Aromatic L-Amino Acid Decarboxylase (AAAD) Inhibitors as Carcinoid Tumor-Imaging Agents: Synthesis of 18F-labeled α-fluoromethyl-6-fluoro-m-tyrosine (FM-6-FmT)
The aromatic l-amino acid decarboxylase (AAAD) enzyme is significantly upregulated in neuroendocrine tumors and, thus, would be a good target for PET imaging agents. α-fluoromethyl-DOPA (FMDOPA) is one of the most potent irreversible AAAD inhibitor and its non-catechol derivative, α-fluoromethyl-m-tyrosine (FMmT), is a promising AAAD imaging agent. We synthesized FMmT and its direct electrophilic fluorination provided a mixture of products identified by NMR analysis after HPLC purification as 6-fluoro-, 2-fluoro- and 2,6-difluoro-derivatives of FMmT. Using rat striatal homogenates, α-fluoromethyl-6-fluoro-m-tyrosine (FM-6-FmT) was found to have AAAD inhibitory activity comparable to that of FMDOPA. Electrophilic radiofluorination of FMmT using [18F]AcOF gave 18F labeled 6-fluoro-, 2-fluoro- and 2,6-difluoro-FMmT derivatives in 22.0%, 21.9% and 8.5% radiochemical yields, respectively. Based on its proposed mechanism of inhibition, FM-6-[18F]FmT is expected to irreversibly bind to AAAD and, hence, could be used as a PET agent to image tumors of endocrine origin containing high concentrations of AAAD. Since FM-6-FmT lacks the catechol moiety, it is expected to be better than FMDOPA since it is not a substrate for catechol-O-methyltransferase.
Physics and Astronomy
Applied Radiation and Isotopes
D. Murali, L.G. Flores, A.D. Roberts, R.J. Nickles, and O.T. DeJesus. Aromatic L-Amino Acid Decarboxylase (AAAD) Inhibitors as Carcinoid Tumor-Imaging Agents: Synthesis of 18F-labeled α-fluoromethyl-6-fluoro-m-tyrosine (FM-6-FmT). Applied Radiation and Isotopes, 59(4), 237-243.
Publisher's Copyright and Source
Copyright © 2003 Elsevier, Ltd. Article published by Elsevier in Applied Radiation and Isotopes, volume 59, issue number 4, October 2003, pages 237-243. Available online: https://doi.org/10.1016/S0969-8043(03)00197-0