Fully automated synthesis of a PET AD tau tracer [¹¹C]PBB3

Objectives [¹¹C]PBB3 is a highly selective and specific PET tracer for imaging of tau pathologies in Alzheimer’s disease (AD), and clinical [¹¹C]PBB3-PET results have been reported. Wishing to study this compound in our PET center, we decided to make our own material, and we also investigated a fully automated radiosynthesis of [¹¹C]PBB3.

Methods The authentic standard PBB3 and its precursors N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 for radiolabeling were synthesized from 5-bromo-2-nitropyridine, acrolein diethyl acetal, 6-methoxy-2-methylbenzothiazole, and diethylchlorophosphate in 6, 5 and 6 steps, respectively. TBS-protected N-desmethyl-PBB3 underwent N-[¹¹C]methylation with [¹¹C]CH₃OTf in DMSO/KOH at 100 °C to give a radiolabeled intermediate TBS-protected [¹¹C]PBB3, without isolation, followed by a quick deprotection reaction using H₂O at 80 °C to provide [¹¹C]PBB3. N-desmethyl-PBB3 was labeled by [¹¹C]CH₃OTf through N-[¹¹C]methylation in acetone at 80 °C under neutral condition to directly give [¹¹C]PBB3. The radiosynthesis was performed in a home-built automated [¹¹C]-radiosynthesis module, and the radiolabeling mixture was isolated by HPLC combined with SPE.

Results The overall chemical yield for PBB3, N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 was 1%, 2% and 1%%, respectively. The decay corrected radiochemical yield based on [¹¹C]CO₂ at EOB for [¹¹C]PBB3 was 20-25% using N-desmethyl-PBB3 in 1-pot-1-step radiosynthesis and 15-20% using TBS-protected N-desmethyl-PBB3 in 1-pot-2-step radiosynthesis, respectively. The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/μmol with a total synthesis time of ~40 min from EOB.

Conclusions PBB3, N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 were synthesized by the patent method with modifications. A 1-pot-2-step radiosynthesis of [¹¹C]PBB3 with improvement has described for comparison. An improved, concise and automated 1-pot-1-step radiosynthesis of [¹¹C]PBB3 has been developed, which were superior to previous works.