[123I]TPCNE-A novel SPET tracer for the sigma-1 receptor: First human studies and in vivo haloperidol challenge

• Published in: Synapse (New York, N.Y.) N.Y.), 2006-08, Vol.60 (2), p.109-117
• Main Authors: Stone, James M., Årstad, Erik, Erlandsson, Kjell, Waterhouse, Rikki N., Ell, Peter J., Pilowsky, Lyn S.
• Format: Article
• Language: English
• Subjects: Adult; antipsychotic drugs; Binding, Competitive - drug effects; Binding, Competitive - physiology; brain; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Dopamine Antagonists - metabolism; Dopamine Antagonists - pharmacology; Drug Interactions - physiology; Female; Gyrus Cinguli - diagnostic imaging; Gyrus Cinguli - drug effects; Gyrus Cinguli - metabolism; Haloperidol - metabolism; Haloperidol - pharmacology; Humans; Iodine Radioisotopes - metabolism; Liver - diagnostic imaging; Liver - drug effects; Liver - metabolism; Male; Metabolic Clearance Rate - drug effects; Metabolic Clearance Rate - physiology; Middle Aged; Piperidines - chemical synthesis; Piperidines - metabolism; Piperidines - pharmacokinetics; Radioactive Tracers; Radioligand Assay; Receptors, sigma - drug effects; Receptors, sigma - metabolism; schizophrenia; Schizophrenia - diagnostic imaging; Schizophrenia - metabolism; Schizophrenia - physiopathology; Sigma-1 Receptor; sigma-1 receptors; SPET; Time Factors; Tomography, Emission-Computed, Single-Photon - methods
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.20281

[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) ∼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. [123I]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. Synapse 60:109–117, 2006. © 2006 Wiley‐Liss, Inc.