Simple and Efficient Synthesis of N-Succinimidyl-4-[18F]fluorobenzoate ([18F]SFB)-An Important Intermediate for the Introduction of Fluorine-18 into Complex Bioactive Compounds

Abstract

Background:N-succinimidyl-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) is commonly prepared through a three-step procedure starting from [¹⁸F]fluoride ion. A number of methods for the single-step radiosynthesis of [¹⁸F]SFB have been introduced recently, including the radiofluorination of diaryliodonium salts and the Cu-mediated ¹⁸F-fluorination of pinacol aryl boronates and aryl tributyl stannanes, but they still have the drawbacks of lengthy product purification procedures. In the present work, two approaches for the direct labeling of [¹⁸F]SFB from diaryliodonium (DAI) salt (4) and pinacol aryl boronate (6) are evaluated, with a major focus on developing a fast and simple SPE-based purification procedure. Methods: DAI salt precursor 6 was labeled employing the common "minimalist" approach with a two-step reaction heating sequence. The Cu-mediated radiofluorination of 4 was accomplished using Bu₄NOTf as a phase transfer catalyst for the elution of [¹⁸F]fluoride, followed by radiofluorination in the same solvent. Several types of SPE cartridges were tested in the elution and SPE procedures. Results: The Cu-mediated ¹⁸F-fluorination of the pinacol aryl boronate precursor afforded a higher RCC of 56 ± 3% (n = 7), making it better suited for the one-pot synthesis of [¹⁸F]SFB. SPE-based purification was achieved using cation exchange and reverse-phase polymer resin cartridges, connected in series. In a full-batch test, [¹⁸F]SFB was obtained with an RCY of 30% (n. d. c.), RCP > 99%, A_m 96-155 GBq/µmol, and a synthesis time of ≤35 min. Conclusions: Compared to other published methods, [¹⁸F]SFB production via the Cu-mediated radiofluorination of pinacol aryl boronate precursor provides significant time and cost savings, coupled with an ease of implementation.

Keywords: [18F]SFB; cartridge-based purification; copper-mediated radiofluorination; fluorine-18; one-step synthesis; prosthetic group.

Scheme 1

Three-step radiosynthesis of [¹⁸F]SFB: (i) K⁺/K_2.2.2./¹⁸F⁻, CH₃CN, 90 °C; (ii) TPAH, 120 °C; (iii) TSTU, 90 °C [10].

Scheme 2

Synthesis of [¹⁹F]SFB (2b) and (4-((2,5-dioxopyrrolidin-1-yloxy)carbonyl)phenyl)(phenyl)iodonium trifluoroacetate (4). Reagents and conditions: (i): di(N-succinimidyl) carbonate, Et₃N, CH₃CN, 20 °C, 20 h; yield 2a—41%, 2b—44%, 2c—73%; (ii): n-Bu₆Sn₂, Pd(PPh₃)₄, toluene-DMF, reflux, 4 h, 62%; (iii): PhI(OC(O)CF₃)₂, DCM, 20 °C, 40 h, 28%.

Scheme 3

Labeling of [¹⁸F]SFB via diaryliodonium salt precursor 4 (Table 1).

Scheme 4

Synthesis of 2,5-dioxopyrrolidin-1-yl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (6). Reagents and conditions: (i): di(N-succinimidyl) carbonate, Et₃N, CH₃CN, 20 °C, 20 h, 51%.

Scheme 5

Labeling of the [¹⁸F]SFB using arylboronic acid pinacol ester precursor 6; [Alk₄N]⁺[¹⁸F]⁻-[Et₄N]⁺[¹⁸F]⁻ or [Bu₄N]⁺[¹⁸F]⁻ (Table 3).

Figure 1

RadioTLC analysis of the reaction mixture for the synthesis of [¹⁸F]SFB from 6 (Scheme 5); silica plates, eluent ethyl acetate (TLC system 1); RCC 53% (entry 7, Table 3).