PET brain kinetics studies of (11)C-ITMM and (11)C-ITDM,radioprobes for metabotropic glutamate receptor type 1, in a nonhuman primate

Abstract

The metabotropic glutamate receptor type 1 (mGluR1) is a novel target protein for the development of new drugs against central nervous system disorders. Recently, we have developed (11)C-labeled PET probes (11)C-ITMM and (11)C-ITDM, which demonstrate similar profiles, for imaging of mGluR1. In the present study, we compared (11)C-ITMM and (11)C-ITDM PET imaging and quantitative analysis in the monkey brain. Respective PET images showed similar distribution of uptake in the cerebellum, thalamus, and cingulate cortex. Slightly higher uptake was detected with (11)C-ITDM than with (11)C-ITMM. For the kinetic analysis using the two-tissue compartment model (2-TCM), the distribution volume (VT) in the cerebellum, an mGluR1-rich region in the brain, was 2.5 mL∙cm(-3) for (11)C-ITMM and 3.6 mL∙cm(-3) for (11)C-ITDM. By contrast, the VT in the pons, a region with negligible mGluR1 expression, was similarly low for both radiopharmaceuticals. Based on these results, we performed noninvasive PET quantitative analysis with general reference tissue models using the time-activity curve of the pons as a reference region. We confirmed the relationship and differences between the reference tissue models and 2-TCM using correlational scatter plots and Bland-Altman plots analyses. Although the scattergrams of both radiopharmaceuticals showed over- or underestimations of reference tissue model-based the binding potentials against 2-TCM, there were no significant differences between the two kinetic analysis models. In conclusion, we first demonstrated the potentials of (11)C-ITMM and (11)C-ITDM for noninvasive PET quantitative analysis using reference tissue models. In addition, our findings suggest that (11)C-ITDM may be superior to (11)C-ITMM as a PET probe for imaging of mGluR1, because regional VT values in PET with (11)C-ITDM were higher than those of (11)C-ITMM. Clinical studies of (11)C-ITDM in humans will be necessary in the future.

Keywords: Central nervous system (CNS); metabotropic glutamate receptor type 1 (mGluR1); positron emission tomography (PET).

Figure 1

Chemical structures and in vitro binding affinities of ¹⁸F-FITM, ¹¹C-ITMM, and ¹¹C-ITDM for mGluR1.

Figure 4

Input curves of ¹¹C-ITMM (open circles) and ¹¹C-ITDM (solid squares) in monkey plasma. The radioactivities were expressed as SUV.

Figure 6

Bland-Altman plot between BP_ND based on reference tissue methods, which are SRTM (A), MRTM (B), and Logan R (C), and DVR-1 based on 2-TCM in PET studies with ¹¹C-ITMM (blue circles) or ¹¹C-ITDM (red squares).

Figure 2

MRI and summed (10-90 min) PET images in the monkey brain. Prior to PET assessment, a monkey was scanned via high-resolution MRI (A-D). PET scans with ¹¹C-ITMM (E-H) or ¹¹C-ITDM (I-L) were performed on the same monkey. The tomograms were reconstructed in sagittal or coronal planes. Abbreviations: Ci, cingulate cortex; Th, thalamus; Po, pons; Ce, cerebellum.

Figure 3

Time-activity curves of ¹¹C-ITMM (A) and ¹¹C-ITDM (B) in brain regions. Regions of interest were drawn on the cerebellum (open circles), thalamus (open squares), caudate (open triangles), putamen (open diamonds), cingulate cortex (solid circles), hippocampus (solid squares), and pons (solid triangles). The uptakes were expressed as SUV.

Figure 5

Correlation between BP_ND based on reference tissue model and DVR-1 based on 2-TCM in PET studies with ¹¹C-ITMM (solid circles) or ¹¹C-ITDM (open squares). Reference tissue models were used SRTM (A), MRTM (B), and Logan R (C).