Characterization of in vivo binding kinetics and non-displaceable binding of [18F]SynvesT-1 in the rat brain

Abstract

Background: The synaptic vesicle glycoprotein 2 A (SV2A) has been identified as a biomarker of interest for neurological pathology. The SV2A specific radiotracer [¹⁸F]SynVesT-1 has shown good binding characteristics in mouse and human. The aim of this study was to characterize the binding parameters of [¹⁸F]SynVesT-1 in the rat brain and investigate simplified quantification methods. Twenty-one Positron Emission Tomography (PET) scans were conducted in male Sprague-Dawley rats with a bolus injection of [¹⁸F]SynVesT-1. Varying concentrations of non-radioactive SynVesT-1 were injected in an increasing mass dose paradigm (n = 21 ) with radioactivity in arterial blood recorded throughout. The radiometabolism was characterized in a further group (n = 7). The total volume of distribution (V_T) was estimated using compartmental modelling and Logan plot and then compared to the standardized uptake value at 30-60 min (SUV_{30 - 60}). Occupancy plots and a Lassen plot were generated.

Results: The pharmacokinetics of [¹⁸F]SynVesT-1 PET showed rapid brain uptake and increasing doses of SynVesT-1 revealed a robust reduction in radiotracer uptake over all brain regions. The two-tissue compartmental model was most appropriate and the estimated V_T was highly correlated with Logan V_T, as was the SUV_{30 - 60}. The V_ND was estimated to be 3.75, which is 12.5% (pons) to 22% (thalamus) of the V_T. The estimated upper mass limit required to achieve 5% target occupancy is 0.48 µg/kg.

Conclusion: [¹⁸F]SynVesT-1 shows good characteristics for imaging the rat brain, however care must be taken to achieve adequate molar activity to avoid mass dose affects (< 5% occupancy). Data showed no suitable reference region for [¹⁸F]SynVesT-1, however SUV_{30 - 60} does give an appropriate surrogate for V_T.

Clinical trial number: Not applicable.

Keywords: Mass dose; Preclinical PET; Rat; SV2A; [18F]SynVesT-1.