A novel prosthetic group for site-selective labeling of peptides for positron emission tomography.
Efficient methodologies for the radiolabeling of peptides with [(18)F]fluoride are a prerequisite to enabling commercialization of peptide-containing radiotracers for positron emission tomography (PET) imaging. It was the purpose of this study to investigate a novel chemoselective ligation reaction comprising conjugation of an [(18)F]-N-methylaminooxy-containing prosthetic group to a functionalized peptide. Twelve derivatives of general formula R1-CO-NH-Lys-Gly-Phe-Gly-Lys-OH were synthesized where R1 was selected from a short list of moieties anticipated to be reactive toward the N-methylaminooxy group. Conjugation reactions were initially carried out with nonradioactive precursors to assess, in a qualitative manner, their general suitability for PET chemistry with only the most promising pairings progressing to full radiochemical assessment. Best results were obtained for the ligation of O-[2-(2-[(18)F]fluoroethoxy)ethyl]-N-methyl-N-hydroxylamine 18 to the maleimidopropionyl-Lys-Gly-Phe-Gly-Lys-OH precursor 10 in acetate buffer (pH 5) after 1 h at 70 degrees C. The non-decay-corrected isolated yield was calculated to be 8.5%. The most encouraging result was observed with the combination 18 and 4-(2-nitrovinyl)benzoyl-Lys-Gly-Phe-Gly-Lys-OH, 9, where the conjugation reaction proceeded rapidly to completion at 30 degrees C after only 5 min. The corresponding non-decay-corrected radiochemical yield for the isolated (18)F-labeled product 27 was 12%. The preliminary results from this study demonstrate the considerable potential of this novel strategy for the radiolabeling of peptides.
Institute of Pharmacy, Department of Pharmaceutics and Biopharmaceutics, University of Tromsø, N- 9037 Tromsø, Norway. dag.erlend.olberg@farmasi.uit.no
Dag Erlend
DE
Olberg
Ole Kristian
OK
Hjelstuen
Magne
M
Solbakken
Joseph
J
Arukwe
Hege
H
Karlsen
Alan
A
Cuthbertson
D000085:Acetates / Q000737:chemistry; D001665:Binding Sites; D002021:Buffers; D005462:Fluorine Radioisotopes; D006863:Hydrogen-Ion Concentration; D006898:Hydroxylamines / Q000737:chemistry; D008301:Maleimides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D013194:Staining and Labeling / Q000379:methods*; D013379:Substrate Specificity; D013696:Temperature; D013997:Time Factors
D000085:Acetates; D002021:Buffers; D005462:Fluorine Radioisotopes; D006898:Hydroxylamines; D008301:Maleimides; D010455:Peptides