A Resin-linker-vector approach to radiopharmaceuticals containing 18F: application in the synthesis of O-(2-[18F]-fluoroethyl)-L-tyrosine.

A Resin-linker-vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide 18F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene-bound arylsulfonate linker with [18F]-fluoride ion. Three model linker-vector molecules 7?ac containing different alkyl spacer groups were assembled in solution from (4-chlorosulfonylphenyl)alkanoate esters, exploiting a lipase-catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker-vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8?ac with acetate, butyrate and hexanoate spacers, which were characterised by using magic-angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8?a,?b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4-fluorobutyl)phenylcarbamic acid tert-butyl ester (9) in NMR kinetic studies and gave superior radiochemical yields (RCY approximate to 60?%) of the 18F-labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]-FET), delivering protected [18F]-FET in >90?% RCY. Acid deprotection gave [18F]-FET in an overall RCY of 41?% from the RLV.