Evaluation of an image-derived input function and population-based metabolite correction for quantification of synaptic density with [18F]SynVesT-1 and PET in male and female rats

Positron emission tomography (PET) quantification of radiotracers targeting synaptic vesicle glycoprotein 2A (SV2A), such as [ 18 F]SynVesT-1, requires arterial blood sampling and metabolite analysis to derive an arterial input function (AIF). However, arterial blood sampling is an invasive—almost necessarily terminal—procedure for preclinical rodent models, limiting the possibility of longitudinal study designs. The use of an image-derived input function (IDIF) and population-based metabolite correction (PBMC) represents a possible non-invasive alternative; thus, the purpose of these studies was to evaluate the potential of an IDIF and PBMC for in vivo PET quantification of [ 18 F]SynVesT-1 in rats. Eight male and nine female rats received infusions of [ 18 F]SynVesT-1. Arterial blood sampling with metabolite analyses ( n = 13 studies) and dynamic PET data were acquired for 60 minutes post-injection ( n = 16 scans) on FOCUS 220 and NeuroEXPLORER cameras. The kinetic model parameters, volume of distribution ( V T ) and radiotracer delivery from the blood to the tissue compartment ( K 1 ), were calculated using one-tissue compartment (1TC) and 2TC models with the IDIF-PBMC and compared with AIF-based V T and K 1 calculated using the AIF ( n = 9 scans). Test-retest reproducibility was evaluated in four rats. The 1TC model produced higher confidence estimates for VT and K1 relative to 2TC; thus, subsequent analyses proceeded with the 1TC model. Individual metabolite corrected (IMC) IDIF V T values underestimated AIF-IMC V T (absolute difference: 24.5 ± 8.1%). However, IDIF and AIF V T values were significantly correlated (R 2 = 0.92, p < 0.001). Due to sex differences in radiotracer metabolism, a sex-specific PBMC was applied, and the correlation between the IDIF-PBMC and AIF V T values remained significant ( R 2 = 0.39, p < 0.001). Further, the IDIF-PBMC produced the highest confidence parameter estimates, test-retest variability (TRV = − 7.0 ± 15.5%), and absolute TRV (aTRV = 15.7 ± 6.0%). These data add to the growing evidence supporting the use of the IDIF-PBMC as a suitable, non-invasive method for PET quantification of [ 18 F]SynVesT-1 that would enable longitudinal evaluation of SV2A density in rats.