Cu‐mediated radiofluorination is a versatile tool for the preparation of ¹⁸F‐labeled (hetero)aromatics. In this work, we systematically evaluated a series of complexes and identified several generally applicable mediators for highly efficient radiofluorination of aryl boronic and stannyl substrates. Utilization of these mediators in nBuOH/DMI or DMI significantly improved ¹⁸F‐labeling yields despite use of lower precursor amounts. Impressively, application of 2.5 μmol aryl boronic acids was sufficient to achieve ¹⁸F‐labeling yields of up to 75 %. The practicality of the novel mediators was demonstrated by efficient production of five PET‐tracers and transfer of the method to an automated radiosynthesis module. In addition, (S)‐3‐[¹⁸F]FPhe and 6‐[¹⁸F]FDOPA were prepared in activity yields of 23±1 % and 30±3 % using only 2.5 μmol of the corresponding boronic acid or trimethylstannyl precursor.

¹⁸F-Fluorination of sensitive molecules is often challenging, but can be accomplished under suitably mild conditions using radiofluorinated prosthetic groups (PGs). Herein, 1-alkylamino-7-[¹⁸F]fluoro-8-azaisatoic anhydrides ([¹⁸F]AFAs) are introduced as versatile ¹⁸F-labeled building blocks that can be used as amine-reactive or "click chemistry" PGs. [¹⁸F]AFAs were efficiently prepared within 15 min by "on cartridge" radiolabeling of readily accessible trimethylammonium precursors. Conjugation with a range of amines afforded the corresponding 2-alkylamino-6-[¹⁸F]fluoronicotinamides in radiochemical conversions (RCCs) of 15-98%. In addition, radiolabeling of alkyne- or azide-functionalized precursors with azidopropyl- or propargyl-substituted [¹⁸F]AFAs using Cu-catalyzed click cycloaddition afforded the corresponding conjugates in RCCs of 44-88%. The practical utility of the PGs was confirmed by the preparation of three ¹⁸F-labeled PSMA ligands in radiochemical yields of 28-42%. Biological evaluation in rats demonstrated excellent in vivo stability of all three conjugates. In addition, one conjugate ([¹⁸F]JK-PSMA-15) showed favorable imaging properties for high-contrast visualization of small PSMA-positive lesions.

Purpose: The preclinical evaluation of 3-l- and 3-d-[¹⁸F]FPhe in comparison to [¹⁸F]FET, an established tracer for tumor imaging. Methods: In vitro studies were conducted with MCF-7, PC-3, and U87 MG human tumor cell lines. In vivo µPET studies were conducted in healthy rats with/without the inhibition of peripheral aromatic l-amino acid decarboxylase by benserazide pretreatment (n = 3 each), in mice bearing subcutaneous MCF-7 or PC-3 tumor xenografts (n = 10), and in rats bearing orthotopic U87 MG tumor xenografts (n = 14). Tracer accumulation was quantified by SUV_max, SUV_mean and tumor-to-brain ratios (TBrR). Results: The uptake of 3-l-[¹⁸F]FPhe in MCF-7 and PC-3 cells was significantly higher relative to [¹⁸F]FET. The uptake of all three tracers was significantly reduced by the suppression of amino acid transport systems L or ASC. 3-l-[¹⁸F]FPhe but not 3-d-[¹⁸F]FPhe exhibited protein incorporation. In benserazide-treated healthy rats, brain uptake after 42–120 min was significantly higher for 3-d-[¹⁸F]FPhe vs. 3-l-[¹⁸F]FPhe. [¹⁸F]FET showed significantly higher uptake into subcutaneous MCF-7 tumors (52–60 min p.i.), while early uptake into orthotopic U87 MG tumors was significantly higher for 3-l-[¹⁸F]FPhe (SUV_max: 3-l-[¹⁸F]FPhe, 107.6 ± 11.3; 3-d-[¹⁸F]FPhe, 86.0 ± 4.3; [¹⁸F]FET, 90.2 ± 7.7). Increased tumoral expression of LAT1 and ASCT2 was confirmed immunohistologically. Conclusion: Both novel tracers enable accurate tumor delineation with an imaging quality comparable to [¹⁸F]FET.

O-([¹⁸F]Fluoroethyl)-l-tyrosine ([¹⁸F]FET) is actively transported into the brain and cancer cells by LAT1 and possibly other amino acid transporters, which enables brain tumor imaging by positron emission tomography (PET). However, tumor delivery of this probe in the presence of competing amino acids may be limited by a relatively low affinity for LAT1. The aim of the present work was to evaluate the meta-substituted [¹⁸F]FET analog m-[¹⁸F]FET and the methyl ester [¹⁸F]FET-OMe, which were designed to improve tumor delivery by altering the physicochemical, pharmacokinetic, and/or transport properties. Both tracers could be prepared with good radiochemical yields of 41-56% within 66-90 min. Preclinical evaluation with [¹⁸F]FET as a reference tracer demonstrated reduced in vitro uptake of [¹⁸F]FET-OMe by U87 glioblastoma cells and no advantage for in vivo tumor imaging. In contrast, m-[¹⁸F]FET showed significantly improved in vitro uptake and accelerated in vivo tumor accumulation in an orthotopic glioblastoma model. As such, our work identifies m-[¹⁸F]FET as a promising alternative to [¹⁸F]FET for brain tumor imaging that deserves further evaluation with regard to its transport properties and in vivo biodistribution.