title: [123I]TPCNE--a novel SPET tracer for the sigma-1 receptor: first human studies and in vivo haloperidol challenge.
abstract: [123I]TPCNE (1(trans-[123I]iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl] piperidine; Ki = 0.67 nM; log P = 3.36) is a novel sigma-1 receptor SPET ligand. In this study, we developed an optimized labeling method for [123I]TPCNE and investigated the kinetics, binding characteristics, and whole-body distribution of this tracer for the first time in humans. We also performed a challenge with the sigma-1 receptor antagonist haloperidol against [123I]TPCNE. Seven healthy volunteers were recruited. Dynamic brain SPET scans were performed following i.v. administration of 185 MBq [123I]TPCNE in all seven subjects. Three of the subjects were given oral haloperidol (2.5 mg) approximately 1 h before the scan. The dynamic data were analyzed with both reversible and irreversible compartmental models.[123I]TPCNE showed high uptake in brain and liver. All non-haloperidol-treated subjects showed a high whole-brain uptake (average: 8.7% of injected activity). No significant clearance of the tracer was seen up to 30 h post injection. In the haloperidol-treated subjects, the time-activity curves clearly demonstrated clearance of the tracer from the brain. Regional radioactivity concentrations were reduced by haloperidol from 42% in the cerebellum to 73% in the thalamus.[(123)I]TPCNE demonstrated high brain uptake, with highest binding found in the posterior cingulate. A region in which binding was unaffected by haloperidol pretreatment could not be identified, and the time-activity data were best described by an irreversible model.
authors.affiliation: Institute of Psychiatry, King's College London, London, UK. j.stone@iop.kcl.ac.uk
authors.forename: James M
authors.initials: JM
authors.lastname: Stone
authors.forename: Erik
authors.initials: E
authors.lastname: Arstad
authors.forename: Kjell
authors.initials: K
authors.lastname: Erlandsson
authors.forename: Rikki N
authors.initials: RN
authors.lastname: Waterhouse
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ell
authors.forename: Lyn S
authors.initials: LS
authors.lastname: Pilowsky
mesh_terms: D000328:Adult; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D008099:Liver / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics*; D011849:Radioactive Tracers; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D000097605:Sigma-1 Receptor
chemical_list: D018492:Dopamine Antagonists; D006220:Haloperidol; D007457:Iodine Radioisotopes; D010880:Piperidines; D011849:Radioactive Tracers; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C106316:1-(3-iodopropen-2-yl)-4-((4-cyanophenoxy)methyl)piperidine