Novel approach to the synthesis of 6-[F-18]-fluoro-(meta)-tyrosine and related [F-18]-fluorocatecholamines
Abstract
There are an estimated 1–2 million victims of Parkinson's disease (PD) in the United States today. Two 18F-labeled tyrosine derivatives, 6-fluoro-DOPA (FDOPA) and 6-fluoro-meta-tyrosine (FMT), have been demonstrated to be useful PET (positron emission tomography) radiopharmaceuticals for the diagnosis and study of PD and related movement disorders in humans. However, existing electrophilic and nucleophilic radiosynthetic approaches to these agents have drawbacks, which make it difficult for most cyclotron-PET facilities to prepare FDOPA or FMT for routine clinical diagnostic applications. This work explored a novel two-step, no-carrier-added, nucleophilic labeling approach to [18F]FMT that may also be applicable to FDOPA and other 18F-fluorocatecholamines. The basic strategy was developed through chemical and radiochemical studies on model compounds. Aromatic nucleophilic [18F]fluoride labeling of a benzophenone precursor containing a 3,5-(bis)trifluoromethylbenzoyl (BTFB) “latent phenol” function on a phenyl substituted with leaving groups (nitro or trimethylammonium), followed by “unmasking” the BTFB function by Baeyer-Villiger oxidation gave [18F]fluorophenols rapidly and in good radiochemical yields. Catalytic enantioselective alkylation was used to attach the protected amino acid (AA) side-chain to the benzophenone moiety and construct the homochiral FMT labeling precursor. Important radiosynthetic intermediates in unlabeled (19F) form were synthesized independently. The Baeyer-Villiger reaction was optimized so that the latent phenol and AA protecting groups could be unmasked quickly and efficiently without over-oxidation of the aromatic ring or destruction of the AA side-chain. The optimization process was conducted on a 1–3 mg scale using authentic intermediates in unlabeled form. Products were verified by HPLC and high-resolution mass spectrometry. Optimization of the radiofluorination step is ongoing. The AA side-chain protecting group in the first precursor candidate interfered with labeling, apparently by forming covalent 18F-adducts involving the hexafluoroacetonide protecting group instead of the aromatic ring. Other AA protecting groups are being evaluated to overcome this difficulty. It is anticipated that minor modifications of this general route will provide a straightforward, practical synthesis of [18F]FMT and related PET agents.
Degree
Ph.D.
Advisors
Mulholland, Purdue University.
Subject Area
Organic chemistry|Radiology
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