In vivo evaluation of [18F]UCB-H binding at SV2A protein, through a new and efficient radiosynthesis of [18F]UCB-H.

Background: [18F]UCB-H is a validated radiotracer with a high affinity for the synaptic vesicle glycoprotein 2A (SV2A), known as the binding site of the antiepileptic drug levetiracetam [1, 2]. The major drawback of [18F]UCB-H was a long, multi-step radiosynthesis with limited yield of radiotracer [3]. We provide here in vivo evaluation of a new efficient single-step radiosynthesis of [18F]UCB-H, that allows us to highlight the role of the enantio-selectivity while targeting SV2A. Then, we synthetized and radiolabeled the major metabolite, namely [18F]UCB-H-N-oxyde, and investigated its impact on rat brain PET images.
Methods: [18F]UCB-H was produced with a simple, one-step production strategy which consisted in radiolabeling an enantiomerically pure (S- or R-) N-heteroaryliodonium precursor [4]. 5 Sprague-Dawley (SD) rats underwent 1 dynamic PET scan (60 minutes) with each enantiomer and a third one with the racemic mixture. We used a population-based input function (PBIF) to quantify [18F]UCB-H binding with Logan graphical analysis. [18F]UCB-H-N-oxyde was produced by a direct oxidation with a large excess of pure m-CPBA in Et2O. 5 SD rats underwent 1 dynamic PET scan (60 minutes) with this radiosynthetic [18F]UCB-H-N-oxyde.
Results: The radiosynthesis lasted 60 min and afforded a 34 ± 2% radiochemical yield, non-corrected for decay, with a high specific activity (820 ± 180 GBq/µmol). Time activity curves showed higher values for the [18F]UCB-H compared to both the S-[18F]UCB-H and the racemic. Distribution volume (Vt) of the [18F]UCB-H, measured with the PBIF were consistent with previous study [2]. Analysis of [18F]UCB-H-N-oxyde PET images confirmed the absence of Blood-Brain-Barrier crossing.
Conclusions: This new [18F]UCB-H radiosynthesis allows us to reach high specific activities. In vivo results are consistent with previous work and emphasize the need of high enantiomeric purity to reach accurate quantitative values of radiotracer binding. The use of a PBIF to quantify [18F]UCB-H binding in the rat brain is reliable and afford longitudinal study. At the end, our study demonstrated that [18F]UCB-H fulfils an important criterion for PET radiopharmaceuticals with the lack of troublesome brain radiometabolites.