Mathematical modelling of [11C]-(+)-PHNO human competition studies

The D2/D3 agonist radioligand [11C]-(+)-PHNO is currently the most suitable D3 imaging agent available, despite its limited selectivity for the D3 over the D2. Given the collocation of D2 and D3 receptors, and generally higher densities of D2, the separation of D2 and D3 information from [11C]-(+)-PHNO PET data are somewhat complex. This complexity is compounded by recent data suggesting that [11C]-(+)-PHNO PET scans might be routinely performed in non-tracer conditions (with respect to D3 receptors), and that the cerebellum (used as a reference region) might manifest some displaceable binding signal. Here we present the modelling and analysis of data from two human studies which employed an adequate dose range of selective D3 antagonists (GSK598809 and GSK618334) to interrogate the [11C]-(+)-PHNO PET signal. Models describing the changes observed in the PET volume of distribution (VT) and binding potential (BPND) were used to identify and quantify a [11C]-(+)-PHNO mass dose effect at the D3, and displaceable signal in the cerebellum, as well as providing refined estimates of regional D3 fractions of [11C]-(+)-PHNO BPND. The dose of (+)-PHNO required to occupy half of the available D3 receptors (ED50PHNO,D3) was estimated as 40ng/kg, and the cerebellum BPND was estimated as 0.40. These findings confirm that [11C]-(+)-PHNO human PET studies are in fact routinely performed under non-tracer conditions. This suggests that (+)-PHNO injection masses should be minimised and tightly controlled in order to mitigate the mass dose effect. The specific binding detected in the cerebellum was modest but could have a significant effect, for example on estimates of D3 potency in drug occupancy studies. A range of methods for the analysis of future [11C]-(+)-PHNO data, incorporating models for the effects quantified here, were developed and evaluated. The comparisons and conclusions drawn from these can inform the design and analysis of future PET studies with [11C]-(+)-PHNO. ► Selective D3 blockade enables clarification of [11C]-(+)-PHNO binding. ► (+)-PHNO mass dose effect and cerebellar binding were detected. ► Mathematical models describe and account for these effects. ► 11C-(+)-PHNO can be used to measure availability of D2 and D3 receptors in human.