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| Home > Publications database > Next generation copper complexes for efficient production of radiolabeled aromatics |
| Conference Presentation (After Call) | FZJ-2024-03430 |
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2023
Abstract: Objectives: Cu-mediated radiofluorination is a versatile tool for thepreparation of radiofluorinated (hetero)aromatics from readily accessibleboronate (-B(OH)2, -Bpin) or trialkylstannyl (-SnR3) substrates. Themain drawback of this procedure is a requirement for large amounts ofprecursor and mediator (≥20 μmol) to achieve reproducibly highradiochemical conversions (RCCs), which often complicates purification.The aim of this work was the preparation of a series of copper(II)complexes and the statistical evaluation of their suitability asmediators for radiofluorination. In addition, reaction parameters(reaction solvent, temperature and time) were optimized, and thepractical applicability of the modified protocol was confirmed byproduction of several well-known PET tracers.Methods: [18F]Fluoride was loaded onto a QMA-CO3 cartridge andeluted with Et4NOTf (1 mg) in nBuOH (400 μL) directly into a solutionof the respective boronate precursor (≤10 μmol) and Cu-complex(10 μmol) in DMA, PC, or DMI (800 μL). For stannyl substrates, [18F]F−elution was performed with Et4NOTf (1 mg) in MeOH (500 μL)followed by removal of MeOH and addition of a solution of therespective stannyl precursor (≤10 μmol) and Cu-complex (10 μmol).The reaction mixtures were heated at 110 °C for 10 min and RCCs weredetermined by radio-HPLC. 4-Ph- and 4-Ac-Ph-X [X = B(OH)2, Bpin,Bneo, and SnMe3] were used as model substrates. The results of thescreening experiments were statistically evaluated using GraphPadPrism software. For further optimization, reactions were performed atdifferent temperatures (60–150 °C) and reaction times (1–40 min). Theoptimized conditions were used for manual or automated (AllinOne,Trasis) synthesis of seven known PET tracers (precursor amount:≤10 μmol).Results: Out of a total of 36 evaluated Cu-complexes, especially theuse of Cu(4-PhPy)4(ClO4)2 and Cu(3,4-Me2Py)4(OTf)2 in nBuOH/DMI orDMI resulted in considerably improved RCCs in relation to previousprotocols [≥57% for Ar-B(OH)2/BPin/Bneo; ≥47% for Ar-SnMe3;previous protocols: 2–30%]. Additionally, with Cu(4-PhPy)4(ClO4)2,high and reproducible RCCs of up to 84% were obtained over a broadtemperature range (80–130 °C) and reaction times (5–20 min). Atreaction temperatures below 80 °C, radiofluorination of the respectiveboronic acid precursor afforded 4-[18F]F-Ph-Ph in good RCCs of 69–80%when the reaction time was increased to 40 min. Application of the optimized reaction conditions for the preparation of the PET tracers[18F]R91150, [18F]ALX5407 and (S)-/(R)-3-[18F]FPhes afforded isolatedactivity yields (AYs) of 23–41% (Lit.: 10–17%). RCCs of up to 75% for thepreparation of (S)-3-[18F]FPhe and 6-[18F]FDOPA were obtained withprecursor amounts as lowas 2.5 μmol, which resulted in AYs of 23–30%after deprotection of the respective radiolabeled intermediates andHPLC isolation. Production of (S)-3-[18F]FPhe in an automatedsynthesis module using 2.5 μmol precursor afforded the desired PETprobein AYs of 18 ± 3%.Conclusions: Our screening study led to the discovery of severalhighly efficient mediators for Cu-mediated radiofluorination, which,especially, in nBuOH/DMI or DMI, enabled highly efficient 18F-labelingof different boronic and stannyl substrates. The practicality of themethod was demonstrated by preparation of several radiotracers,including 6-[18F]FDOPA, in improved radiochemical yields and/orusing significantly lower precursor loadings.
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