System a amino acid transport-targeted brain and systemic tumor PET imaging agents 2-amino-3-[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid

Abstract

Introduction Amino 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 18F-labeled amino acids, (R)- and (S)-[18F]FAMP 1 and (R)- and (S)-[18F]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). Methods The transport of enantiomers of [18F]FAMP 1 and [18F]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. Results All four tracers showed moderate to high levels of uptake (1- 9 %ID/5×105 cells) by the cancer cell lines tested in vitro. AAT cell inhibition assays demonstrated that (R)-[18F]1 and (S)-[18F]1 entered these tumor cells via mixed AATs, likely but not limited to system A and system L. In contrast, (R)-[18F]2 and (S)-[18F]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. Conclusions These preclinical studies demonstrate good imaging properties in a wide range of tumors for all four amino acids evaluated with (R)-[18F]2 having the highest selectivity for system A AAT.

Synthesis and biological properties of radiohalogenated α,α‐disubstituted amino acids for PET and SPECT imaging of amino acid transporters (AATs)

“…The transport mechanisms of (R)-and (S)-FAMP (74) and (S)-and (R)-N-MeFAMP (90) have been elucidated in human lung, prostate, glioma, breast, and ovarian cancers ( Table 4). 108 Similar to the findings…”

“…The transport mechanisms of ( R ) ‐ and ( S )‐FAMP ( 74 ) and ( S ) ‐ and ( R )‐ N‐ MeFAMP ( 90 ) have been elucidated in human lung, prostate, glioma, breast, and ovarian cancers (Table ) . Similar to the findings for 9L, ( R ) ‐ and ( S )‐FAMP ( 74 ) and ( R ) ‐ and ( S )‐ N‐ MeFAMP 90 were shown to be affected by stereochemistry in the human cancer cell lines.…”

Synthesis and Biological Evaluation of (S)-Amino-2-methyl-4-[76Br]bromo-3-(E)-butenoic Acid (BrVAIB) for Brain Tumor Imaging

“…The washout of tracer from the tumor and normal tissues is consistent with a component of reversible amino acid transport such as system L. The kidneys and pancreas had a high initial uptake of [ 76 Br] 5 with 47.5 ± 4.3% ID/g and 27.0 ± 7.2% ID/g, respectively although this distribution of activity is typical for radiolabeled amino acids. 13,42,53–56 …”

PET Tracers Beyond FDG in Prostate Cancer

“…120 Finally, 11 C and 18 F system A transport radiotracers are being studied in the preclinical setting of prostate cancer in preparation for human translation. 46, 121, 122 …”