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 a – c 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 a – c 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≈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.