title: (11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to α(1) adrenoceptors in brain.
abstract: The PET radioligand (11)C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for α1 adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo.
  
  
  METHODS
  The functional assay was performed using (35)S-GTPγS (GTP is guanosine triphosphate) in primate brains. The cross-reactivity of CUMI-101 with α1 adrenoceptors was performed using in vitro radioligand binding studies in rat, monkey, and human brains as well as in vivo PET imaging in mouse, rat, and monkey brains.
  
  
  RESULTS
  CUMI-101 did not stimulate (35)S-GTPγS binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated (35)S-GTPγS binding. Both in vitro and in vivo studies showed that CUMI-101 had significant α1 adrenoceptor cross-reactivity. On average, across all 3 species examined, cross-reactivity was highest in the thalamus (>45%) and lowest in the neocortex and cerebellum (<10%). PET imaging further confirmed that only preblocking with WAY-100635 plus prazosin decreased (11)C-CUMI-101 brain uptake to that of self-block.
  
  
  CONCLUSIONS
  CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain, with significant, regional-dependent α1 adrenoceptor cross-reactivity, limiting its potential use as a PET radioligand in humans.
authors.affiliation: National Institute of Mental Health Intramural Research Program, Bethesda, Maryland; and.
authors.forename: Stal Saurav
authors.initials: SS
authors.lastname: Shrestha
authors.forename: Jeih-San
authors.initials: JS
authors.lastname: Liow
authors.forename: Shuiyu
authors.initials: S
authors.lastname: Lu
authors.forename: Kimberly
authors.initials: K
authors.lastname: Jenko
authors.forename: Robert L
authors.initials: RL
authors.lastname: Gladding
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Morse
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D008024:Ligands; D051379:Mice; D010879:Piperazines / Q000737:chemistry; D049268:Positron-Emission Tomography; D011224:Prazosin / Q000737:chemistry; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000737:chemistry; D051381:Rats; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000737:chemistry; D014227:Triazines / Q000737:chemistry
chemical_list: C529131:2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5-(2H,4H)-dione; D002250:Carbon Radioisotopes; D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D018340:Receptors, Adrenergic, alpha-1; D058829:Serotonin 5-HT1 Receptor Antagonists; D014227:Triazines; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D011224:Prazosin
keywords: 35S-GTPγS; 5-HT1A receptor; CUMI-101; cross-reactivity; homogenate binding; positron emission tomography (PET); α1 adrenoceptor