TEST-RETEST VARIABILITY OF SEROTONIN 5-HT2A RECEPTOR-BINDING MEASUREDWITH POSITRON-EMISSION-TOMOGRAPHY AND [F-18] ALTANSERIN IN THE HUMAN BRAIN

The role of serotonin in CNS function and in many neuropsychiatric dis eases (e.g., schizophrenia, affective disorders, degenerative dementia s) support the development of a reliable measure of serotonin receptor binding in vivo in human subjects. To this end, the regional distribu tion and intrasubject test-retest variability of the binding of [F-18] altanserin were measured as important steps in the further development of [F-18]altanserin as a radiotracer for positron emission tomography (PET) studies of the serotonin 5-HT2A receptor. Two high specific act ivity [F-18]altanserin PET studies were performed in normal control su bjects (n = 8) on two separate days (2-16 days apart). Regional specif ic binding was assessed by distribution volume (DV), estimates that we re derived using a conventional four compartment (4C) model, and the L ogan graphical analysis method. For both analysis methods, levels of [ F-18]altanserin binding were highest in cortical areas, lower in the s triatum and thalamus, and lowest in the cerebellum. Similar average di fferences of 13% or less were observed for the 4C model DV determined in regions with high receptor concentrations with greater variability in regions with low concentrations (16-20%). For all regions, the abso lute value of the test-retest differences in the Logan DV values avera ged 12% or less. The test-retest differences in the DV ratios (regiona l DV values normalized to the cerebellar DV) determined by both data a nalysis methods averaged less than 10%. The regional [F-18] altanserin DV values using both of these methods were significantly correlated w ith literature-based values of the regional concentrations of 5-HT2A r eceptors determined by postmortem autoradiographic studies (r(2) = 0.9 5, P < 0.001 for the 4C model and r(2) = 0.96, P < 0.001 for the Logan method). Brain uptake studies in rats demonstrated that two different radiolabeled metabolites of [F-18] altanserin (present at levels of 3 -25% of the total radioactivity in human plasma 10-120 min postinjecti on) were able to penetrate the blood-brain barrier. However, neither o f these radiolabeled metabolites bound specifically to the 5-HT2A rece ptor and did not interfere with the interpretation of regional [F-18] altanserin-specific binding parameters obtained using either a convent ional 4C model or the Logan graphical analysis method. In summary, the se results demonstrate that the test-retest variability of [F-18] alta nserin-specific binding is comparable to that of other PET radiotracer s and that the regional specific binding of [F-18]altanserin in human brain was correlated with the known regional distribution of 5-HT2A re ceptors. These findings support the usefulness of [F-18] altanserin as a radioligand for PET studies of 5-HT2A receptors. (C) 1998 Wiley-Lis s, Inc.