title: In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer.
abstract: Positron emission tomography studies of 5-hydroxytryptamine (5-HT)(1A) receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT(1A) agonist radiotracer [(11)C]CUMI-101. This study evaluates the sensitivity of [(11)C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [(11)C]CUMI-101 intravenous bolus of 4.5 ± 1.5 mCi. Binding potential (BP(F)=B(avail)/K(D)) was measured before (n=10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n=3; 4 mg/kg, n=3) and fenfluramine (2.5 mg/kg, n=3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BP(F) (P=0.031, P=0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [(11)C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BP(F) may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges.
authors.affiliation: Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. mm2354@columbia.edu
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Milak
authors.forename: Alin J
authors.initials: AJ
authors.lastname: Severance
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
authors.forename: Vattoly J
authors.initials: VJ
authors.lastname: Majo
authors.forename: R Todd
authors.initials: RT
authors.lastname: Ogden
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology; D005277:Fenfluramine / Q000008:administration & dosage / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007275:Injections, Intravenous; D008297:Male; D048530:Papio anubis; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D014227:Triazines / Q000493:pharmacokinetics*
chemical_list: D015283:Citalopram; D005277:Fenfluramine; D010879:Piperazines; D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D014227:Triazines; C529131:2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5-(2H,4H)-dione