title: A Resin-linker-vector approach to radiopharmaceuticals containing 18F: application in the synthesis of O-(2-[18F]-fluoroethyl)-L-tyrosine.
abstract: A Resin-linker-vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide (18)F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene-bound arylsulfonate linker with [(18)F]-fluoride ion. Three model linker-vector molecules 7a-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 8a-c with acetate, butyrate and hexanoate spacers, which were characterised by using magic-angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8a,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 (18) F-labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O-(2-[(18)F]-fluoroethyl)-L-tyrosine ([(18) F]-FET), delivering protected [(18) F]-FET in >90% RCY. Acid deprotection gave [(18)F]-FET in an overall RCY of 41% from the RLV.
authors.affiliation: Department of Chemistry, University of Southampton, Southampton, Hampshire, SO17 1BJ, UK.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Topley
authors.forename: Valerio
authors.initials: V
authors.lastname: Isoni
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Logothetis
authors.forename: Duncan
authors.initials: D
authors.lastname: Wynn
authors.forename: Harry
authors.initials: H
authors.lastname: Wadsworth
authors.forename: Alex M R
authors.initials: AM
authors.lastname: Gibson
authors.forename: Imtiaz
authors.initials: I
authors.lastname: Khan
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Wells
authors.forename: Cécile
authors.initials: C
authors.lastname: Perrio
authors.forename: Richard C D
authors.initials: RC
authors.lastname: Brown
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D007700:Kinetics; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000596:Amino Acids; D005462:Fluorine Radioisotopes; C117289:O-(2-fluoroethyl)tyrosine; D019275:Radiopharmaceuticals; D014443:Tyrosine