A Resin-Linker-Vector Approach to Radiopharmaceuticals Containing 18F: Application in the Synthesis of O-(2-[18F]-Fluoroethyl)-L-tyrosine

• Published in: Chemistry : a European journal Vol. 19; no. 5; pp. 1720 - 1725
• Main Authors: Topley, Amy C., Isoni, Valerio, Logothetis, Thomas A., Wynn, Duncan, Wadsworth, Harry, Gibson, Alex M. R., Khan, Imtiaz, Wells, Neil J., Perrio, Cécile, Brown, Richard C. D.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 28-01-2013; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: amino acids; Amino Acids - chemistry; Chemistry; Chromatography, High Pressure Liquid; Fluorine Radioisotopes - chemistry; Kinetics; Molecular Structure; Positron-Emission Tomography; Radiochemistry; radiopharmaceuticals; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; solid-phase synthesis; Tyrosine - analogs & derivatives; Tyrosine - chemical synthesis; Tyrosine - chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201202474

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.
Detachable labels: A resin‐linker‐vector (RLV) strategy has been developed for the radiosynthesis of tracer molecules containing the radionuclide 18F, in which the linker has tosylate‐like reactivity. The potential for the application of the 4‐alkylphenylsulfonate in practical radiosyntheses has been illustrated herein by the synthesis of the positron‐emission tomography radiotracer O‐(2‐[18F]‐fluoroethyl)‐L‐tyrosine ([18F]‐FET; see scheme).