Noninvasive quantification of [¹⁸F]SynVesT-1 binding using simplified reference tissue model 2

[¹⁸F]SynVesT-1, a positron emission tomography (PET) radiotracer for the synaptic vesicle glycoprotein 2A (SV2A), demonstrates kinetics similar to [¹¹C]UCB-J, with high brain uptake, fast kinetics fitting well with the one-tissue compartment (1TC) model, and excellent test-retest reproducibility. Challenges arise due to the similarity between k₂ and \(\:{k}_{2}^{{\prime\:}}\) (efflux rate of the reference region), when applying the simplified reference tissue model (SRTM) and related methods in [¹¹C]UCB-J studies to accurately estimate \(\:{k}_{2}^{{\prime\:}}\) . This study evaluated the suitability of these methods to estimate [¹⁸F]SynVesT-1 binding using centrum semiovale (CS) or cerebellum (CER) as reference regions.

Seven healthy participants underwent 120-min PET scans on the HRRT scanner with [¹⁸F]SynVesT-1. Six participants underwent test and retest scans. Arterial blood sampling and metabolite analysis provided input functions for the 1TC model, serving as the gold standard for kinetic parameters values. SRTM, coupled SRTM (SRTMC) and SRTM2 estimated were applied to estimate \(\:{BP}_{\text{ND}}\) (ref: CS) and DVR_CER(ref: CER) values. For SRTM2, the population average of \(\:{k}_{2}^{{\prime\:}}\) was determined from the 1TC model applied to the reference region. Test-retest variability and minimum scan time were also calculated.

The 1TC k₂ (1/min) values for CS and CER were 0.031 ± 0.004 and 0.021 ± 0.002, respectively. Although SRTMC \(\:{k}_{2}^{{\prime\:}}\) was much higher than 1TC \(\:{k}_{\text{2}}\) , SRTMC underestimated BP_ND(ref: CS) and DVR_CER by an average of 3% and 1% across regions, respectively, due to similar bias in k₂ and \(\:{k}_{2}^{{\prime\:}}\) estimation. SRTM underestimated BP_ND(ref: CS) by an average of 3%, but with the CER as reference region, SRTM estimation was unstable and DVR_CER underestimation varied by region (mean 10%). Using population average \(\:{k}_{2}^{{\prime\:}}\) values, SRTM2 BP_ND and DVR_CER showed the best agreement with 1TC estimates.

Our findings support the use of population \(\:{k}_{2}^{{\prime\:}}\) value in SRTM2 with [¹⁸F]SynVesT-1 for the estimation of \(\:{BP}_{\text{ND}}\) or DVR_CER, regardless of the choice of reference region.