Advancements in SV2A Imaging: Development and Evaluation of [18F]SDM-16, a Novel Metabolically Stable PET Tracer

The study aimed to develop a high affinity PET radiotracer for synaptic vesicle glycoprotein 2A (SV2A) to observe changes in the central nervous system under various conditions. The new tracer, based on the UCB-A molecular structure, was evaluated for its pharmacokinetics, stability, and binding in nonhuman primate brains compared to other tracers.

The compound SDM-16 and its enantiomers were synthesized and tested for binding to human SV2A. The pure form of 18F-SDM-16 was created using a specific precursor and was used in PET scans on nonhuman primates. Blood samples were taken to measure plasma free fraction, analyze radiometabolites, and construct the plasma input function. The regional time-activity curves were analyzed using a one-tissue compartment model to determine the volume of distribution and nondisplaceable binding potential.

The results showed that SDM-16 was synthesized with a high yield and had the strongest affinity to human SV2A of all known ligands. The radiotracer 18F-SDM-16 was prepared with a high radiochemical yield and purity, demonstrating high specific binding in monkey brains and greater metabolic stability than other tracers. It also had a higher plasma free fraction than comparable tracers. The time-activity curves were well-fitted, and the test-retest variability was low.

In conclusion, the novel SV2A PET tracer 18F-SDM-16 was successfully synthesized with the highest binding affinity and metabolic stability among known SV2A PET tracers. The PET images provided clear contrast and the tracer showed high specific and reversible binding in the brains of nonhuman primates, making it a reliable and sensitive tool for quantifying SV2A and potentially useful for visualizing and quantifying SV2A in other areas.