RT Journal Article SR Electronic T1 Improved synthesis of [11C]UCB-J for PET Imaging of SV2A JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 2418 OP 2418 VO 63 IS supplement 2 A1 Xin, Yangchun A1 DiFilippo, Alexandra A1 Murali, Dhanabalan A1 Higgins, Andrew A1 Barnhart, Todd A1 Aluicio-Sarduy, Eduardo A1 Ellison, Paul A1 Engle, Jonathan A1 Christian, Bradley YR 2022 UL http://jnm.snmjournals.org/content/63/supplement_2/2418.abstract AB 2418 Introduction: Synaptic loss is a hallmark of many neurodegenerative diseases such as Alzheimer’s disease. [11C]UCB-J specifically binds to synaptic vesicle protein (SV2A) and has been used to measure an index for synaptic density in the brain. However, the widespread use of this tracer is partially hampered by the C-11 radiolabel and accompanying challenges with radiochemical synthesis. Our experience has revealed that demands with production could be eased through hydrolysis of the precursor several days prior to the radiolabeling procedure. Another challenge is the high variability in labelling yields accompanying the various commercial sources of the Pd2(dba)3 catalyst. We report a method using in-house synthesized Pd2(dba)3 catalyst and pre-hydrolyzed precursor for the overall improvement in production yields and time efficiency of [11C]UCB-J. Methods: The Pd2(dba)3 was purchased from commercial vendors (Sigma-Aldrich, Alfa Aesar, Thermo Scientific) or synthesized in-house from palladium chloride in 77.5% yield (Ukai T, J., Organomet. Chem., 1974). The preparation of hydrolyzed UCB-J precursor involved heating the solution of precursor ((R)-3-(difluoroboranyl)-4-((2-oxo-4-(3,4,5-trifluorophenyl) pyrrolidin-1-yl) methyl)-pyridin-1-ium fluoride (BF3 form), 1.5-2.0 mg) in 1 M HCl (200 µL) and methanol (400 µL) at 55 °C for 15 min and then fully drying down the solution under argon gas for 2-4 h. The hydrolyzed precursor was used on the same day or kept under -20 °C. [11C]Methane was produced using a PETTrace cyclotron, converted via gas-phase chemistry to [11C]MeI (200 - 800 mCi), and bubbled through a mixture containing Pd2(dba)3 (0.75 mg), P(o-tol)3 (1 mg) and 0.215 M K2CO3 (28 µL) in DMF (222 µL). The hydrolyzed precursor in DMF (1.5-2.0 mg/200 µL) was added and the resulting mixture was heated at 130°C for 5 minutes, and then quenched by 1 M HCl (1.6 mL). High-performance liquid chromatography purification (radioHPLC) and formulation were performed following our previously reported procedure (Difilippo, SNMMI 2019). To accurately compare the yields, the percentage of [11C]UCB-J obtained from semi-preparative radio-HPLC was used to estimate the radiolabeling efficiency.Results: The use of Pd2(dba)3 from Alfa Aesar gave the best yield (33.0 ± 7.0%, n = 5) compared to other commercial Pd2(dba)3. The use of in-house synthesized Pd2(dba)3 further improved the radiolabeling efficiency based on semi-preparative radio-HPLC (Fig. 1). [11C]UCB-J was obtained using in-house synthesized Pd2(dba)3 in 52.8% decay corrected radiochemical yield in ~ 36 min in the final dosage form with a radiochemical purity of >99% and a molar activity of ~ 20 Ci/µmol. The hydrolyzed precursor was stable for at least a week under -20 °C. By using the pre-hydrolyzed precursor, the preparation time saved at least 2 h without compromising the product yields (Fig. 2). Conclusions: The radiochemical production yields of [11C]UCB-J were increased by employing in-house synthesized Pd2(dba)3 catalyst and the preparation time of the radiosynthesis was significantly reduced by using pre-hydrolyzed precursor. This improved process provides a reliable and time-saving method for radiosynthesis of [11C]UCB-J which is applicable to other [11C]CH3I-involved Suzuki-Miyaura reactions.