Multi-step, remote synthesis of 6-[¹⁸F]fluorodopamine via nucleophilic aromatic substitution

Objectives 6-[¹⁸F]fluorodopamine ([¹⁸F]FDA) is a catecholamine that is actively taken into cells via norepinephrine transporters and is useful in PET imaging of pheochromocytomas and other neuroendocrine tumors. We sought to develop and optimize a method for remote, routine production of [¹⁸F]FDA for clinical research by nucleophilic aromatic substitution with ¹⁸F^-.

Methods Using a PETChem Solutions, Inc. remote synthesis module, [¹⁸F]FDA was prepared via modification of the method of Ding, et al {1991}. Aqueous ¹⁸F- was trapped on QMA, removed with Kryptofix 2.2.2/K₂CO₃ in CH₃CN and H₂O, and dried. 6-Nitropiperonal was fluorinated in DMSO at 120°C for 10 min and transferred onto a C-18 SepPak after dilution in water and passage through an alumina cartridge. 6-[¹⁸F]Fluoropiperonal was eluted with CH₂Cl₂ and sent to a second reactor where all remaining steps occurred. After evaporation of solvent, nitropropene was formed by addition of 6:1 CH₃NO₂/acetic acid and heating to 100°. Solvent was again evaporated followed by reduction with LAH/THF and removal of THF. [¹⁸F]FDA was formed by deprotection of the catechol with HI at 160° and diluted in phosphate buffer. Filtration (0.22 µm) to remove aluminate salts and semi-prep HPLC on a C-18 column yielded purified [¹⁸F]FDA in 9 minutes. RP-HPLC was used to determine radiochemical purity of the final product.

Results Final, radiochemical yield of purified [¹⁸F]FDA (not optimized) was 4% (corrected to EOB) with an overall synthesis time of 2 hours. Radiochemical purity was 96% resulting in 3 mCi of final product (prior to reformulation) starting from 200 mCi.

Conclusions While optimization is still ongoing, we succeeded in developing a method for the remote, nucleophilic production of [¹⁸F]FDA. Even with lower yield than previously reported, this synthesis is easily capable of producing enough activity for a single patient (5-10 mCi), when scaled up. Further optimization, reformulation, and quality control studies are underway