A non-anhydrous, minimally basic protocol for the simplification of nucleophilic 18F-fluorination chemistry

Abstract

Fluorine-18 radiolabeling typically includes several conserved steps including elution of the [¹⁸F]fluoride from an anion exchange cartridge with a basic solution of K₂CO₃ or KHCO₃ and Kryptofix 2.2.2. in mixture of acetonitrile and water followed by rigorous azeotropic drying to remove the water. In this work we describe an alternative "non-anhydrous, minimally basic" ("NAMB") technique that simplifies the process and avoids the basic conditions that can sometimes limit the scope and efficiency of [¹⁸F]fluoride incorporation chemistry. In this approach, [¹⁸F]F^- is eluted from small (10-12 mg) anion-exchange cartridges with solutions of tetraethylammonium bicarbonate, perchlorate or tosylate in polar aprotic solvents containing 10-50% water. After dilution with additional aprotic solvent, these solutions are used directly in nucleophilic aromatic and aliphatic ¹⁸F-fluorination reactions, obviating the need for azeotropic drying. Perchlorate and tosylate are minimally basic anions that are nevertheless suitable for removal of [¹⁸F]F^- from the anion-exchange cartridge. As proof-of-principle, "NAMB" chemistry was utilized for the synthesis of the dopamine D₂/D₃ antagonist [¹⁸F]fallypride.

Figure 1

Traditional (a) and “non-anhydrous, minimally-basic” NAMB (b) approaches to the extraction, preparation and use of [¹⁸F]F⁻ for the manufacture of PET radiopharmaceuticals. X⁻ = HCO₃⁻, ClO₄⁻, or OTs⁻.

Figure 2

Example radiosynthesis of model compound [¹⁸F]1 using the “NAMB” ¹⁸F-fluorination method (Table 2, entry 11).

Figure 3

Analytical HPLCs of representative reaction mixtures of (a) model compound [¹⁸F]1 and (b) [¹⁸F]FBA using the “NAMB” strategy. Both traces were obtained using HPLC 1, Program A, as described in the Supplementary Information. (a) Reaction conditions: TEAP, 97% MeCN, 150 °C, 10 min. t_R [¹⁸F]1 = 10.88 min. t_R tosylated precursor 2 = 11.73 min. (b) Reaction conditions: TEAP, 97% DMSO, 150 °C, 10 min. t_R [¹⁸F]3 = 11.41 min., t_R 4 = 11.48 min.

Figure 4

Radiosynthesis of 4-[¹⁸F]fluorobenzaldehyde ([¹⁸F]3) from 4-nitrobenzaldehyde (4). TEAX = TEAB, TEAP or TEATos.

Figure 5

Tetraethylammonium salt-mediated radiosynthesis of [¹⁸F]fallypride ([¹⁸F]5) under “NAMB” ¹⁸F-fluorination conditions.

Figure 6

Analytical HPLCs of (a) [¹⁸F]fallypride ([¹⁸F]5) reaction mixture and (b) co-injection of [¹⁸F]5 with non-radioactive standard. (a) HPLC conditions: HPLC 1, Program A, as described in the Supplementary Information. Reaction conditions: TEATos, 97% MeCN, 150 °C, 10 min. [¹⁸F]5 t_R = 9.23 min. Precursor 6 t_R = 11.05 min. (b) HPLC conditions: HPLC 1, Program C (See the Supplementary Information). UV- and γ-detectors were placed in serial, which results in slight differences in t_Rs between [¹⁸F]5 (t_R = 10.90 min) and [¹⁹F]5 (t_R = 10.68 min).