Validation and Reproducibility of Measurement of 5-HT_1A Receptor Parameters with [carbonyl-¹¹C]WAY-100635 in Humans: Comparison of Arterial and Reference Tissue Input Functions

Abstract

Serotonin 5-HT(1A) receptors are implicated in the pathophysiology of neuropsychiatric conditions. The goal of this study was to evaluate methods to derive 5-HT(1A) receptor parameters in the human brain with positron emission tomography (PET) and [carbonyl-(11)C]WAY 100635. Five healthy volunteer subjects were studied twice. Three methods of analysis were used to derive the binding potential (BP), and the specific to nonspecific equilibrium partition coefficient (k3/k4). Two methods, kinetic analysis based on a three compartment model and graphical analysis, used the arterial plasma time-activity curves as the input function to derive BP and k3/k4. A third method, the simplified reference tissue model (SRTM), derived the input function from uptake data of a region of reference, the cerebellum, and provided only k3/k4. All methods provided estimates of regional 5-HT(1A) receptor parameters that were highly correlated. Results were consistent with the known distribution of 5-HT(1A) receptors in the human brain. Compared with kinetic BP, graphical analysis slightly underestimated BP, and this phenomenon was mostly apparent in small size-high noise regions. Compared with kinetic k3/k4, the reference tissue method underestimated k3/k4 and the underestimation was apparent primarily in regions with high receptor density. Derivation of BP by both kinetic and graphical analysis was highly reliable, with an intraclass correlation coefficient (ICC) of 0.84 +/- 0.14 (mean +/- SD of 15 regions) and 0.84 +/- 0.19, respectively. In contrast, the reliability of k3/k4 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, respectively. In conclusion, derivation of BP by kinetic analysis using the arterial plasma input function appeared as the method of choice because of its higher test-retest reproducibility, lower vulnerability to experimental noise, and absence of bias.

in vivo Variation in Metabotropic Glutamate Receptor Subtype 5 Binding Using Positron Emission Tomography and [11C]ABP688

“…Although the unconstrained 2TC model fit the TACs well, in light of the observed unexpected increase in binding between test and retest, the data were modeled using four additional techniques: (1) a 2TC model constrained such that the ratio of kinetic constants, K 1 /k 2 , for each region is restricted to the ratio of K 1 to k 2 in the reference region (Parsey et al, 2000b), (2) a 2TC model fit using non-iterative methods in which the experimental data are matched to the most similar curve in a library of precalculated functions, rather than by performing a nonlinear least squares iterative fit, (3) Logan graphical analysis, in which outcome measures are calculated from the slope of the linear part of an integral plot (Logan et al, 1996), and (4) likelihood estimation in graphical analysis, which has been shown to reduce bias introduced by the Logan approach (Ogden, 2003). One-tissue compartment models were not used in the comparison because they did not fit the data well (data not shown).…”

Occupancy of Agonist Drugs at the 5-HT1A Receptor

“…Compared to the alternative plasma input function method (PIFM), the SRTM underestimates BP values, particularly in regions of higher receptor density (Oikonen et al, 2000;Parsey et al, 2000;Slifstein et al, 2000). It may thus be less sensitiveFa concern when low levels of occupancy are being investigated.…”

Differential Occupancy of Somatodendritic and Postsynaptic 5HT1A Receptors by Pindolol A Dose-Occupancy Study with [11C]WAY 100635 and Positron Emission Tomography in Humans

“…PET imaging sessions were conducted as previously described (Parsey et al 2000). Subject preparation included placement of arterial and venous catheters, fiducial markers and polyurethane head immobilizer.…”

“…The six measured fractions of parent compound were fitted to the sum of one exponential plus a constant in order to interpolate values between and after these measurements (Parsey et al 2000). The input function was calculated as the product of the total counts and interpolated fraction of parent compound at each time.…”

“…WAY-100635 [N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide] is a potent and selective 5-HT 1A antagonist with high affinity and selectivity for the 5-HT 1A receptors (K D ϭ 0.1-0.4 nM) (Forster et al 1995;Gozlan et al 1995). [ 11 C]WAY 100635 is a newly developed radiotracer that enables reliable quantification of 5-HT 1A receptor availability in the human brain (Pike et al 1995;Farde et al 1998;Gunn et al 1998;Drevets et al 1999;Parsey et al 2000;Sargent et al 2000).…”