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Synthesis, Radiolabeling, and Biological Evaluation of the trans-Stereoisomers of 1-Amino-3-(fluoro-¹⁸F)-4-fluorocyclopentane-1-carboxylic Acid as PET Imaging Agents.

ABSTRACT: The enantiomeric non-natural cyclic amino acids (3R,4R)-1-amino-3-fluoro-4-(fluoro-¹⁸F)cyclopentane-1-carboxylic acid and (3S,4S)-1-amino-3-fluoro-4-(fluoro-¹⁸F)cyclopentane-1-carboxylic acid ([ ¹⁸ F]5) have been prepared as a racemic mixture in 1.3% decay corrected radiochemical yield and in greater than 99% radiochemical purity. [ ¹⁸ F]5 is transported primarily via system L with some transport occurring via system ASC, as assessed in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells. In rats bearing intracranial 9L gliosarcoma, [ ¹⁸ F]5 gave tumor to contralateral brain tissue ratios of up to 2.8. Biodistribution studies in healthy rats demonstrated that bladder accumulation is delayed until 10 min postinjection.

SUBMITTER: Pickel TC

PROVIDER: S-EPMC8205243 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Synthesis, Radiolabeling, and Biological Evaluation of the trans-Stereoisomers of 1-Amino-3-(fluoro-18F)-4-fluorocyclopentane-1-carboxylic Acid as PET Imaging Agents.

Pickel Thomas C TC Pashikanti Gouthami G Voll Ronald J RJ Yu Weiping W Zhang Zhaobin Z Nye Jonathon A JA Bacsa John J Olson Jeffrey J JJ Liebeskind Lanny S LS Goodman Mark M MM

ACS pharmacology & translational science 20210405 3

The enantiomeric non-natural cyclic amino acids (3R,4R)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid and (3S,4S)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([ 18 F]5) have been prepared as a racemic mixture in 1.3% decay corrected radiochemical yield and in greater than 99% radiochemical purity. [ 18 F]5 is transported primarily via system L with s ...[more]

PMID: 34151209

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Project description:IntroductionAmino acid based radiotracers target tumor cells through increased uptake by membrane-associated amino acid transport (AAT) systems. In the present study, four structurally related non-natural (18)F-labeled amino acids, (R)- and (S)-[(18)F]FAMP 1 and (R)- and (S)-[(18)F]MeFAMP 2 have been prepared and evaluated in vitro and in vivo for their potential utility in brain and systemic tumor imaging based upon primarily system A transport with positron emission tomography (PET).MethodsThe transport of enantiomers of [(18)F]FAMP 1 and [(18)F]MeFAMP 2 was measured through in vitro uptake assays in human derived cancer cells including A549 (lung), DU145 (prostate), SKOV3 (ovary), MDA MB468 (breast) and U87 (brain) in the presence and absence of amino acid transporter inhibitors. The in vivo biodistribution of these tracers was evaluated using tumor mice xenografts at 15, 30, 60 and 120 min post injection.ResultsAll four tracers showed moderate to high levels of uptake (1-9%ID/5×10(5) cells) by the cancer cell lines tested in vitro. AAT cell inhibition assays demonstrated that (R)-[(18)F]1 and (S)-[(18)F]1 entered these tumor cells via mixed AATs, likely but not limited to system A and system L. In contrast, (R)-[(18)F]2 and (S)-[(18)F]2 showed high selectivity for system A AAT. Similar to the results of in vitro cell studies, the tumor uptake of all four tracers was good to high and persisted over the 2 hours time course of in vivo studies. The accumulation of these tracers was higher in tumor than most normal tissues including blood, brain, muscle, bone, heart, and lung, and the tracers with the highest in vitro selectivity for system A AAT generally demonstrated the best tumor imaging properties. Higher uptake of these tracers was observed in the pancreas, kidney and spleen compared to tumors.ConclusionsThese preclinical studies demonstrate good imaging properties in a wide range of tumors for all four amino acids evaluated with (R)-[(18)F]2 having the highest selectivity for system A AAT.

Dataset Information

Synthesis, Radiolabeling, and Biological Evaluation of the trans-Stereoisomers of 1-Amino-3-(fluoro-¹⁸F)-4-fluorocyclopentane-1-carboxylic Acid as PET Imaging Agents.

Publications

Synthesis, Radiolabeling, and Biological Evaluation of the <i>trans</i>-Stereoisomers of 1-Amino-3-(fluoro-<sup>18</sup>F)-4-fluorocyclopentane-1-carboxylic Acid as PET Imaging Agents.

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