Radiolabeled Amino Acids for Tumor Imaging with PET:  Radiosynthesis and Biological Evaluation of 2-Amino-3-[¹⁸F]fluoro-2-methylpropanoic Acid and 3-[¹⁸F]Fluoro-2-methyl-2-(methylamino)propanoic Acid

Abstract

Novel radiopharmaceuticals, including amino acids, that target neoplasms through their altered metabolic states have shown promising results in preclinical and clinical studies. Two fluorinated analogues of alpha-aminoisobutyric acid, 2-amino-3-fluoro-2-methylpropanoic acid (FAMP) and 3-fluoro-2-methyl-2-(methylamino)propanoic acid (N-MeFAMP), have been radiolabeled with fluorine-18, characterized in amino acid uptake assays, and evaluated in vivo in normal rats and a rodent tumor model. The key steps in the syntheses of both radiotracers involved the preparation of cyclic sulfamidate precursors. Radiosyntheses of both [18F]FAMP and [18F]N-MeFAMP via no-carrier-added nucleophilic substitution provided high yields (>78% decay-corrected) in high radiochemical purity (>99%). Amino acid transport assays using 9L gliosarcoma cells demonstrated that both compounds are substrates for the A type amino acid transport system, with [18F]N-MeFAMP showing higher specificity than [18F]FAMP for A type transport. Tissue distribution studies in normal Fischer rats and Fischer rats implanted intracranially with 9L gliosarcoma tumor cells were also performed. At 60 min postinjection, the tumor vs normal brain ratio of radioactivity was 36:1 in animals receiving [18F]FAMP and 104:1 in animals receiving [18F]N-MeFAMP. On the basis of these studies, both [18F]FAMP and [18F]N-MeFAMP are promising imaging agents for the detection of intracranial neoplasms via positron emission tomography.

Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family

“…Elevated uptake of [ 11 C]MeAIB into lymphoid tumors tissues in human subjects has been observed by positron emission tomography (PET) [87]. Meanwhile, the development of radiofluorinated MeAIB analogues (which are also transported by System A in 9L gliosarcoma cells) are promising agents for the detection of intracranial neoplasia via PET [61,62].…”

Non-natural amino acids for tumor imaging using positron emission tomography and single photon emission computed tomography

“…Another limitation of both [ 11 C]AIB and [ 11 C] MeAIB is the short half-life of carbon-11 which, as in the case of [ 11 C]MET, makes widespread use of these tracers problematic. Several fluorine-18 and iodine-123 analogues of [ 11 C]AIB and [ 11 C]MeAIB have been developed, including 2-amino-3-fluoro-2-methylpropanoic acid (FAMP) and 2-methyl-3-fluoro-2-(methylamino)propanoic acid (N-MeFAMP), which show high tumor to brain ratios in the 9L gliosarcoma brain tumor model with the highest tumor to brain ratio (up to 104:1) obtained with the most selective system A substrate, N-Me[ 18 F]FAMP [185,186]. In a comparison of the enantiomers of [ 123 I]IVAIB, a radioiodinated analogue of AIB, the (S)-enantiomer demonstrated high tumor uptake as well as high tumor to brain ratios (up to 75:1) in the 9L gliosarcoma model and was primarily a system A substrate in vitro.…”

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

“…In our initial study with a rat brain tumor model, these fluorinated AIB/MeAIB analogs showed high and selective in vitro uptake by the system A AAT, and demonstrated excellent tumor to normal brain ratios of 20:1 to 115:1 in vivo in part due to the lack of system A transport at the normal BBB [35, 36]. To test the tumor imaging potential of these tracers for a wider range of human cancers including prostate cancer, breast cancer, and non-small cell lung cancer, we further evaluated ( R )-and ( S )- FAMP 1 and ( R )- and ( S )- MeFAMP 2 through in vitro AA uptake assays and in tumor-bearing mice implanted with human derived cancer cell lines.…”