Using cerebral white matter for estimation of nondisplaceable binding of 5-HT1A receptors in temporal lobe epilepsy.

Abstract

The estimation of nondisplaceable binding from cerebellar white matter, rather than from whole cerebellum, was proposed for the PET tracer carbonyl-(11)C-WAY-100635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridyl)cyclohexanecarboxamidel]) because of the heterogeneity of total ligand binding in this region. For the 5-hydroxytryptamine receptor 1A (5-HT(1A)) antagonist (18)F-N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-2-pyridyl)trans-4-fluorocyclohexanecarboxamide ((18)F-FCWAY), the estimation of nondisplaceable binding from cerebellum (V(ND)) may be additionally biased by spillover of (18)F-fluoride activity from skull. We aimed to assess the effect of using cerebral white matter as reference region on detection of group differences in 5-HT(1A) binding with PET and (18)F-FCWAY. In 22 temporal lobe epilepsy patients (TLE) and 10 healthy controls, (18)F-FCWAY distribution volume in cerebral white matter (V(WM)) was computed using an extrapolation method as part of a partial-volume correction (PVC) algorithm. To assess the feasibility of applying this method to clinical studies in which PVC is not performed, V(WM) was also calculated by placing circular, 6-mm-diameter regions of interest (ROIs) in the centrum semiovalis on parametric images. Binding potentials were BP(F) = (V(T) - V(ND))/f(P) and BP(F-WM) = (V(T) - V(WM))/f(P), where V(T) is total distribution volume and f(P) = (18)F-FCWAY plasma free fraction. Statistical analysis was performed using t tests and linear regression. In the whole group, V(WM) was 14% +/- 19% lower than V(ND) (P < 0.05). V(WM)/f(P) was significantly (P < 0.05) lower in patients than in controls. All significant (P < 0.05) reductions of 5-HT(1A) receptor availability in TLE patients detected by BP(F) were also detected using BP(F-WM). Significant (P < 0.05) reductions of 5-HT(1A) specific binding were detected by BP(F-WM), but not BP(F), in ipsilateral inferior temporal cortex, contralateral fusiform gyrus, and contralateral amygdala. However, effect sizes were similar for BP(F-WM) and BP(F). The value of V(WM) calculated with the ROI approach did not significantly (P > 0.05) differ from that calculated with the extrapolation approach (0.67 +/- 0.32 mL/mL and 0.72 +/- 0.34 mL/mL, respectively). Cerebral white matter can be used for the quantification of nondisplaceable binding of 5-HT(1A) without loss of statistical power for detection of regional group differences. The ROI approach is a good compromise between computational complexity and sensitivity to spillover of activity, and it appears suitable to studies in which PVC is not performed. For (18)F-FCWAY, this approach has the advantage of avoiding spillover of (18)F-fluoride activity onto the reference region.