caa a22 4500 378907077 CHVBK 20180305123532.0 cr unu---uuuuu 161128e20040401xx s 000 0 eng 10.1524/ract.92.4.317.35591 doi (NATIONALLICENCE)gruyter-10.1524/ract.92.4.317.35591 Chemoselective pre-conjugate radiohalogenation of unprotected mono- and multimeric peptides via oxime formation [Elektronische Daten] [Thorsten Poethko, Margret Schottelius, Georgette Thumshirn, Michael Herz, Roland Haubner, Gjermund Henriksen, Horst Kessler, Markus Schwaiger, Hans-Jürgen Wester] As part of our ongoing efforts in the development of new 18F-labeled peptides for clinical PET imaging, a new two-step 18F-labeling methodology based on the chemoselective oxime formation between an unprotected aminooxy-functionalized peptide and a 18F-labeled aldehyde was investigated and optimized. 4-[18F]Fluorobenzaldehyde ([18F]FB-CHO) was prepared by direct n.c.a. fluorination of 4-formyl-N,N,N-trimethylanilinium triflate and purified by radio-HPLC or a strong-cation-exchange/reverse phase cartridge system. The aminooxyacetic acid (Aoa) modified model peptide LEF-NH2 (Leu-Glu-Phe-NH2) and monomeric, dimeric and tetrameric RGD-containing cyclopeptides were synthesized by solid phase peptide synthesis. Radiochemical yields of N-(4-[18F]fluorobenzylidene)-oxime-formation ([18F]FBOA) with the Aoa-modified unprotected peptides were investigated. Optimized reaction conditions (60°C, 0.5mM peptide, 15min, aqueous solution, pH 2.5) resulted in 70%-90% conjugation yields for all unprotected peptides studied. Chemoselectivity was demonstrated in competition experiments with amino acid mixtures. Biodistribution in M21 melanoma bearing mice showed improved tumor uptake and excretion behaviour in the series c(RGDfE)HEG-Dpr-[18F]FBOA < (c(RGDfE)HEG)2K-Dpr-[18F]FBOA < ((c(RGDfE)HEG)2K)2K-Dpr-[18F]FBOA. Two hours p.i. the fraction of intact c(RGDfE)HEG-K-Dpr-[18F]FBOA in blood, liver, kidney and tumor was >90%, indicating high in vivo stability of the oxime linkage. Initial PET studies with ((c(RGDfE)HEG)2-K)2-K-Dpr-[18F]FBOA showed excellent imaging of M21-melanomas in mice. In conclusion, the new two-step chemoselective 18F-labeling fulfills all requirements for large scale syntheses of peptides in clinical routine. This methodology is also adaptable to other radioisotopes (e.g. radiohalogenation in general) and will thus offer a broad field of application. © 2004 Oldenbourg Wissenschaftsverlag GmbH Laboratory techniques, experiments nationallicence Analytical chemistry nationallicence Inorganic chemistry nationallicence Poethko Thorsten aut Schottelius Margret aut Thumshirn Georgette aut Herz Michael aut Haubner Roland aut Henriksen Gjermund aut Kessler Horst aut Schwaiger Markus aut Wester Hans-Jürgen aut Radiochimica Acta/International journal for chemical aspects of nuclear science and technology Oldenbourg Wissenschaftsverlag GmbH 92/4-6/2004(2004-04-01), 317-327 0033-8230 92:4-6/2004<317 2004 92 ract https://doi.org/10.1524/ract.92.4.317.35591 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1524/ract.92.4.317.35591 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Poethko Thorsten aut NATIONALLICENCE 700 1- Schottelius Margret aut NATIONALLICENCE 700 1- Thumshirn Georgette aut NATIONALLICENCE 700 1- Herz Michael aut NATIONALLICENCE 700 1- Haubner Roland aut NATIONALLICENCE 700 1- Henriksen Gjermund aut NATIONALLICENCE 700 1- Kessler Horst aut NATIONALLICENCE 700 1- Schwaiger Markus aut NATIONALLICENCE 700 1- Wester Hans-Jürgen aut NATIONALLICENCE 773 0- Radiochimica Acta/International journal for chemical aspects of nuclear science and technology Oldenbourg Wissenschaftsverlag GmbH 92/4-6/2004(2004-04-01), 317-327 0033-8230 92:4-6/2004<317 2004 92 ract CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter