Evaluation of ¹⁸F-UCB-H as a Novel PET Tracer for Synaptic Vesicle Protein 2A in the Brain

Abstract

Synaptic vesicle protein 2 isoforms are critical for proper nervous system function and are involved in vesicle trafficking. The synaptic vesicle protein 2A (SV2A) isoform has been identified as the binding site of the antiepileptic levetiracetam (LEV), making it an interesting therapeutic target for epilepsy. 18 F-UCB-H is a novel PET imaging agent with a nanomolar affinity for human SV2A. Methods: Preclinical PET studies were performed with isoflurane-anesthetized rats. The arterial input function was measured with an arteriovenous shunt and a β-microprobe system. 18 F-UCB-H was injected intravenously (bolus of 140 ± 20 MBq). Results: Brain uptake of 18 F-UCB-H was high, matching the expected homogeneous distribution of SV2A. The distribution volume (V t ) for 18 F-UCB-H was calculated with Logan graphic analysis, and the effect of LEV pretreatment on V t was measured. In control animals the whole-brain V t was 9.76 ± 0.52 mL/cm 3 (mean ± SD; n 5 4; test-retest), and the reproducibility in test-retest studies was 10.4% ± 6.5% (mean ± SD). The uptake of 18 F-UCB-H was dose dependently blocked by pretreatment with LEV (0.1-100 mg/kg intravenously). Conclusion: Our results indicated that 18 F-UCB-H is a suitable radiotracer for the imaging of SV2A in vivo. To our knowledge, this is the first PET tracer for the in vivo quantification of SV2A. The necessary steps for the implementation of 18 F-UCB-H production under good manufacturing practice conditions and the first human studies are being planned.

Development and Validation of a New Mouse Model to Investigate the Role of SV2A in Epilepsy

“…These results were confirmed by in vitro autoradiography using the 18 F-UCB-H radioligand. This radiotracer has been shown to specifically bind to the SV2A protein [15, 16]. Autoradiograms obtained post-incubation using a constant radiotracer concentration enabled us to visualize decreased binding of 18 F-UCB-H in all hippocampus regions of the Grik4:SV2A-cKO animals compared to WT littermates (***: p <0.001) (Fig 3C and 3D).…”

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

“…Recently, [ 18 F]UCB-H, a high-affinity PET ligand for SV2A, was developed [73, 74]. This tracer shows a nanomolar affinity for SV2A in the brain, which has been demonstrated using µPET in a preclinical study by Warnock et al [75] in the rat brain. After a single intravenous administration in rats, [ 18 F]UCB-H showed rapid and high-level brain uptake, with a free brain-to-plasma ratio of greater than 1 at 5, 10, and 20 min after administration.…”

“…In addition to their potential value in the study of epilepsy, SV2A PET tracers could be of interest as useful tools to measure synaptic density in humans [55, 75]. SV2A does not appear to affect vesicle formation as synaptic morphology and vesicle density were not altered in SV2A knockout animals [34, 36].…”

“…These data suggested that SV2A could influence SV cycling. As this cycling is a continuous process within the presynaptic terminal, it could be postulated that reduced uptake of an SV2A PET tracer is a consequence of synaptic loss [75], which clearly appears to be the case in patients with mesial TLE [55]. Such a non-invasive measure of synaptic density could be of great value, not only for the diagnosis of epilepsy but also other neurodegenerative disorders, including AD.…”

Synthesis and Preclinical Evaluation of11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain

“…UCB-A has been radiolabeled with 11 C and tested in mini-pigs (12), rats (13), and rhesus monkeys (Nabulsi et al, unpublished data, 2012) but showed slow kinetics (prolonged retention in brain tissue) and may therefore not be suitable for PET imaging (unpublished data). UCB-H was radiolabeled with 18 F and displayed good kinetics in rats (14) and nonhuman primates (15) and acceptable dosimetry in humans (16); however, its radiosynthesis has proven challenging and specific binding was relatively low. In this study, we report the radiosynthesis and characterization of 11 C-UCB-J as a best-in-class SV2A PET tracer.…”