2023
Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates
Chen B, Ojha D, Toyonaga T, Tong J, Pracitto R, Thomas M, Liu M, Kapinos M, Zhang L, Zheng M, Holden D, Fowles K, Ropchan J, Nabulsi N, De Feyter H, Carson R, Huang Y, Cai Z. Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates. European Journal Of Nuclear Medicine And Molecular Imaging 2023, 50: 2081-2099. PMID: 36849748, DOI: 10.1007/s00259-023-06162-y.Peer-Reviewed Original ResearchConceptsPositron emission tomographyHealthy nonhuman primatesVolume of distributionDistribution volume ratioBrain kineticsRat glioblastoma modelPreclinical evaluationBrain regionsGlioblastoma modelPET tracersNonhuman primatesTumor-bearing ratsEx vivo biodistributionPET imaging resultsActive clinical trialsTreatment of glioblastomaHigh specific uptakeDynamic PET scansNoninvasive quantificationBrain positron emission tomographyNondisplaceable volumeBrain penetrationLow nonspecific uptakePrognostic informationClinical trialsIn Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates
Smart K, Zheng M, Holden D, Felchner Z, Zhang L, Han Y, Ropchan J, Carson R, Vasdev N, Huang Y. In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates. Pharmaceuticals 2023, 16: 194. PMID: 37259346, PMCID: PMC9959234, DOI: 10.3390/ph16020194.Peer-Reviewed Original ResearchPositron emission tomographyNon-human primatesMetabolite-corrected arterial input functionML/Free fractionWarrants further evaluationPotential therapeutic targetGood brain uptakeAdult rhesus macaquesPlasma free fractionArterial blood samplingGray matter regionsTwo-tissue compartment modelBrain uptakeRegional time-activity curvesBlood samplingPsychiatric disordersPET scansTherapeutic targetTime-activity curvesGray matterBrain regionsEmission tomographyFurther evaluationArterial input function
2022
Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q
Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T, Holden D, Siegert TR, Laird W, Allnutt MA, Chiasseu M, Brody AH, Takahashi H, Nies SH, Pérez-Cañamás A, Sadasivam P, Lee S, Li S, Zhang L, Huang YH, Carson RE, Cai Z, Strittmatter SM. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Science Translational Medicine 2022, 14: eabi8593. PMID: 35648810, PMCID: PMC9554345, DOI: 10.1126/scitranslmed.abi8593.Peer-Reviewed Original ResearchConceptsPositron emission tomographySilent allosteric modulatorsAlzheimer's diseaseMouse modelPhospho-tau accumulationAged mouse modelAlzheimer mouse modelImmune-mediated attackSAM treatmentMicroglial mediatorsSynaptic engulfmentSynaptic lossAD miceComplement component C1qSynapse lossGlutamate responseSynaptic densityDrug washoutSynaptic localizationTherapeutic benefitCognitive impairmentAllosteric modulatorsEmission tomographyNonhuman primatesComponent C1qImaging the effect of ketamine on synaptic density (SV2A) in the living brain
Holmes SE, Finnema SJ, Naganawa M, DellaGioia N, Holden D, Fowles K, Davis M, Ropchan J, Emory P, Ye Y, Nabulsi N, Matuskey D, Angarita GA, Pietrzak RH, Duman RS, Sanacora G, Krystal JH, Carson RE, Esterlis I. Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Molecular Psychiatry 2022, 27: 2273-2281. PMID: 35165397, PMCID: PMC9133063, DOI: 10.1038/s41380-022-01465-2.Peer-Reviewed Original ResearchConceptsKetamine's therapeutic effectsMajor depressive disorderTherapeutic effectPositron emission tomographyPosttraumatic stress disorderHealthy controlsSynaptic connectionsSynaptic vesicle protein 2APost-synaptic mechanismsEffects of ketamineDiscovery of ketamineNon-human primatesAntidepressant effectsDepressive disorderSingle administrationSynaptic densityPsychiatric disordersDepression severityKetamineEmission tomographyTerminal densityLiving brainStress disorderRobust reductionDissociative symptoms
2020
The rate of dasotraline brain entry is slow following intravenous administration
Lew R, Constantinescu CC, Holden D, Carson RE, Carroll V, Galluppi G, Koblan KS, Hopkins SC. The rate of dasotraline brain entry is slow following intravenous administration. Psychopharmacology 2020, 237: 3435-3446. PMID: 32813030, PMCID: PMC7651685, DOI: 10.1007/s00213-020-05623-8.Peer-Reviewed Original ResearchConceptsSynaptic dopamine levelsDopamine levelsDAT occupancyPositron emission tomographyIntravenous administrationSynaptic dopamineRhesus monkeysSlow oral absorptionNorepinephrine reuptake inhibitorsBlood-brain barrierHalf-maximal displacementDopamine transporter inhibitionRecreational drug abusersBrain entryResultsIntravenous administrationReuptake inhibitorsPharmacodynamic effectsD2 receptorsRaclopride bindingAssociated elevationDasotralineDrug abusersMethylphenidateTransporter inhibitionEmission tomographyDysregulation of Decision Making Related to Metabotropic Glutamate 5, but Not Midbrain D3, Receptor Availability Following Cocaine Self-administration in Rats
Groman SM, Hillmer AT, Liu H, Fowles K, Holden D, Morris ED, Lee D, Taylor JR. Dysregulation of Decision Making Related to Metabotropic Glutamate 5, but Not Midbrain D3, Receptor Availability Following Cocaine Self-administration in Rats. Biological Psychiatry 2020, 88: 777-787. PMID: 32826065, PMCID: PMC8935943, DOI: 10.1016/j.biopsych.2020.06.020.Peer-Reviewed Original ResearchConceptsCocaine-dependent individualsProbabilistic reversalRelapse-like behaviorTest of motivationReceptor availabilityPersistent drug useMetabotropic glutamate 5Neural mechanismsCompulsive patternsDecision-making processDrug-induced adaptationsSelective impairmentDrug useWeeks of abstinenceCocaine takingCocaine Self-AdministrationBrain regionsDegree of disruptionDays of cocaineAdult male ratsCocaine-induced increasesCocaine-induced changesDrug-induced alterationsRobust alterationsPositron emission tomography
2016
Imaging synaptic density in the living human brain
Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, Dhaher R, Matuskey D, Baum E, Holden D, Spencer DD, Mercier J, Hannestad J, Huang Y, Carson RE. Imaging synaptic density in the living human brain. Science Translational Medicine 2016, 8: 348ra96. PMID: 27440727, DOI: 10.1126/scitranslmed.aaf6667.Peer-Reviewed Original ResearchConceptsSynaptic densityPositron emission tomographyPET imagingSynaptic vesicle glycoprotein 2ATemporal lobe epilepsyNumerous brain disordersCentral nervous systemNumber of synapsesJ PET imagingHuman brainHuman PET studiesPredominant neuronsSurgical resectionSynaptic lossLobe epilepsyPsychiatric disordersNervous systemBrain disordersPresynaptic boutonsAlzheimer's diseaseBrain tissueEmission tomographyNeuron contactsTherapeutic monitoringPET studies