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

Abstract

Fluorine-18 and iodine-123 labeled nonnatural alicyclic and methyl branched disubstituted α,α-amino acids are a diverse and useful class of tumor imaging agents suitable for positron emission tomography and single photon emission computed tomography. These tracers target the increased expression of the cell membrane amino acid transporter systems L, ASC, and A exhibited by many human tumor cells. The most established clinical use for these radiolabeled amino acids is imaging primary and recurrent gliomas and primary, recurrent, and metastatic prostate cancer. This review focuses on the synthesis, radiolabeling, and amino acid transport mechanism of a series of nonnatural fluorine-18 and iodine-123 labeled analogs of 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-carboxylic acid, α-aminoisobutyric acid, and α-methylaminoisobutyric acid.

Synthesis, Radiolabeling, and Biological Evaluation of the cis Stereoisomers of 1-Amino-3-Fluoro-4-(fluoro-18F)Cyclopentane-1-Carboxylic Acid as PET Imaging Agents

“…Thin-layer chromatography was performed on Merck silica gel plates and visualized by UV light and/or potassium permanganate. 1 H NMR and 13 C and 19 F NMR spectra were recorded on Bruker 600, Varian INOVA 600, INOVA 500, and INOVA 400 spectrometers. Residual solvent resonances were treated as internal reference signals.…”

“…Residual solvent resonances were treated as internal reference signals. 19 F spectra were referenced to either trifluoroacetic acid (−76.55 ppm) or fluorobenzene (−113.15 ppm). IR spectra were recorded on a Nicolet iS10 FT-IR spectrometer, and the absorption peaks were reported in cm −1 .…”

“…Goodman and coworkers later described the synthesis and biological evaluation of several 18 F radiolabeled ACBC derivatives. 19 The transport of each compound was assessed in 9L gliosarcoma cells and determined to proceed via system ASC, with some contribution from system L. In rats bearing intracranial 9L gliosarcoma, each 18 F-FACBC derivative studied provided superior tumor to contralateral brain tissue uptake in comparison to [ 18 F]FDG. Notably, anti-1-amino-3-(fluoro-18 F)-cyclobutane carboxylic acid (anti-3-FACBC) received FDA approval for imaging nonprimary recurrent prostate cancer.…”

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

“…In contrast, non-natural AAs offer a platform for the incorporation of 18 F, a radionuclide with a more than fivefold longer half-life and a shorter positron range than 11 C. Moreover, certain non-natural AA scaffolds have been demonstrated to confer metabolic stability while maintaining avidity for transport by AATs. Several decades ago, Washburn and coworkers reported that 14 C labeled 1-aminocyclobutane carboxylic acid (ACBC) and 1-aminocyclopentane carboxylic acid (ACPC) have high tumor avidity and good in vivo stability. − Following these reports, Goodman and coworkers prepared and biologically evaluated several 18 F radiolabeled analogues of ACBC . Their biological transport was assessed in 9L gliosarcoma cells and, in each case, was mediated primarily by system ASC, though some transport by system L was observed.…”

“…16−19 Following these reports, Goodman and coworkers prepared and biologically evaluated several 18 F radiolabeled analogues of ACBC. 20 Their biological transport was assessed in 9L gliosarcoma cells and, in each case, was mediated primarily by system ASC, though some transport by system L was observed. In Fischer rats bearing 9L gliosarcoma, [ 18 F]FACBC derivatives demonstrated good brain uptake and much higher tumor to contralateral brain tissue ratios than [ 18 F]FDG.…”