Alcohol-Supported Cu-Mediated 18F-Fluorination of Iodonium Salts under "Minimalist" Conditions

Abstract

In the era of personalized precision medicine, positron emission tomography (PET) and related hybrid methods like PET/CT and PET/MRI gain recognition as indispensable tools of clinical diagnostics. A broader implementation of these imaging modalities in clinical routine is closely dependent on the increased availability of established and emerging PET-tracers, which in turn could be accessible by the development of simple, reliable, and efficient radiolabeling procedures. A further requirement is a cGMP production of imaging probes in automated synthesis modules. Herein, a novel protocol for the efficient preparation of ¹⁸F-labeled aromatics via Cu-mediated radiofluorination of (aryl)(mesityl)iodonium salts without the need of evaporation steps is described. Labeled aromatics were prepared in high radiochemical yields simply by heating of iodonium [¹⁸F]fluorides with the Cu-mediator in methanolic DMF. The iodonium [¹⁸F]fluorides were prepared by direct elution of ¹⁸F^- from an anion exchange resin with solutions of the corresponding precursors in MeOH/DMF. The practicality of the novel method was confirmed by the racemization-free production of radiolabeled fluorophenylalanines, including hitherto unknown 3-[¹⁸F]FPhe, in 22-69% isolated radiochemical yields as well as its direct implementation into a remote-controlled synthesis unit.

Keywords: 18F; copper-mediated; iodonium salts; positron emission tomography; radiolabeling.

Scheme 1

Cu-mediated [¹⁸F]fluorination of (mesityl)(aryl)iodonium salts: A—original protocol of Ichiishi et al. [6]; B—“minimalist” approach [17,21]; C—This work. o-[¹⁸F]FAAA–ortho-[¹⁸F]fluorinated aromatic amino acids.

Scheme 2

Model labeling reaction used for the optimization of the reaction parameters.

Figure 1

¹⁸F-Recovery and ¹⁸F-incorporation (RCC) using different alcohols as co-solvents. Conditions: [¹⁸F]Fluoride (50–200 MBq) was loaded on a QMA-CO₃ cartridge (not conditioned) from the male side and the cartridge was rinsed with MeOH (5 mL) in the same direction. Afterwards, [¹⁸F]fluoride was eluted with a solution of 1·OTs or 1·BF₄ (21 µmol) in ROH/DMF (120/500 μL; 20% ROH) from the female side directly into a solution of Cu(MeCN)₄OTf (7.9 mg, 21 µmol) in DMF (600 µL) and the resulting solution was heated at 85 °C for 20 min. The reaction mixture was diluted with H₂O (2 mL) and RCCs were determined by TLC (for 1·OTs; experiments were carried out in Jülich) or HPLC (for 1·BF₄; experiments were carried out in Saint-Petersburg). Experiments with 1·OTs were carried out once (except for MeOH, n > 20 and nBuOH, n = 2) and with 1·BF₄ in triplicate. Error bars represent standard deviations (SDs). Experiments with 1·OTs were carried out in the self-made semi-automated synthesis module (Saint-Petersburg) and with 1·BF₄ manually (in Jülich).

Figure 2

¹⁸F-Recovery and ¹⁸F-incorporation (RCC) using different concentrations of MeOH. Conditions: A [¹⁸F]Fluoride (50–200 MBq) was eluted from the respective anion exchange cartridge (see legend of Figure 1) with a solution of 1·OTs (9.2 mg, 21 µmol) in MeOH/DMF (620 µL; different ratios of MeOH/DMF) directly to a solution of Cu(MeCN)₄OTf (7.9 mg, 21 µmol) in DMF (600 µL) and the resulting solution was heated at 85 °C for 20 min. The reaction mixture was diluted with H₂O (2 mL) and RCCs were determined by TLC. All reactions were carried out with the self-made semi-automated synthesis module. B: [¹⁸F]Fluoride (50–200 MBq) was eluted from the respective anion exchange cartridge (see legend of Figure 1) with a solution of 1·BF₄ (9.2 mg, 21 µmol) in MeOH/DMF (120/500 µL or 120/250 µL) directly to a solution of Cu(MeCN)₄OTf (7.9 mg, 21 µmol) in DMF (600 µL) and the resulting solution was heated at 85 °C for 20 min. The reaction mixture was diluted with H₂O (2 mL) and RCCs were determined by HPLC. These radiolabeling experiments were carried out manually. Experiments were carried out in triplicate. Error bars represent standard deviations (SDs).

Figure 3

Dependency of RCC on reaction time. [¹⁸F]Fluoride (50–200 MBq) was eluted from the respective anion exchange cartridge (see legend of Figure 1) with a solution of 1·OTs (11 mg, 21 µmol) in MeOH/DMF (120/500 µL) directly into a solution of Cu(MeCN)₄OTf (7.9 mg, 21 µmol) in DMF (600 µL) and the resulting solution was heated at 85 °C for a given time. The reaction mixture was diluted with H₂O (2 mL) and RCCs were determined by TLC. All reactions were carried out in the self-made semi-automated synthesis module. All experiments were carried out in duplicate. Error bars represent standard deviations (SDs).

Figure 4

¹⁸F-Recovery and ¹⁸F-incorporation (RCC) using different amounts of 1·OTs and Cu(MeCN)₄OTf. Conditions: [¹⁸F]Fluoride (50–200 MBq) was eluted from the respective anion exchange cartridge (see legend of Figure 1) with a solution of a given amount 1·OTos in MeOH/DMF (120/500 µL) directly into a solution of equimolar amount of Cu(MeCN)₄OTf in DMF (600 µL) and the resulting solution was heated at 85 °C for 20 min. The reaction mixture was diluted with H₂O (2 mL) and RCCs were determined by TLC. All reactions were carried out in the self-made semi-automated synthesis module.

Scheme 3

Preparation of 2-4-[¹⁸F]FPhes (2-4-[¹⁸F]-8–10). Conditions for manual synthesis (^a): radiolabeling step: refer to caption of Table 1; deprotection step: the reaction mixture was cooled to 65 °C, diluted with H₂O (4.5 mL), and loaded onto a C₁₈ SPE cartridge. The cartridge was washed with H₂O (10 mL) and radiolabeled intermediates were eluted with MeOH (2 mL). MeOH was evaporated to 1 mL at 85 °C within 1 min and the residual solution was diluted with 12 n HCl (0.5 mL) and heated at 80 °C for 10 min. The reaction mixture was cooled and ¹⁸F-labeled FPhes were isolated by HPLC. Conditions for the semi-automated synthesis (^b): refer to GP3 in Materials and Methods ^c–RCC; ^d–RCY (EOB). Each radiosynthesis, except the preparation of 4-[¹⁸F]FPhe from 13, was carried out at least in duplicate.

Scheme 4

Synthesis of radiolabeling precursor 12.

Figure 5

Arrangement of HPLC valves (analytical HPLC).

Figure 6

Process flow diagram (PFD) for the semi-automated radiosynthesis of [¹⁸F]2–10. A: a solution of precursor in MeOH/DMF (0.12/0.5 mL); B: H₂O (4 mL); C: 12 n HCl (0.5 mL); D: H₂O (5 mL); E: MeOH (2.0 mL); RV1: Cu(MeCN)₄OTf (21 µmol) in DMF (0.6 mL).