Exploring Novel ¹⁸F-Fluorination Methodologies for the Synthesis of ¹⁸F-SDM-8, a PET Radiotracer for Synaptic Density Imaging

Objectives: Synaptic abnormalities are implicated in many disorders such as Alzheimer’s disease, epilepsy, Parkinson’s disease, and depression. The synaptic vesicle glycoprotein 2A (SV2A) is crucial to neurotransmission, and therefore can be used as a biomarker for synaptic density measurement in neurodegenerative and psychiatric diseases. We have previously developed and validated ¹¹C-UCB-J as an excellent PET tracer for SV2A. However, with a 20-min half-life of its ¹¹C-radionuclide, ¹¹C-UCB-J is not ideal for use in multi-center clinical trials and clinical diagnosis of diseases. Therefore, we set out to develop ¹⁸F-labeled SV2A tracers and a structure-activity relationship study led to the discovery of ¹⁸F-SDM-8, which has been shown to have the same outstanding pharmacokinetic and imaging characteristics as ¹¹C-UCB-J and higher specific binding in nonhuman primates (1). Thus, ¹⁸F-SDM-8 has the potential to become an excellent PET tracer for synaptic imaging in the clinical setting. The aim of this study was to screen radiolabeling precursors for optimized radiosynthesis of ¹⁸F-SDM-8. Methods: Eight ¹⁸F-fluorination precursors were prepared. Efficiency of fluorination was first tested with each precursor using 10 eq. of KF to the precursor under simulated radiofluorination conditions (heating at 140 ^oC for 20 min in DMA). Test radiolabeling was performed with each precursor under different conditions by varying the methods of ¹⁸F^- elution, reaction solvents, temperatures, and time. The radiochemical yield (RCY) was calculated based on integration of the product peak on the HPLC chromatogram, as well as the ratio between the activity of collected product fractions and the total activity injected onto the HPLC column. Results: All precursors (Fig. 1) were successfully synthesized with overall yield of 20% to 37%. Test runs with KF indicated that the most efficient fluorination was achieved with the trimethyltin precursor (7), followed by boronic acid (3), tributyltin (8), the Ritter precursor (1), boronic ester (4), iodonium ylide (6), iodonium salt (5) and quaternary ammonium salt (2). In radiolabeling tests, highest RCY was found with the copper (II)-catalyzed reaction with the trimethyltin precursor in DMA at 110 ^oC and the Ritter precursor in DMSO at 140 ^oC, at 24% and 30%, respectively. Radiolabeling of the boronic ester precursor led to moderate RCY (11% at 140 ^oC), while ~ 2% RCY was achieved with the iodonium ylide precursor in DMF at 140 ^oC for 20 min. It was also found the radiotracer racemized when heating at above 120 ^oC with high concentration of bases (> 4 mg/mL). Hence, subsequent radiofluorination runs were done at 110 °C and the results shown in the Table. Overall, the best RCY (24%, decay-uncorrected) was achieved with the trimethyltin precursor heating in DMA at 110 °C for 20 min. These conditions were then used in validation runs to produce ¹⁸F-SDM-8 for regulatory submission and human studies. Total synthesis time was ~ 90 min from the end of bombardment, with mean molar activity of 241.7 MBq/nmol (n = 4) for the product at the end of synthesis. Conclusions: Eight precursors for the novel SV2A tracer ¹⁸F-SDM-8 were successfully synthesized and tested in ¹⁸F-radiolabeling. Overall the trimethyltin precursor can be prepared in high yield and radiolabeling of this precursor provided the highest RCY. With a reliable and high-yielding radiosynthesis, ¹⁸F-SDM-8 has since been advanced to evaluation in humans. Reference: 1. Li S, et al. ACS Chem Neurosci. 2018, https://pubs.acs.org/doi/10.1021/acschemneuro.8b00526. Figure 1. Radiosynthesis of ¹⁸F-SDM-8 and summary of results.

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