Evaluation of 3-l- and 3-d-[18F]Fluorophenylalanines as PET Tracers for Tumor Imaging

Abstract

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 SUVmax, SUVmean 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 (SUVmax: 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.

Next Generation Copper Mediators for the Efficient Production of 18F‐Labeled Aromatics

“…18 F‐Labeled fluorophenylalanines ([ 18 F]FPhes) and α‐methyl‐fluorophenylalanines (αMe‐FPhes) are promising PET probes for the visualization of increased amino acid uptake associated with increased protein synthesis rates in cerebral and peripheral tumors [19,21] . We recently published a procedure for preparation of these and other radiolabeled aromatic amino acids via alcohol‐enhanced Cu‐mediated radiofluorination of Bpin‐substituted chiral complexes using Ni/Cu‐BPB/BPA templates as double protecting groups [20] .…”

“…To demonstrate the practical suitability of the novel Cu mediators, we next applied them for the preparation of several PET‐tracers: [ 18 F]R91150, [16] [ 18 F]ALX5407, [17] [ 18 F]MNI1126, [18] 3‐( S )‐ and ( R )‐[ 18 F]FPhes, [19] and ( S )‐αMe‐3‐[ 18 F]FPhe. [20] …”

“…To demonstrate the practical suitability of the novel Cu mediators, we next applied them for the preparation of several PET-tracers: [ 18 F]R91150, [16] [ 18 F]ALX5407, [17] [ 18 F]MNI1126, [18] 3-(S)-and (R)-[ 18 F]FPhes, [19] and (S)-αMe-3-[ 18 F]FPhe. [20] Radiosynthesis of [ 18 F]R91150, a promising 5-HT 2A -selective PET-tracer, [16b] from the corresponding Bpin precursor 7 was performed according to the developed protocol using Cu(4-PhPy) 4 (ClO 4 ) 2 as the mediator.…”

“…18 F-Labeled fluorophenylalanines ([ 18 F]FPhes) and α-methylfluorophenylalanines (αMe-FPhes) are promising PET probes for the visualization of increased amino acid uptake associated with increased protein synthesis rates in cerebral and peripheral tumors. [19,21] We recently published a procedure for preparation of these and other radiolabeled aromatic amino acids via alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral complexes using Ni/Cu-BPB/BPA templates as double protecting groups. [20] Application of 30 μmol Bpin precursor and 60 μmol Cu(Py) 4 (OTf) 2 in nBuOH/DMA delivered the corresponding 18 F-labeled complexes in good to excellent RCCs, but downscaling of the precursor/Cu mediator amounts led to a sharp decrease of the conversions.…”

Recent Advances in 18F-Labeled Amino Acids Synthesis and Application

“…Direct radiofluorination on AAs bearing electron-rich arenes, such as Phe, Tyr, and tryptophan (Trp), is a difficult task when traditional S N 2 or S N Ar reactions are used. To solve this problem, several new fluorine-18 radiochemical methodologies have been reported [ 28 , 29 , 30 , 31 ]. As transition-metal catalysis can accelerate radiofluorination reaction rates and enhance selectivity and reactivity, transition metal-catalyzed methodologies have emerged as an attractive technique with which to fluorinate arenes with nucleophilic fluoride sources [ 32 , 33 ].…”