Partial saturation approach for estimating Bmax and KD

Determination of Bmax and KD is possible if PET data is collected during high and low receptor occupancy. This is usually accomplished by (at least) two radioligand injections, one with low ligand mass (high specific activity) and the other with high ligand mass (low specific activity). Delforge et al. have developed an alternative method applying single-injection protocol, where the injected radioligand dose is between a tracer dose and a saturation dose. This partial saturation approach (PSA) was shown to be suitable for producing quantitative images of receptor binding and affinity without blood sampling in [11C]flumazenil PET studies (Delforge et al., 1995, 1996, 1997).

Partial saturation method is based on the natural decrease in bound ligand concentration in the target tissue during the PET scan. The injected mass of radioligand must be sufficiently high to occupy a notable fraction of receptors, but not too high to prevent a measurable decrease in saturation level during the PET scan. Delforge et al. (1996) estimated that receptor occupancy should ideally be 60-70%, or at least 50%.

Partial saturation method may not be applicable to every PET tracer: kinetics of the binding must be sufficiently fast (high kon and koff), otherwise the decrease in occupancy would be too slow to measure reliably during the PET scan. Also, a receptor-free reference region is required.

Partial saturation approach may be especially well suited to small animal studies, where sufficiently high specific activity of the tracer may be difficult to obtain. The method has been shown to work well in mice studies with [11C]raclopride (Wimberley et al., 2014).

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Bouvard S, Costes N, Bonnefoi F, Lavenne F, Mauguière F, Delforge J, Ryvlin P. Seizure-related short-term plasticity of benzodiazepine receptors in partial epilepsy: a [11C]flumazenil-PET study. Brain 2005; 128: 1330-1343.

Delforge J, Pappata S, Millet P, Samson Y, Bendriem B, Jobert A, Crouzel C, Syrota A. Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol. J Cereb Blood Flow Metab. 1995; 15: 284-300.

Delforge J, Spelle L, Bendriem B, Samson Y, Bottlaender M, Papageorgiou S, Syrota A. Quantitation of benzodiazepine receptors in human brain using the partial saturation method. J Nucl Med 1996; 37(1): 5-11.

Delforge J, Spelle L, Bedriem B, Samson Y, Syrota A. Parametric images of benzodiazepine receptor concentration using a partial-saturation injection. J Cereb Blood Flow Metab. 1997; 17: 343-355.

Leriche L, Björklund T, Breysse N, Besret L, Grégoire M-C, Carlsson T, Dollé F, Mandel RJ, Déglon N, Hantraye P, Kirik D. Positron emission tomography imaging demonstrates correlation between behavioral recovery and correction of dopamine neurotransmission after gene therapy. J Neurosci. 2009; 29(5): 1544-1553.

Vivash L, Gregoire M-C, Bouilleret V, Berard A, Wimberley C, Binns D, Roselt P, Katsifis A, Myers DE, Hicks RJ, O’Brien TJ, Dedeurwaerdere S. In vivo measurement of hippocampal GABAA/cBZR density with [18F]-flumazenil PET for the study of disease progression in an animal model of temporal lobe epilepsy. PLoS ONE 2014; 9(1): e86722.

Wimberley C, Angelis G, Boisson F, Callaghan P, Fischer K, Pichler BJ, Grégoire M-C, Reilhac A. Simulation-based optimisation of the PET data processing for Partial Saturation Approach protocols. Neuroimage 2014; 97: 29-40.

Wimberley CJ, Fischer K, Reilhac A, Pichler BJ, Gregoire MC. A data driven method for estimation of Bavail and appKD using a single injection protocol with [11C]raclopride in the mouse.Neuroimage 2014; 99: 365-376.

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Created at: 2014-09-03
Written by: Vesa Oikonen