First-In-Human PET Imaging of Synaptic Vesicle Glycoprotein 2A with [18F]BIBD-181: Automation, Biodistribution, Dosimetry, and Preliminary Application in Epilepsy

Abstract

Abstract We report the first-in-human evaluation of [18F]BIBD-181, a novel SV2A tracer designed with a fluoropropyl side chain to enable mild, automated radiosynthesis. A fully automated cGMP-compliant production process was developed on a commercial synthesizer, yielding the tracer with >95% radiochemical purity and molar activity >130 GBq/μmol. In eight healthy volunteers, [18F]BIBD-181 demonstrated excellent safety, rapid brain penetration peaking at 15 s post-injection, and a regional uptake pattern consistent with known synaptic vesicle glycoprotein 2A (SV2A) distribution (pallidum SUV = 2.01 ± 0.57 at 30 min). The effective dose was 2.7 μSv/MBq, with predominant renal clearance and no detectable defluorination. In pilot epilepsy patients, [18F]BIBD-181 positron emission tomography (PET) results revealed focal SV2A reductions that were confined to the epileptogenic lesionsa sclerotic hippocampus in one patient and a focal cortical dysplasia (FCD) in anotherwhereas [18F]FDG showed either extensive ipsilateral temporal hypometabolism or concordant focal hypometabolism, suggesting that SV2A imaging may offer more precise lesion delineation, particularly when [18F]FDG abnormalities extend beyond the true epileptogenic zone. These findings establish [18F]BIBD-181 as a clinically practical SV2A PET tracer with favorable dosimetry, simplified production, and promising utility for epilepsy surgical planning, warranting further validation in larger cohorts.