A new method for measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade

Objectives The aim of this work is to introduce the genomic plot: a new technique for estimating the nondisplaceable fraction of a brain PET radioligand without the need of pharmacological blockade. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen Brain Atlas are used as a surrogate measure of the specific bindingMethods We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of six different neuroreceptor radioligands ([11C]WAY100635, [11C]Ro15-4513, [11C]LY2795050, [18F]FIMX, [11C]NOP-1A, [11C](R)rolipram) where nonspecific fractions were either obtained separately using drug displacementResults Both in simulations and measured data, we found that when mRNA expressions are well correlated to the PET signal at baseline (i.e. there were no significant post-transcriptional changes), the genomic plot yields accurate and precise estimates of the tracer non-specific fraction (Table). On the contrary, when this condition is not met, the method was ineffective and its bias directly followed the misspecification between mRNA and PETConclusions The genomic plot allows the estimation of a PET radioligand nondisplaceable fraction in the absence of reference region and without requiring target-competition studies. The method has general applicability to any neuroreceptor PET tracer, because it relies on mRNA brain maps of the whole human genome. Nevertheless, its precision is dependent on the ability of mRNA expression to predict protein density