Parametric PET imaging of 5HT(2A) receptor distribution with F-18-setoperone in the normal human neocortex

Because of 5HT(2A) receptor's (5HT(2A)R) putative role in several neuropsyc hiatric diseases, studying it in vivo is an important goal. F-18-setoperone is a well-validated and widely used PET radioligand for the study of neoco rtical 5HT(2A)R. We have previously developed and validated in baboons a me thod to generate parametric maps of the binding potential (i.e., the k(3)-t o-k(4) ratio) on a pixel-by-pixel basis, based on a single-dose tracer amou nt dynamic F-18-setoperone PET paradigm, and with the receptor-poor cerebel lum as reference structure. However, previous semiquantitative PET human st udies suggested that nonspecific (NS) binding in the neocortex might not be identical to that in the cerebellum. Methods: As a first step in the devel opment of k(3):k(4) parametric mapping in humans, we therefore estimated di rectly the NS binding of F-18-setoperone in the neocortex of four young hea lthy volunteers who were studied with PET both before and after 2 wk of dai ly therapeutic oral doses of sertindole, an atypical neuroleptic possessing strong 5HT(2A)R antagonistic activity. Results: Visual analysis of the dyn amic PET data obtained over 120 min confirmed that virtually full receptor saturation had indeed been achieved; however, the late neocortical time-act ivity curves (TACs) progressively fell to lower uptake values than correspo nding cerebellar TACs and could not be fitted according to a four-compartme nt (four-Cpt) nonlinear model. indicating lack of specific binding. The cer ebellum TACs for both the control and the challenge conditions, as well as the challenge neocortical TACs, were fitted according to three-Cpt modeling , providing the k(5)/k(6) ratio and in turn the f(2) fraction for both stru ctures. Despite the smalt sample of only four subjects, the f(2) fraction f or the neocortex was significantly larger (i.e., NS binding was smaller) th an that estimated for the cerebellum. This allowed us to determine the k(3) -to-k(4) ratio for the control neocortex using the challenge neocortex as r eference structure, that is, without using the cerebellum at all. This "ass umption-free" approach was also successfully used to generate k(3):k(4) map s for these four subjects, which showed highest values for the temporal cor tex. Conclusion: This study shows that, for every new PET or SPECT radiolig and and when estimation of specific binding is based on a reference structu re, it is important to determine the uniformity of nonspecific binding befo re proceeding with human investigations.