Synthesis and evaluation of ¹⁸F-UCB-H, a novel PET imaging tracer for the synaptic vesicle protein 2A

Objectives SV2A is a 90-kDa protein widely distributed in the cerebral cortex and the target of action for the antiepileptic drug levetiracetam (LEV). Although abundant evidence pointed to the importance of SV2A in epilepsy and other brain diseases, the cellular mechanisms of these diseases are largely unknown due to the lack of suitable in vivo probes. ¹⁸F-UCB-H is a potent SV2A ligand and a previous study in rodents indicated its potential as a PET radiotracer. Here we report a simplified synthesis of ¹⁸F-UCB-H and its evaluation in rhesus monkeys.

Methods ¹⁸F-UCB-H was prepared by isotopic exchange using ¹⁹F-UCB-H as the starting material. Imaging experiments were carried out on the Focus 220 PET scanner with generation of arterial input function and metabolite analysis by HPLC. Brain regional time-activity curves (TACs) were analyzed by one-tissue (1T) or 2-tissue (2T) compartmental models, as well as the multilinear analysis (MA1) method to derive binding parameters.

Results ¹⁸F-UCB-H was synthesized in 45 ± 13% radiochemical yield and specific activity of 0.44 ± 0.24 Ci/umol at the end of synthesis (n = 4). In rhesus monkeys, the metabolism of ¹⁸F-UCB-H was moderate, with ~ 40% of parent remaining at 30 min after tracer injection. In the brain, ¹⁸F-UCB-H displayed fast kinetics (regional activity peak times < 15 min) and an uptake pattern consistent with the distribution of SV2A in primates: cingulate cortex (CIN) ~ occipital cortex (OCC) > frontal cortex (FNT) > striatum (STR)> cerebellum (CER) ~ thalamus (THA) > pons (PON) ~ brainstem (BST). Both 1T and MA1 produced reliable estimates of regional distribution volume (VT). MA1 VT values were 16.5, 16.0, 15.2, 14.6, 12.9, 12.4, 11.0 and 10.8 for CIN, OCC, FNT, STR, CER, THA, PON and BST, respectively. Pretreatment with LEV (10 mg/kg, iv, n=2) resulted in 79% occupancy, indicating binding specificity of the tracer.

Conclusions ¹⁸F-UCB-H is a specific tracer for PET imaging of SV2A in non-human primates.