title: Contribution of SPECT measurements of D2 and 5-HT2A occupancy to the clinical development of the antipsychotic SB-773812.
abstract: The aim of this study was to assess human striatal dopamine receptor 2 (D(2)) and cortical 5-hydroxytryptamine receptor 2A (5-HT(2A)) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics-receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials.
  
  
  METHODS
  D(2) and 5-HT(2A) occupancy were measured over time (both at the time of maximum [T(max); 6 ± 2 h] and at the time of minimum [T(trough); 24 ± 4 h] plasma concentration after dosing) by means of (123)I-iodobenzamide and (123)I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers-D(2) occupancy measured at 48 (n = 9) and 56 mg (n = 9) and 5-HT(2A) occupancy at 56 mg (n = 9); study B consisted of D(2) and 5-HT(2A) occupancy measured in 12 stabilized-schizophrenia patients on stable doses (16-18 d of 56 mg/d) after washout of previous medication; and study C included D(2) occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n = 10) on stable doses (18-21 d) of SB-773812 (100 mg/d; n = 7) or risperidone (6 mg/d; n = 3).
  
  
  RESULTS
  Study A showed less than 30% D(2) occupancy at T(max), maintained at T(trough). 5-HT(2A) occupancy was 74%-97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D(2) occupancy. 5-HT(2A) occupancy ranged from 91% to 100%. In study C, SB-773812-induced D(2) occupancy was 60.3% ± 13.3% at T(max) and 55.1% ± 4.9% at T(trough). The pharmacokinetics-receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC(50)) of 92.7 ± 13.5 ng/mL for D(2) and 2.11 ± 0.50 ng/mL for 5-HT(2A).
  
  
  CONCLUSIONS
  In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D(2) occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics-receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.
authors.affiliation: Neurosciences Discovery Medicine, Barcelona Imaging Unit, GlaxoSmithKline, Barcelona, Spain. acatafau@bcnig.com
authors.forename: Ana M
authors.initials: AM
authors.lastname: Catafau
authors.forename: Santiago
authors.initials: S
authors.lastname: Bullich
authors.forename: Gianluca
authors.initials: G
authors.lastname: Nucci
authors.forename: Clare
authors.initials: C
authors.lastname: Burgess
authors.forename: Frank
authors.initials: F
authors.lastname: Gray
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo-Pich
mesh_terms: D000328:Adult; D000465:Algorithms; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D015331:Cohort Studies; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007462:Iodobenzenes; D008297:Male; D010880:Piperidines; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018967:Risperidone / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D007462:Iodobenzenes; D010880:Piperidines; C105020:R 91150; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; C426805:idobenzamide; D018967:Risperidone