Improved synthesis of [11C]UCB-J for PET Imaging of SV2A

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.

• Download figure
• Open in new tab
• Download powerpoint