Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-C-11]WAY-100635 in humans: Comparison of arterial and reference tissue input functions

Serotonin 5-HT1A receptors are implicated in the pathophysiology of neurops ychiatric conditions. The goal of this study was to evaluate methods to der ive 5-HT1A receptor parameters in the human brain with positron emission to mography (PET) and [carborzyl-C-11]WAY 100635. Five healthy volunteer subje cts were studied twice. Three methods of analysis were used to derive the b inding potential (BP), and the specific to nonspecific equilibrium partitio n coefficient (k(3)/k(4)). Two methods, kinetic analysis based on a three c ompartment model and graphical analysis, used the arterial plasma time-acti vity curves as the input function to derive BP and k(3)/k(4). A third metho d, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided on ly k(3)/k(4). All methods provided estimates of regional 5-HT1A receptor pa rameters that were highly correlated. Results were consistent with the know n distribution of 5-HT1A receptors in the human brain. Compared with kineti c BP, graphical analysis slightly underestimated BP, and this phenomenon wa s mostly apparent in mall size-high noise regions. Compared with kinetic k( 3)/k(4), the reference tissue method underestimated k,flc, and the underest imation was apparent primarily in regions with high receptor density. Deriv ation of BP by both kinetic and graphical analysis was highly reliable, wit h an intraclass correlation coefficient (ICC) of 0.84 +/- 0.14 (mean +/- SD of 15 regions) and 0.84 +/- 0.19, respectively. In contrast, the reliabili ty of k(3)/k(4) was lower, with ICC of 0.53 +/- 0.28, 0.47 +/- 0.28, and 0. 55 +/- 0.29 for kinetic, graphical, and reference tissue methods, respectiv ely. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its high er test-retest reproducibility, lower vulnerability to experimental noise, and absence of bias.