One-Step Synthesis of [18F]Aromatic Electrophile Prosthetic Groups via Organic Photoredox Catalysis

Abstract

To avoid the harsh conditions that are oftentimes adopted in direct radiofluorination reactions, conjugation of bioactive ligands with ¹⁸F-labeled prosthetic groups has become an important strategy to construct novel PET agents under mild conditions when the ligands are structurally sensitive. Prosthetic groups with [¹⁸F]fluoroarene motifs are especially appealing because of their stability in physiological environments. However, their preparation can be intricate, often requiring multistep radiosynthesis with functional group conversions to prevent the decomposition of unprotected reactive prosthetic groups during the harsh radiofluorination. Here, we report a general and simple method to generate a variety of highly reactive ¹⁸F-labeled electrophiles via one-step organophotoredox-mediated radiofluorination. The method benefits from high step-economy, reaction efficiency, functional group tolerance, and easily accessible precursors. The obtained prosthetic groups have been successfully applied in PET agent construction and subsequent imaging studies, thereby demonstrating the feasibility of this synthetic method in promoting imaging and biomedical research.

Figure 1

Functional-group-tolerant organophotoredox-catalyzed radiofluorination enables one-step radiosynthesis of prosthetic groups with [¹⁸F]fluoroaryl motif.

Figure 2

One-step radiosyntheses of prosthetic groups via organophotoredox-catalyzed S_NAr. ^aCondition A: precursor 1 (0.05 mmol), TBAB/MeCN (15 μL, 60 mg/mL), oxygen flow, solvent mixture (800 μL), photocatalyst S1 (5 mol %), laser irradiation (450 nm, 30 min). ^bCondition B: precursor 1 (0.05 mmol), no TBAB/MeCN, air flow, solvent mixture (800 μL), photocatalyst S1 (5 mol %), laser irradiation (450 nm, 20 min). ^cCondition C: precursor 1 (0.05 mmol), TBAB/MeCN (25 μL, 60 mg/mL), air flow, solvent mixture (400 μL), photocatalyst S1 (5 mol %), laser irradiation (450 nm, 20 min). ^dCondition D: precursor 1 (0.05 mmol), no TBAB/MeCN, air flow, solvent mixture (400 μL), photocatalyst S1 (5 mol %), laser irradiation (450 nm, 20 min). ^eEstimated RCC calculated from isolated RCY of 2d and radio-HPLC peak ratio between 2d and 2g.^fCondition F: precursor 1 (0.016 mmol), no air flow, TBAB/MeCN (8.3 μL, 60 mg/mL), solvent mixture (133 μL), photocatalyst S1 (5 mol %), sealed quartz tube, LED irradiation (450 nm, 20 min). ^gAll radiochemical yields (RCYs) reported in this figure are determined from an aliquot of the reaction crude and the collected activity after HPLC column and decay correction.

Figure 3

PET agent constructions utilizing [¹⁸F]SFB analogue 2c, [¹⁸F]FBB analogue 2d, and isocyanate synthon 2h. ^aPSMA, DIPEA, MeCN, and DMF, 60 °C, 30 min. ^bFAPI, DIPEA, and MeCN, 60 °C, 30 min. ^cNT20.3, DIPEA, MeCN, and water, 60 °C, 30 min. ^dPSMA, MeCN, water, DMF, and Na₂CO₃, 70 °C, 30 min. ^ePSMA, DIPEA, MeCN, and DMF, 70 °C, 30 min. ^fPSMA, MeCN, water, and Na₂CO₃, 70 °C, 30 min. ^gEstimated RCC of 3f was calculated on the basis of the isolated RCY of 3e and the radio-HPLC peak integration ratio between 3e and 3f. ^hAll radiochemical yields (RCYs) reported in this figure are determined from an aliquot of the reaction crude and the collected activity after HPLC column and decay correction. RCYs in this figure are the single-step coupling reaction RCYs.

Figure 4

PET/CT imaging study of PC3-PSMA tumor-bearing mice with PET tracer 3a. (A) Regular imaging study. Tumor circled in red. (B) PSMA-blocking experiment; representative PET/CT images of PSMA-blocked tumor-bearing mice at 0.5, 1.5, and 3 h postinjection; and organ uptakes with the comparison with normal [¹⁸F]3a tracer injection. T, tumor; B, bladder.