Cerebellar heterogeneity and its impact on PET data quantification of 5-HT receptor radioligands

In the quantification of positron emission tomography (PET) radiotracer binding, a commonly used method is reference tissue modeling (RTM). RTM necessitates a proper reference and a ubiquitous choice for G-protein coupled receptors is the cerebellum. We investigated regional differences in uptake within the grey matter of the cerebellar hemispheres (CH), the cerebellar white matter (CW), and the cerebellar vermis (CV) for five PET radioligands targeting the serotonin system. Furthermore, we evaluated the impact of choosing different reference regions when quantifying neocortical binding. The PET and MR images are part of the Cimbi database: 5-HT_1AR ([¹¹C]CUMI-101, n = 8), 5-HT_1BR ([¹¹C]AZ10419369, n = 36), 5-HT_2AR ([¹¹C]Cimbi-36, n = 29), 5-HT₄R ([¹¹C]SB207145, n = 59), and 5-HTT ([¹¹C]DASB, n = 100). We employed SUIT and FreeSurfer to delineate CV, CW, and CH and quantified mean standardized uptake values (SUV) and nondisplaceable neocortical binding potential (BP_ND). Statistical difference was assessed with paired nonparametric two-sided Wilcoxon signed-rank tests and multiple comparison corrected via false discovery rate. We demonstrate significant radioligand specific regional differences in cerebellar uptake. These differences persist when using different cerebellar regions for RTM, but the influence on the neocortical BP_ND is small. Nevertheless, our data highlight the importance of validating each radioligand carefully for defining the optimal reference region.