Background
The sigma-1 receptor is of increasing relevance to neuropsychiatric function and illness (Leonard 2004). [123I]TPCNE (1(trans-[123I]iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]piperidine; Ki = 0.67 nM; log P = 3.36) is a novel SPET ligand for the sigma-1 receptor which has demonstrated high selectivity and potency for the receptor in pre-clinical studies (Waterhouse et al 1997). Haloperidol is an antipsychotic drug known to be a potent antagonist of the sigma-1 receptor. Here we have used a pre-dose haloperidol challenge to validate the specific binding of [123I]TPCNE binding in healthy volunteers.
Method
Seven healthy volunteer subjects were recruited (2 female, 5 male, mean age=31, range=20–52). Three of the subjects (1 female, 2 male, mean age=30 range=22–40) received an oral dose of haloperidol (2.5 mg) approximately 1 h prior to the commencement of the scan. All subjects were given a bolus dose of approximately 185MBq [123I]TPCNE. Dynamic data acquisition with a brain dedicated Picker Prism 3000XP and arterial sampling began simultaneously. In two of the haloperidol treated subjects, arterial sampling was not possible, but venous samples were taken to generate time activity blood data for future analyses. Scanning continued at time points up to 3.5 hours. Data were metabolite-corrected and analysed by compartmental modelling with both reversible and irreversible models. The outcome measure was total volume of distribution (VT) in the case of the reversible models, and effective uptake rate (Ki) for the irreversible models.
Results
Time activity curves from all three haloperidol treated subjects indicated clear displacement in all brain regions. The haloperidol treated subject with full arterial sampling had lower measures of binding in all regions regardless of the kinetic modelling method used than any of the control subjects. The mean estimated occupancy by haloperidol varied depending on region from 42% in the cerebellum to 73% in the thalamus.
Conclusions
[123I]TPCNE is a selective and specific ligand for the sigma-1 receptor that is displaceable in humans in vivo with haloperidol. As expected based on the widespread expression of the sigma-1 receptor in the primate CNS, we failed to identify a non-displaceable reference region in the brain for this radioligand.