Introduction
Quantifying brain nicotinic acetylcholine receptors in vivo could be very useful in neurodegenerative diseases, such as Parkinson and Alzheimer diseases, and in tobacco addiction. 2-[18F]fluoro-A-85380 is a high affinity alpha4beta2 nicotinic receptor radioligand 1 . Volume of distribution has already been quantified in healthy humans 2 . The aim of this study was to quantify the receptor site density B'max and the equilibrium dissociation constant KdVR, and characterize all compartmental kinetics.
Methods
The two experimental protocols were based on the multi-injection approch 3 . They consisted of three injections of labeled and/or unlabeled ligand. The first one aimed to estimating B'max and KdVR. and was composed of a tracer injection, followed by a partial saturation injection and then a displacement (TPSD protocol). The second protocol was designed to estimate the dissociation rate constant koff more precisely. It consisted of a tracer injection followed by a displacement and finally a second injection of labeled ligand (TDI protocol). Two baboons were scanned with a CPS HR+ positron tomograph. Each baboon underwent one TDI and two TPSD experiments. Eight regions of interest were delineated (thalamus, putamen, caudate, cortices, cerebellum). The model structure was composed of three compartments (plasma, free, and specifically bound ligand) and 6 parameters. The relative standard error on the parameter estimates (RSD) was evaluated with a sensitivity analysis and the covariance matrix. The arterial plasma concentration, after correcting for metabolites, was used as the input function.
Results
In all regions, B'max and KdVR could be estimated from a single TPSD experiment. However, kon/VR and koff were highly correlated, and could not be identified separately. The TDI experiments allowed to estimate koff with good accuracy in the thalamus. The estimated values (0.35 and 0.36 min−1) were in good accordance with the value found in vitro in rats at 37 C (0.3 min−1). In the extra-thalamic regions, koff could not be estimated and was therefore assumed to be equal to the one found in the thalamus. The use of this koff value in the TPSD experiment analyses allowed to estimate kon/VR in all regions. The other parameters RSD were slightly improved without any significant change of the estimates. B'max estimates ranged from 3.0±0.4 pmol/mL in thalamus, 1.2±0.4 pmol/mL in putamen, 0.82±0.08 pmol/mL in cerebellum, 0.65±0.06 pmol/mL in frontal cortex, to 0.24±0.01 pmol/mL in occipital cortex. B'max RSD were 5%, 12%, 19% and 27% in thalamus, frontal cortex, putamen and occipital cortex, respectively. kon/VR estimates were 0.5±0.2 mL/min/pmol, 0.3±0.1 mL/min/pmol and 0.1±0.1 mL/min/pmol in the occipital cortex, thalamus and putamen, respectively.
Conclusion
This study shows that a three injection experiment, using the TPSD protocol can provide estimates of the B'max and KdVR values in baboon brain. An additional experiment is required to identify kon/VR and koff and to characterize all compartmental kinetics.