18F chemistry without azeotropic distillations: tetraethylammonium salts as combined anion exchange reagents and phase transfer catalysts.

328 Objectives The practice of preparing anhydrous, activated [18F]F- for nucleophilic substitution reactions typically involves: a) the trapping of [18F]fluoride onto an anion exchange sorbent, b) elution with a H2O/MeCN mixture containing anion exchanging salt (commonly K2CO3 or KHCO3) and phase transfer catalyst (commonly Kryptofix 2.2.2.) and finally c) the scrupulous removal of water, which includes the sequential addition of additional portions of acetonitrile to enhance water evaporation by way of azeotropic distillation (b.p. H2O-MeCN = 76.5 °C). This final step constitutes a major efficiency sink in these types of radiochemical syntheses, owing to a) lost time, b) adsorption of dried K[18F]F onto the vessel walls and c), evaporation of H[18F]F. Thus Brichard and Aigbirhio introduced an innovative strategy by which [18F]F- was eluted from QMA sorbent with tetraethylammonium hydrogen carbonate (TEAB) in organic solvents containing small (0.5-5%) amounts of water. Aliquots of this bulk eluant were then used in test [18F]fluorination reactions (Eur. J. Org. Chem.2014, 6145). In our hands however, the reported method resulted in low and variable elution efficiencies (activity trapped on sorbent/recovered activity × 100) from a QMA cartridge [8-22 % decay-corrected (DC), n = 4]. We therefore sought alternate protocols which would efficiently concentrate [18F]F- and permit its use as a single portion, using TEAB or tetraethylammonium perchlorate (TEAP) as dual anion exchangers and [18F]F- phase transfer catalysts. Methods [18F]F- in H2[18O]O was trapped on a small MP-1 anion exchange cartridge and the cartridge was subsequently washed with hexanes and dried with Ar. Elutions were carried out using TEAB or TEAP in 100 % H2O (100 µL) or 90 % organic solvent (DMSO, MeCN, 500 µL) or 50 % organic solvent (DMSO, MeCN, 100 µL). Model precursor compound 1a or tosylated rhodamine-6G analogue 2a were added in anhydrous organic solvent such that the final percent concentration of water was 5 %. The reaction mixtures were heated at various temperatures using microwave irradiation and radiochemical incorporation was assayed by radio-HPLC and radio-TLC. Results Results are summarized in Table 1 below. In most cases, elution efficiencies were greater than 90 %. Fluoride incorporation to yield 18F compound 1b proved highest using the conditions described in Table 1, Row 4. These conditions were further used to synthesize 1b in a preparative fashion; a yield of 18 % DC was achieved after HPLC purification and concentration by solid phase extraction. Total synthesis time was 108 min. An initial attempt to synthesize rhodamine-6G-18F (2b), a promising myocardial perfusion imaging agent, was less successful. In 95 % DMSO at 110 °C (10 min), radiochemical conversion was 16 % vs. 38 % (n=3, unpublished results) using traditional K[18F]F/Kryptofix 2.2.2./K2CO3 chemistry. This is presumably due to the presence of the hydrolytically cleavable ester moiety in 2a and 2b. Conclusions The method described above holds outstanding promise in the area of 18F PET tracer development owing to its potentially far-reaching utility, its straightforward implementation, and its compatibility with automated syntheses. Efforts to optimize this chemistry and define its scope through the preparation of novel tracers for neurology and cardiology PET applications is currently underway. Table 1. Summary of Trial [18F]Fluorinations of Precursor 1a. Anion Exchange (AEX) sorbent was MP-1. NA = Not Available. % Yield is the average of 4 separate TLC traces, except where noted. Number in parentheses is ±standard deviation. [asterisk]Average of 3 traces.Research Support: This research is being supported by NIH Grants 5R01HL10810701 and 3R21MH103718, with additional funding from the Children’s Hospital Radiology Foundation.