Synthesis, uptake mechanism characterization and biological evaluation of 18F labeled fluoroalkyl phenylalanine analogs as potential PET imaging agents

Wang, Limin; Qü, Wenchao; Lieberman, Brian P.; Plößl, Karl; Kung, Hank F.

doi:10.1016/j.nucmedbio.2010.07.005

Cited by 19 publications

(13 citation statements)

References 33 publications

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“…Nonnatural tracers, such as 18 F-FACBC, 18 F-FET, and 18 F-FDOPA, mainly represent transport, whereas the natural tracer 11 C-MET represents transport, protein synthesis, and nonprotein metabolic pathways. 15,25 Theoretically, this could indicate that dynamic analysis of 18 F-FACBC uptake could be useful in noninvasive grading of gliomas, as shown for 18 F-FET. [26][27][28][29][30] However, different AA transporter systems are involved for different AA PET tracers, 31 which may impact tracer distribution, including uptake in inflamed tissue, and blood-brain barrier (BBB) passage.…”

mentioning

confidence: 82%

18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas

Karlberg¹,

Berntsen²,

Johansen

et al. 2019

Clin Nucl Med

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Purpose: This pilot study aimed to evaluate the amino acid tracer 18 F-FACBC with simultaneous PET/MRI in diagnostic assessment and neurosurgery of gliomas. Materials and Methods: Eleven patients with suspected primary or recurrent low-or high-grade glioma received an 18 F-FACBC PET/MRI examination before surgery. PET and MRI were used for diagnostic assessment, and for guiding tumor resection and histopathological tissue sampling. PET uptake, tumor-to-background ratios (TBRs), time-activity curves, as well as PET and MRI tumor volumes were evaluated. The sensitivities of lesion detection and to detect glioma tissue were calculated for PET, MRI, and combined PET/MRI with histopathology (biopsies for final diagnosis and additional image-localized biopsies) as reference. Results: Overall sensitivity for lesion detection was 54.5% (95% confidence interval [CI], 23.4-83.3) for PET, 45.5% (95% CI, 16.7-76.6) for contrast-enhanced MRI (MRI CE), and 100% (95% CI, 71.5-100.0) for combined PET/MRI, with a significant difference between MRI CE and combined PET/MRI (P = 0.031). TBRs increased with tumor grade (P = 0.004) and were stable from 10 minutes post injection. PET tumor volumes enclosed most of the MRI CE volumes (>98%) and were generally larger (1.5-2.8 times) than the MRI CE volumes. Based on image-localized biopsies, combined PET/MRI demonstrated higher concurrence with malignant findings at histopathology (89.5%) than MRI CE (26.3%). Conclusions: Low-versus high-grade glioma differentiation may be possible with 18 F-FACBC using TBR. 18 F-FACBC PET/MRI outperformed MRI CE in lesion detection and in detection of glioma tissue. More research is required to evaluate 18 F-FACBC properties, especially in grade II and III tumors, and for different subtypes of gliomas.

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mentioning

confidence: 82%

18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas

Karlberg¹,

Berntsen²,

Johansen

et al. 2019

Clin Nucl Med

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“…This synthetic approach was based on the literature route described for the synthesis of para -substituted phenylalanine amino acids 25,28 . Commercially available N-Boc-2-bromophenylalanine was protected as its tert -butyl ester with t-butyl 2, 2, 2-trichloroacetimidate (TBTA) and vinylated with a Stille coupling reaction to give 25 and 26 .…”

Section: Resultsmentioning

confidence: 99%

“…Molecular imaging using PET may provide relevant additional information on tumor metabolism and may be useful in case of ambiguous MRI findings following neuro-oncological treatment 35 . In this study, two recently developed fluoroalkyl phenylalanine analogues, 4-FELP and 4-FEDP 25 , together with four new compounds, 2-FELP , 2-FEDP , 3-FELP , 3-FEDP were successfully synthesized and compared in vitro to the reference compound FET, currently used in the clinic. The influence of the stereochemistry on the affinity for the LAT1 transporter was evaluated as there are some conflicting reports in literature.…”

Section: Discussionmentioning

confidence: 99%

“…have developed para -fluoroethyl ( 15 & 16 , Fig. 1) and -fluoropropyl alkylated phenylalanine derivatives, where the former showed appreciable uptake in the 9 L glioma tumor model 25 .

Figure 1Structures of clinically used radiotracers or previously described amino acid tracers (upper part). Structures of the prepared modified phenylalanine analogs in this manuscript (lower part).…”

Section: Introductionmentioning

confidence: 99%

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New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma

Verhoeven

Hulpia

Kersemans

et al. 2019

Sci Rep

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The use of O -(2-[ 18 F]fluoroethyl)- l -tyrosine ([ 18 F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro K i determination, the most promising compound, 2-[ 18 F]-2-fluoroethyl- l -phenylalanine (2-[ 18 F]FELP), was selected for further evaluation and in vitro comparison with [ 18 F]FET. Subsequently, 2-[ 18 F]FELP was assessed in vivo and compared with [ 18 F]FET and [ 18 F]FDG in a F98 glioblastoma rat model. 2-[ 18 F]FELP showed improved in vitro characteristics over [ 18 F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[ 18 F]FELP is a promising new PET tracer for brain tumor imaging.

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“…We also included DNA and phenylalanine as increase in these molecules may be indicative of malignancy. Cancer cells exhibit an increased uptake of amino acids such as phenylalanine, which serve as an energy source [43]. Of note, the STAM ™ NASH model is known to progress to HCC over time.…”

Section: Resultsmentioning

confidence: 99%

Development of a classification model for non‐alcoholic steatohepatitis (NASH) using confocal Raman micro‐spectroscopy

Yan

Kang

et al. 2017

Journal of Biophotonics

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Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in developed countries [1]. A subset of individuals with NAFLD progress to non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD which predisposes individuals to cirrhosis, liver failure and hepatocellular carcinoma. The current gold standard for NASH diagnosis and staging is based on histological evaluation, which is largely semi-quantitative and subjective. To address the need for an automated and objective approach to NASH detection, we combined Raman micro-spectroscopy and machine learning techniques to develop a classification model based on a well-established NASH mouse model, using spectrum pre-processing, biochemical component analysis (BCA) and logistic regression. By employing a selected pool of biochemical components, we identified biochemical changes specific to NASH and show that the classification model is capable of accurately detecting NASH (AUC=0.85–0.87) in mice. The unique biochemical fingerprint generated in this study may serve as a useful criterion to be leveraged for further validation in clinical samples.

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Synthesis, uptake mechanism characterization and biological evaluation of 18F labeled fluoroalkyl phenylalanine analogs as potential PET imaging agents

Cited by 19 publications

References 33 publications

18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas

18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas

New fluoroethyl phenylalanine analogues as potential LAT1-targeting PET tracers for glioblastoma

Development of a classification model for non‐alcoholic steatohepatitis (NASH) using confocal Raman micro‐spectroscopy

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