Abstract
Simple SummaryThe early detection and treatment of malignant brain tumors can significantly improve the survival time and life quality of affected patients. Whereas positron emission tomography (PET) with O-(2-[18F]fluoroethyl)tyrosine ([18F]FET) offers improved diagnostic accuracy compared to other imaging methods, there is still a need for PET tracers with better tumor-specificity. A higher protein incorporation rate, as well as a higher affinity for the amino acid transporter LAT1, could provide probes with superior image quality compared to [18F]FET. The aim of the present study was a preclinical evaluation of the two enantiomeric phenylalanine (Phe) analogues, 3-l- and 3-d-[18F]fluorophenylalanine ([18F]FPhes), as possible alternatives to [18F]FET. Based on promising in vitro evaluation results, the radiolabeled amino acids were studied in vivo in two subcutaneous and one orthotopic rodent tumor xenograft models using µPET. The results show that 3-l- and 3-d-[18F]FPhe enable high-quality visualization of tumors with certain advantages over [18F]FET, making them promising candidates for further preclinical and clinical evaluations. 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.
Highlights
Gliomas are the second most common primary brain tumors in adults after meningiomas [1]
The vast majority of neoplastic tissues, such as gliomas, breast, and prostate cancers, prominently overexpress the system L amino acid transporter LAT1 [3,8,9,10] and other amino acid transporters, such as ASCT2 [11,12], which have been identified as “cancer-promoting targets” and part of the “tumor metabolome” [11,13]. This is exploited for Positron emission tomography (PET)-based imaging with O-(2-[18F]fluoroethyl)tyrosine ([18F]FET), which acts as a substrate of these transporters and accumulates preferentially in neoplastic tissues [3]
3-L- and 3-D-[18F]FPhes were prepared from the corresponding diastereomerically and enantiomerically pure Ni-BPB-Phe precursors (BPB: (S)-2-[N(N -benzylprolyl)amino]benzophenone) bearing a pinacol boronate moiety [22] in 15–39% activity yields (n > 10) within 90 min and with molar activities of 180–250 GBq/μmol using alcohol-enhanced Cu-mediated 18F-fluorodeboronation (Figure 1) [21]
Summary
Gliomas are the second most common primary brain tumors in adults after meningiomas [1]. The vast majority of neoplastic tissues, such as gliomas, breast, and prostate cancers, prominently overexpress the system L amino acid transporter LAT1 [3,8,9,10] and other amino acid transporters, such as ASCT2 [11,12], which have been identified as “cancer-promoting targets” and part of the “tumor metabolome” [11,13] This is exploited for PET-based imaging with O-(2-[18F]fluoroethyl)tyrosine ([18F]FET), which acts as a substrate of these transporters and accumulates preferentially in neoplastic tissues [3]. [18F]FET-PET can be used to distinguish therapy-associated pseudo-progression from real tumor progression during therapy monitoring [14,15]
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