphoma, T-Cell, CutaneousLymphoma, T-Cell, PeripheralMaleMaximum Tolerated DoseMiddle AgedPhosphoinositide-3 Kinase InhibitorsPrognosisPurinesSafetySkin NeoplasmsTissue DistributionConceptsT-cell lymphomaPhospho-AktImmunosuppressive M2-like phenotypeCutaneous T-cell lymphomaNonmalignant immune cellsOpen-label studySerum cytokine profilesAcceptable safety profileImmune-mediated effectsPhase 1 trialOverall response rateM1-like phenotypePatient-derived xenograftsTumor-associated macrophagesM2-like phenotypeInflammatory M1-like phenotypeT cell growthRefractory PTCLTransaminase increaseAdverse eventsClinical responseCytokine profileMaculopapular rashComplete responsePreclinical evidenceDuvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies
Flinn IW, O'Brien S, Kahl B, Patel M, Oki Y, Foss FF, Porcu P, Jones J, Burger JA, Jain N, Kelly VM, Allen K, Douglas M, Sweeney J, Kelly P, Horwitz S. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies. Blood 2017, 131: 877-887. PMID: 29191916, PMCID: PMC6033052, DOI: 10.1182/blood-2017-05-786566.Peer-Reviewed Original ResearchConceptsT-cell lymphomaChronic lymphocytic leukemiaIndolent non-Hodgkin lymphomaOral dual inhibitorAdvanced hematologic malignanciesComplete responseTransaminase increaseHematologic malignanciesRefractory chronic lymphocytic leukemiaPeripheral T-cell lymphomaCutaneous T-cell lymphomaAlanine transaminase increaseHematologic malignancy treatmentDose-escalation phaseSevere adverse eventsPhase 1 studyDual inhibitorOverall response rateLate-stage clinical developmentNon-Hodgkin lymphomaCLL tumor cellsRange of dosesAdverse eventsClinical responseMedian timeOrexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors
Qiao SN, Zhou W, Liu LL, Zhang DQ, Zhong YM. Orexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors. Investigative Ophthalmology & Visual Science 2017, 58: 4712-4721. PMID: 28910447, PMCID: PMC5598320, DOI: 10.1167/iovs.17-21835.Peer-Reviewed Original ResearchConceptsDopaminergic amacrine cellsInner retinal photoreceptorsOrexin receptorsAmacrine cellsVisual functionRetinal photoreceptorsWhole-cell voltage-clamp techniqueOuter retinal photoreceptorsVoltage-clamp techniqueNeuropeptide orexinEndogenous orexinsDopaminergic systemUpstream neuronsOrexinCone functionMammalian retinaMouse retinaGenetic deletionRetinaVertebrate retinaIpRGCsReceptorsLight-induced responsesPhotoreceptorsResponseElevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study
Holmes SE, Hinz R, Conen S, Gregory CJ, Matthews JC, Anton-Rodriguez JM, Gerhard A, Talbot PS. Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study. Biological Psychiatry 2017, 83: 61-69. PMID: 28939116, DOI: 10.1016/j.biopsych.2017.08.005.Peer-Reviewed Original ResearchConceptsAnterior cingulate cortexMajor depressive episodeMajor depressive disorderPositron emission tomographyTSPO availabilityDepressive episodeControl subjectsDepressive disorderTranslocator proteinPK11195 positron emission tomographySevere major depressive episodeEmission tomographySuicidal thinkingSuicidal thoughtsPrefrontal cortexInvolvement of inflammationPeripheral inflammatory markersPositron emission tomography studyAnti-inflammatory therapyHealthy control subjectsLeast moderate severityMedication-free patientsEmission tomography studiesTSPO-specific radioligandBrains of individualsTotal Synthesis of (+)-Pancratistatin by the Rh(III)-Catalyzed Addition of a Densely Functionalized Benzamide to a Sugar-Derived Nitroalkene
Potter TJ, Ellman JA. Total Synthesis of (+)-Pancratistatin by the Rh(III)-Catalyzed Addition of a Densely Functionalized Benzamide to a Sugar-Derived Nitroalkene. Organic Letters 2017, 19: 2985-2988. PMID: 28537406, PMCID: PMC5541686, DOI: 10.1021/acs.orglett.7b01220.Peer-Reviewed Original ResearchMeSH KeywordsAlkenesAmaryllidaceae AlkaloidsBenzamidesCatalysisIsoquinolinesMolecular StructureNitro CompoundsRhodiumSugarsConceptsTotal synthesisNovel Pharmacologic Candidates for Treatment of Primary Open-Angle Glaucoma.
