General: All reagents were bought from commercial sources and used as received unless otherwise noted. All reactions were performed under an inert N 2 atmosphere and all solvents were distilled before use unless otherwise noted. CH 2 Cl 2 was distilled over CaH 2 . Chromatographic purification of products was accomplished by using forced-flow chromatography on EM Science Geduran silica gel 60 (35-75 µm). Thin layer chromatography was performed on EM Science silica gel 60 F254 plates (250 µm). Visualization of the developed chromatogram was accomplished by UV lamp and/or by staining with aqueous potassium permanganate/K 2 CO 3 solutions, or aqueous ceric ammonium molybdate (CAM) solutions. Nuclear magnetic resonance (NMR) spectra were acquired on Bruker DRX-500/400 operating at 125/100 MHz for 1 H and 13 C, respectively; residual protio solvent signals were used as internal standards for calibration purposes. Data for 1 H NMR are reported as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), integration, coupling constant (Hz). Freshly prepared samples (ca. 1 mg/mL in CH 2 Cl 2 ) were subject to electrospray mass spectra (ESI-MS) analysis. A 5 μL sample was injected by flow injection with the use of an autosampler and the data were recorded on with an m/z range of 0-3000. Both the nebulizing and drying gas are purified nitrogen. Typical instrumental parameters were: drying gas temperature 350 °C, nebulizer pressure 35 psi, drying gas flow 12.0 L/min, and fragmentor voltage 0 or 70 V.

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The epidermal growth-factor receptor (EGFR) and its ligands have been recognized as critical factors in the pathophysiology of tumorigenesis. Overexpression of the EGFR plays a significant role in the tumor progression of a wide variety of solid human cancers. Therefore, the EGFR represents an attractive target for the design of novel diagnostic and therapeutic agents for cancer. Cetuximab (C225, Erbitux) was the first monoclonal antibody targeted against the ligand-binding site of EGFR approved by the Food and Drug Administration for the treatment of patients with EGFR-expressing, metastatic colorectal carcinoma, although clinical trials showed variability in the response to this treatment. The aim of this study involved using cetuximab to design a positron emission tomography (PET) agent to image the overexpression of EGFR in tumors. Cetuximab was conjugated with the chelator, DOTA, for radiolabeling with the positron-emitter, 64Cu (T(1/2) = 12.7 hours). 64Cu-DOTA-cetuximab showed high binding affinity to EGFR-positive A431 cells (K(D) of 0.28 nM). Both biodistribution and microPET imaging studies with 64Cu-DOTA-cetuximab demonstrated greater uptake at 24 hours postinjection in EGFR-positive A431 tumors (18.49% +/- 6.50% injected dose per gram [ID/g]), compared to EGFR-negative MDA-MB-435 tumors (2.60% +/- 0.35% ID/g). A431 tumor uptake at 24 hours was blocked with unlabeled cetuximab (10.69% +/- 2.72% ID/g), suggesting that the tumor uptake was receptor mediated. Metabolism experiments in vivo showed that 64Cu-DOTA-cetuximab was relatively stable in the blood of tumor-bearing mice; however, there was significant metabolism in the liver and tumors. 64Cu-DOTA-cetuximab is a potential agent for imaging EGFR-positive tumors in humans.

Teamwork: Der Zweikernkomplex [Ag2(OTf)2(bp)2] katalysiert die intermolekulare Aminierung gesättigter C‐H‐Bindungen mit der Nitrenvorstufe PhINNs (siehe Schema; Ns=p‐Nitrosulfonyl, OTf=Trifluormethansulfonat, bp=Bathophenanthrolin). Dabei scheint das Zweikern‐Strukturmotiv entscheidend für die katalytische Aktivität zu sein.

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