Aromatic L-amino acid decarboxylase (AAAD) inhibitors as carcinoid tumor-imaging agents: synthesis of 18F-labeled alpha-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. Alpha-fluoromethyl-DOPA (FMDOPA) is one of the most potent irreversible AAAD inhibitor and its non-catechol derivative, alpha-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, alpha-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.
Murali
D
D
Department of Medical Physics, University of Wisconsin Medical School, 1530 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706, USA.
Flores
L G
LG
Roberts
A D
AD
Nickles
R J
RJ
DeJesus
O T
OT
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000737:chemistry / Q000378:metabolism; D002276:Carcinoid Tumor / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007553:Isotope Labeling / Q000379:methods*; D018358:Neuroendocrine Tumors / Q000000981:diagnostic imaging* / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed / Q000379:methods; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D014443:Tyrosine; C046880:beta-fluoromethylene-3-tyrosine; D001142:Aromatic-L-Amino-Acid Decarboxylases