Synthesis of a new heterobifunctional linker, N-[4-(aminooxy)butyl]maleimide, for facile access to a thiol-reactive 18F-labeling agent.
A new heterobifunctional linker containing an aldehyde-reactive aminooxy group and a thiol-reactive maleimide group, namely N-[4-(aminooxy)butyl]maleimide, was synthesized as a stable HCl salt by O-alkylation of either N-hydroxyphthalimide or N-(4-monomethoxytrityl)hydroxylamine, followed by N-alkylation of maleimide, in an overall yield of 18% (seven steps) or 29% (five steps), respectively. This heterobifunctional linker allowed a simple and efficient synthesis of a maleimide-containing thiol-reactive (18)F-labeling agent. Thus, N-[4-[(4-[(18)F]fluorobenzylidene)aminooxy]butyl]maleimide (specific activity: approximately 3000 Ci/mmol at end of synthesis) was synthesized in two steps involving the preparation of 4-[(18)F]fluorobenzaldehyde, followed by its aminooxy-aldehyde coupling reaction to the heterobifunctional linker, with an overall radiochemical yield of approximately 35% (decay corrected) within approximately 60 min from end of bombardment. Initial (18)F-labeling experiments were carried out using a thiol-containing tripeptide glutathione (GSH) and a 5'-thiol-functionalized oligodeoxynucleotide (5'-S-ODN) in phosphate-buffered saline (PBS, pH 7.5). After standing at room temperature for 10 min, the (18)F-labeled GSH and 5'-S-ODN were obtained in (18)F-labeling yields of approximately 70% and approximately 5% (decay-corrected), respectively. The heterobifunctional linker is easy to synthesize and provides a facile access to the maleimide-containing thiol-reactive (18)F-labeling agent, which could be advantageously employed in the development of (18)F-labeled biomomolecules for use with positron emission tomography.
Toyokuni
Tatsushi
T
Crump Institute for Molecular Imaging, Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095-1770, USA. ttoyokuni@mednet.ucla.edu
Walsh
Joseph C
JC
Dominguez
Alan
A
Phelps
Michael E
ME
Barrio
Jorge R
JR
Gambhir
Sanjiv S
SS
Satyamurthy
Nagichettiar
N
D005462:Fluorine Radioisotopes / Q000737:chemistry*; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry; D007553:Isotope Labeling; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D005462:Fluorine Radioisotopes; D008301:Maleimides; C487560:N-(4-(aminooxy)butyl)maleimide; D013438:Sulfhydryl Compounds; D005978:Glutathione