Lu LJ, Tsai JC, Liu J. Novel Pharmacologic Candidates for Treatment of Primary Open-Angle Glaucoma. The Yale Journal Of Biology And Medicine 2017, 90: 111-118. PMID: 28356898, PMCID: PMC5369028.Peer-Reviewed Original ResearchConceptsPrimary open-angle glaucomaOpen-angle glaucomaIntraocular pressureProstaglandin analoguesDrug-related side effectsCurrent medical treatment optionsLowering of IOPTarget intraocular pressureMedical treatment optionsVisual field lossAlpha-adrenergic agonistsNew pharmacologic optionsLower intraocular pressureMultiple daily administrationBeta-adrenergic antagonistsAdenosine receptor agonistsLow patient complianceAqueous humor outflowRho-kinase inhibitorTrabecular meshwork outflow pathwaysLatanoprostene bunodPharmacologic optionsPharmacologic treatmentTopical medicationsDaily administration
2016
Dose–response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man
Heerdt PM, Sunaga H, Owen JS, Murrell MT, Malhotra JK, Godfrey D, Steinkamp M, Savard P, Savarese JJ, Lien CA. Dose–response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man. Anesthesiology 2016, 125: 1136-1143. PMID: 27749289, DOI: 10.1097/aln.0000000000001386.Peer-Reviewed Original ResearchConceptsCardiopulmonary side effectsHistamine releaseSide effectsBlood pressureHealthy subjectsHeart rateSevoflurane/nitrous oxideDose-escalation clinical trialDynamic airway complianceNeuromuscular-blocking drugsEscalation clinical trialPlasma histamine concentrationSigmoid Emax modelClinical recoveryClinical durationAdductor pollicisTwitch depressionAirway complianceNeuromuscular blockadeClinical trialsPreclinical studiesArterial bloodEmax modelHistamine concentrationCW002In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study
Holmes SE, Hinz R, Drake RJ, Gregory CJ, Conen S, Matthews JC, Anton-Rodriguez JM, Gerhard A, Talbot PS. In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study. Molecular Psychiatry 2016, 21: 1672-1679. PMID: 27698434, DOI: 10.1038/mp.2016.180.Peer-Reviewed Original ResearchConceptsMedicated patientsTSPO availabilityMicroglial activationMicroglial activityNegative symptomsAntipsychotic-naive groupBrain microglial activityRegular intramuscular injectionsPositron emission tomography studySubset of patientsAnti-inflammatory statePrimary negative symptomsBrain of adultAntipsychotic-free patientsPathophysiology of schizophreniaPotential modulatory effectsEmission tomography studiesHealthy comparison subjectsTranslocator proteinNegative Syndrome ScaleEmission Tomography ImagingPositron emission tomography (PET) imagingParietal cortical regionsAntipsychotic medicationMedicated schizophreniaMTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells
Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE, Vazquez F, Weir BA, Fitzgerald ME, Tanaka M, Bielski CM, Scott JM, Dennis C, Cowley GS, Boehm JS, Root DE, Golub TR, Clish CB, Bradner JE, Hahn WC, Garraway LA. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 2016, 351: 1214-1218. PMID: 26912360, PMCID: PMC4997612, DOI: 10.1126/science.aad5214.Peer-Reviewed Original ResearchConceptsProtein arginine methyltransferase 5Methylthioadenosine phosphorylaseCancer cell linesMultiple cancer lineagesPutative drug targetsCell linesTumor suppressor geneComprehensive genomic profilingCancer cell dependenciesEnzyme methylthioadenosine phosphorylaseArginine methyltransferaseCancer lineagesFunctional characterizationCancer dependenciesPRMT5 inhibitorsSuppressor geneDrug targetsTherapeutic strategiesPreferential impairmentMTAP deletionEnzymatic activityGenomic alterationsGenomic profilingCell dependencyCancer cells
2015
Novel neuromuscular blocking drugs and antagonists
Heerdt PM, Sunaga H, Savarese JJ. Novel neuromuscular blocking drugs and antagonists. Current Opinion In Anaesthesiology 2015, 28: 403-410. PMID: 26087274, DOI: 10.1097/aco.0000000000000209.Peer-Reviewed Original ResearchMeSH KeywordsCysteinegamma-CyclodextrinsHumansIsoquinolinesNeuromuscular BlockadeNeuromuscular Nondepolarizing AgentsSugammadexConceptsMuscle relaxantsClinical trialsNeuromuscular blocking drugsNondepolarizing muscle relaxantsNew muscle relaxantsL-cysteine injectionNondepolarizing drugSugammadex reversalBlocking drugsHistamine releasePreclinical studiesComplete paralysisCysteine injectionClinical developmentCW002RelaxantsRapid reversalIntermediate durationDrugsGantacuriumTrialsInjectionDurationRocuroniumSugammadexEffect of gantacurium on evoked laryngospasm and duration of apnea in anesthetized healthy cats.
Martin-Flores M, Cheetham J, Campoy L, Sakai DM, Heerdt PM, Gleed RD. Effect of gantacurium on evoked laryngospasm and duration of apnea in anesthetized healthy cats. American Journal Of Veterinary Research 2015, 76: 216-23. PMID: 25710757, DOI: 10.2460/ajvr.76.3.216.Peer-Reviewed Original ResearchConceptsDuration of apneaHemoglobin oxygen saturationLast doseLaryngeal stimulationNeuromuscular blockOxygen saturationPelvic limbsLaryngeal mask airwayComplete neuromuscular blockDomestic shorthair catAdult domestic shorthair catsHealthy adult domestic shorthair catsMask airwayLaryngeal maskSE durationAnesthetized catsHemoglobin desaturationLaryngospasmShorthair catClinical relevanceGantacuriumHealthy catsApneaRima glottidisDose
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