Studies On Synthesis Of The New Precursors Of ¹⁸F-Labelled Amino Acids Radiopharmaceuticals For Positron Emission Tomography

Positron Emission Tomography (PET) is a powerful medical imaging method that has found wide applications in the last decade for research and clinical diagnosis of tumor, neuropsychosis and cardiovascular disease. PET radiopharmaceticals play an important role in application and development of PET. One of the positron emitting isotopes is fluorine-18 that is often used as a substitute for hydrogen in organic molecules with a half-life of 110 minutes which allows complex synthesis and detailed imaging studies and similar properties of hydrogen. However, there is few fluorine-18 labeled imaging agents can be used for clinical diagnosis except [¹⁸F]FDG. Exploitation and screening of other precursors of fluorine-18 radiopharmaceticals and successful labeling fluorine-18 has become the high light in the PET research field now.Here synthesis of the new precursors of ¹⁸F-labeled amino acids and ¹⁸F-structural analogues of norepinephrine radiopharmaceuticals was described in this paper.Some main factors limiting the development of ¹⁸F-labeled radiopharmaceuticals are the complicated preparation steps to synthesis of the precursors used in nucleophilic fluorination and the low radiochemical yield of nucleophilic aromatic substitution. So we designed the target products which have the good leaving groups on the C-O side chain and could proform aliphatic nucleophilic displacement. Methanesulfonate ethyl, methylbenzenesulfonate ethyl and nitrobenzenesulfonate ethyl were introduced into 3-phenolic hydroxyl group of L-DOPA to give the precursors of O-(3-[¹⁸F]fluoroethyl)-L-DOPA by simple experimental procedure.The precursors of ¹⁸F-labeled fluorobutyl-L-phenylalanine, ¹⁸F-labeled fluorobutyl-L-tyrosine and ¹⁸F-labeled fluorobutyl-L-DOPA were synthesized from L-phenylalanine, L-tyrosine and L-DOPA through iodination reaction, group protection and Sonogashira cross-coupling reaction with but-3-yn-1-ol and so on under mild reaction conditions. The method for introducing C-C side chain with good leaving group changed the structure of materials, but the changes didn't affect the active groups of the amino acids. As the three prepared stable non-natural amino acid analogues were slowly metabolized in vivo, the pharmacokinetic analysis became quite simple and little defluorination was observed when they were labeled by fluorine-18. Synephrine extracted from plant was a kind of adrenergic agonist and could be used to prepare the precursors which had the good leaving groups on the C-O side chain and could proform aliphatic nucleophilic displacement with good yields. After completion of Fluorine-18 labeling, the agents could be used in assessment of the integrity of cardiac sympathetic nervous system with PET.