Radioactive Peptides DOI: 10.1002/anie.200600795 18 F-Labeling of Peptides by means of an Organosilicon-Based Fluoride Acceptor** Ralf Schirrmacher,* Gerrit Bradtmöller, Esther Schirrmacher, Oliver Thews, Julia Tillmanns, Thomas Siessmeier, HansG. Buchholz, PeterBartenstein,BjörnWängler,ChristofM.Niemeyer, and Klaus Jurkschat* Fluorine-18 is among the most commonly used radionuclides for positron emission tomography (PET). [1] This non-invasive imaging technique is capable of providing in vivo information about the distribution of radiolabeled biomolecules by 1808 coincidence detection of two simultaneously emitted photons from positron–electron annihilation. Although a number of different radiotracers have been successfully employed in PET, only a few, such as 2-[ 18 F]fluoro-2-deoxy-d-glucose (FDG) [2] and [ 18 F]fluorodopa, [3] have gained widespread application in nuclear medicine. The reason for this is that the regioselective introduction of 18 F into tracer molecules is often non-specific and radiochemical yields (RCY) of the 18 F- labelled product are low. The introduction of 18 F  into tracer molecules requires high temperatures and often leads to undesired by-products. [1] The research over the last decade clearly indicates that the success of PET in nuclear medicine justifies the intense search for versatile labeling formulations for the syntheses of 18 F-radiopharmaceuticals. Especially the development of rational 18 F-labelling strategies for peptides, until now characterized by multistep procedures, is consid- eredtobeoneofthemostimportanttasks. [4] As an alternative to conventional 18 F-labelling chemistry, the use of [ 18 F]fluorosilanes as labeling synthons was first proposed by Rosenthal et al. who treated chlorotrimethylsilane with n.c.a. (no carrier added) 18 F  in aqueous acetonitrile isolating the corresponding [ 18 F]fluorosilanein65%yield. [5] A preliminary in vivo evaluation revealed fast hydrolysis of the compound accompanied by high radioactivity ( 18 F) uptake by the bone making it unsuitable as a labeling synthon. Another approach is based on the work by Pilcher et al. [6] who fluorinated organosilanoles with nonradioactive HF in high yields. An analogous labeling strategy was proposed in a symposium abstract. [7] However, so far no labeling experi- ments using aqueous 18 F  /[ 18 F]HF solutions have been reported. Most recently Ting et al. used organotriethoxysi- lanes as labeling precursors for the synthesis of [ 18 F]fluorosilanesbutnopracticalapplicationforthesynthesis of potential radiopharmaceuticals has been demonstrated. [8] Herein we report the syntheses of substituted [ 18 F]organofluorosilanes using organochlorosilanes as label- ing precursors and their in vitro and in vivo stability. As an alternative labeling approach we also describe the 18 F– 19 F isotopic exchange using [ 19 F]di-tert-butylphenyl fluorosilane as a highly efficient silicon-based fluoride acceptor (SiFA compound). As proof of applicability we transferred the SiFA approach to the development of a simple and practical formulation for the synthesis of a 18 F-labelled SiFA derivat- ized Tyr 3 -octreotate, a peptide used in oncology for the visualization of neuro-endocrine tumors. [9] We synthesized three [ 18 F]organofluorosilanes, namely [ 18 F]fluorotriphenylsilane (1), [ 18 F]fluoro-tert-butyldiphenyl- silane (2), and [ 18 F]fluorodi-tert-butylphenylsilane (3), and evaluated their in vitro stability in human serum as well as their invivo stability in rats, studied by animal-PET. These data are essential for finding the most suitable compound and for evaluating the labeling concept. The reaction in acetonitrile of the triorganochlorosilanes (5–11.8 mmolmL 1 ) Ph 3 SiCl, tBuPh 2 SiCl, and tBu 2 PhSiCl, with the azeotropically dried complex 18 F  /Kryptofix2.2.2./ K + at room temperature provided almost quantitatively the corresponding [ 18 F]triorganofluorosilanes 1–3 (Figure 1), as demonstrated by means of radio-HPLC. Their identities were confirmed by coelution of the radioactive probes spiked with the related nonradioactive 19 F-analogues. The specific activity of 1, 2,and 3 was determined using UV-calibration curves and was in the range 1500–1700 GBq mmol 1 . To investigate the applicability of the 18 F-labelled com- pounds for the development of Si– 18 F containing radio- pharmaceuticals, their in vitro stability in human serum was investigated (Figure 1). In agreement with previously pub- lished data, [10,11] the [ 18 F]triphenylfluorosilane 1 was found to be stable for 4 h in neutral water (data not shown) but unstable at pH 7.4–7.6 in human serum. In contrast, the tert- [*] Dr. R. Schirrmacher, [+] Dr. E. Schirrmacher, [+] J. Tillmanns, Dr. T. Siessmeier, Dipl.-Ing. H. G. Buchholz, Prof. Dr. P. Bartenstein Klinik und Poliklinik für Nuklearmedizin Johannes Gutenberg Universität Mainz 55131 Mainz (Germany) Fax: (+ 49) 6131-172386 E-mail: schirrmacher@klinik.nuklearmedizin.uni-mainz.de Dipl.-Chem. G. Bradtmöller, [+] Prof. Dr. K. Jurkschat Lehrstuhl für Anorganische Chemie Universität Dortmund 44221 Dortmund (Germany) Fax: (+ 49) 231-755-5048 E-mail: klaus.jurkschat@uni-dortmund.de Dr. B. Wängler Abteilung für Radiopharmazeutische Chemie Deutsches Krebsforschungszentrum Heidelberg (Germany) Priv.-Doz. Dr. O. Thews Institut für Physiology und Pathophysiologie Universität Mainz (Germany) Prof. Dr. C. M. Niemeyer Lehrstuhl für Biologisch-Chemische Mikrostrukturtechnik Universität Dortmund (Germany) [ + ] These authors contributed equally. [**] This work was supported by the International Isotope Society Central European Division. The authors thank Philips for support and would like to thank Prof. Dr. H. J. Wester (TU Munich) for providing a protocol for oxime ligation. C.M.N. and G.B. acknowl- edge financial support from the Zentrum für Angewandte Chemi- sche Genomik, a joint research initiative of the European Union and the Ministry of Innovation and Research of North Rhine-Westphalia. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 6047 Angew. Chem. Int. Ed. 2006, 45, 6047 –6050 # 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim