Kinetic modeling of the serotonin 5-HT(1B) receptor radioligand [(11)C]P943 in humans

Abstract

[(11)C]P943 is a new radioligand recently developed to image and quantify serotonin 5-Hydroxytryptamine (5-HT(1B)) receptors with positron emission tomography (PET). The purpose of this study was to evaluate [(11)C]P943 for this application in humans, and to determine the most suitable quantification method. Positron emission tomography data and arterial input function measurements were acquired in a cohort of 32 human subjects. Using arterial input functions, compartmental modeling, the Logan graphical analysis, and the multilinear method MA1 were tested. Both the two tissue-compartment model and MA1 provided good fits of the PET data and reliable distribution volume estimates. Using the cerebellum as a reference region, BP(ND) binding potential estimates were computed. [(11)C]P943 BP(ND) estimates were significantly correlated with in vitro measurements of the density of 5-HT(1B) receptors, with highest values in the occipital cortex and pallidum. To evaluate noninvasive methods, two- and three-parameter graphical analyses, Simplified Reference Tissue Models (SRTM and SRTM2), and Multilinear Reference Tissue Models (MRTM and MRTM2) were tested. The MRTM2 model provided the best correlation with MA1 binding-potential estimates. Parametric images of the volume of distribution or binding potential of [(11)C]P943 could be computed using both MA1 and MRTM2. The results show that [(11)C]P943 provides quantitative measurements of 5-HT(1B) binding potential.

Figure 1

Time–activity curves, Logan plots, and fits obtained in selected ROIs: cerebellum (circles), parietal (squares), calcarine cortex (triangles), and pallidum (solid diamonds). (A) Fits obtained with the one-tissue (1T) compartment model (dashed line) or the two-tissue (2T) compartment model (solid line). (B) Graphical analysis with input function (GA_IF). (C) Fits obtained with the multilinear analysis using the input function (MA1). (D) Graphical analysis using reference region data GA_REF2. (E) Fits obtained with multilinear analyses using reference region data (MRTM). (F) Fits obtained with the simplified reference tissue model (SRTM). t^* was set to 40 mins for panels B and C, and to 10 and 20 mins for panels D and E, respectively. 313 × 352 mm² (600 × 600 d.p.i.).

Figure 2

Selected correlations between V_T estimated with analyses using input function data. Solid line represents the line of best fit. Dashed line is the line of identity. (A) 1T versus 2T (B) GA_IF versus 2T (C) MA1 versus 2T. See Table 2 for regression values. 156 × 352 mm² (600 × 600 d.p.i.).

Figure 3

Selected correlations between BP_ND estimated with methods using the cerebellum as a reference region and MA1. Solid line is the line of best fit. Dashed line is the line of identity. (A) GA_REF2 versus MA1. t^* is 10 mins for GA_REF2 and 40 mins for MA1. (B) MRTM versus MA1. t^* is 20 mins for MRTM and 40 mins for MA1 (C) MRTM2, with b′ coupled across regions for each subject, versus MA1. t^* is 30 mins for MRTM2 and 40 mins for MA1. (D) MRTM2^*, with b′ fixed at −37 mins, versus MA1. t^* is 40 mins for both methods. (E) SRTM versus MA1. (F) SRTM2, with k′₂ coupled across region for each subject, versus MA1. See Table 2 for regression values. 313 × 352 mm² (600 × 600 d.p.i.).

Figure 4

MR anatomic image (row A) and parametric images of V_T obtained on the same healthy control subject with MA1 (row B), and BP_ND obtained with MRTM2 (row C) and SRTM2 (row D), in axial, sagittal, and coronal views (from left to right). The slices were selected to display high binding regions: pallidum (axial view), occipital (sagittal view), and substantia nigra (coronal view). The V_T color scale ranges form 0 to 17.3 mL/cm³, and the BP_ND color scale ranges from −1 (to maximize the visual identity between V_T and BP_ND images) to 3. Differences between the SRTM2 images and the MA1 or MRTM2 images are especially visible in the small receptor-rich regions, where SRTM2 BP_ND values are underestimated. 79 × 106 mm² (300 × 300 d.p.i.).

Figure 5

Correlations between BP_F (B_avail/K_d) estimates from [¹¹C]P943 regional TAC fits with MA1 (t^*=40 mins) and the 5-HT_1B B_max measurements using in vitro autoradiography and [³H]GR 125743 reported by Varnäs et al (2001) (A) and Varnäs et al (2004) (B). Region labels are defined as: GP, pallidum; SN, substantia nigra; RN, raphe nucleus; PN, pulvinar nucleus; DN, dorsomedial nucleus; CN, caudate nucleus; PU, putamen; AAC, anterior cingulate cortex; PCC, posterior cingulate cortex; CC, calcarine cortex; FC, frontal cortex; IC, insular cortex; TC, temporal cortex. For cortical regions, the labels are grouped and displayed in the order of the points following the y axis (B_max) values. In subfigure B, for the cortical regions, the in vitro B_max values were computed as the unweighted average across cortical layers. For the pallidum, the in vitro B_max values were computed as the unweighted average of the (internal and external) globus pallidus and ventral pallidum values. The regression line equations are BP_F=0.36 B_max−3, r²=0.671, n=10, P<0.05 (panel A) and BP_F=0.23 B_max+0.2, r²=0.576, n=13, P<0.001 (panel B). The slope of each regression line is an estimate of the in vivo K_d value, and these values are in good agreement with the reported in vitro K_i value (0.77 nmol/L; McCarthy et a, (2007); 1.2 nmol/L; NIMH Psychoactive Drug Screening Program). 355 × 133 mm² (600 × 600 d.p.i.).