Imaging agents with integrated

^99mTc complexes, mimetics of pharmaceuticals

For targeted cancer imaging with radionuclides such as ^99mTc, different concepts of combining a receptor specific molecule with a metal complex are applied, namely the pendent and the metal-essential approach. The former strategy is the most common one; a bifunctional chelator is conjugated to a biomolecule and labeled with a complex precursor (see “link” Imaging agents with pendent ^99mTc labels). The introduction of a pendent chelator often affects the pharmacology of the receptor ligand. We therefore introduced a new concept in imaging; we select a particular substructure of a known pharmaceutical and replace it by integrating a structurally similar metal complex into the lead. This approach is common in “cold” medicinal inorganic chemistry but has not been translated to radiopharmacy so far since the corresponding chemistry might be quit demanding. Our Cp- and arene chemistry allows replacing phenyl groups by e.g. a piano stool complexes. This structural change will influence the biological behavior but may lead to a new medicinal inorganic compound with diagnostic properties. In extension of the concept, we prepare the cold rhenium homologues and investigate these for an eventual therapeutic action. Since technetium and rhenium complexes in low valencies are isostructural, the combination of both aims at a new concept in small molecule theranostics, the ^99mTc receptor ligand for imaging and the very same Re compound for therapy. 

Based on this concept, we are currently working on different lead structures. We started with a mimic of phenylalanine, continued to carbonic anhydrase inhibitors and also investigated the HDAC inhibitor Vorinostat^Ò, a clinical applied anti-cancer pharmaceutical. We replace phenyl groups by Cp-complexes based on our fundamental investigations (see ….) and, more recently, extended these studies to the arene complexes (see Arene complexes) The CA inhibitors proved successful in particular. Other lead structures are under investigation.

Identification of appropriate lead structures – organic syntheses of precursors – organometallic preparation – transformation to aqueous conditions for clinical use – biological studies for cytotoxicity and in vivo accumulation

Angelo Frei, Carla Gotzmann, Daniel Hernandez Valdes, Dr. Henrik Braband

Cooperation with Prof. Isabel Santos, University of Lisbon PT, Dr. Matthias Bauwens, University of Maastricht NL

• Preparation and biological evaluation of cyclopentadienyl based ^99mTc-complexes [(Cp-R)^99mTc(CO)₃] mimicking benzamides for malignant melanoma targeting.H.W. Peindy N’Dongo, P. D. Raposinho, C. Fernandes, I. Santos, D. Can, P. Schmutz, B. Spingler and R. Alberto (2010):  Nucl. Med. Biol, 37, 255-264
• [(Cp-R)M(CO)₃] (M = Re or ^99mTc) Sulphonamide Conjugates for Selective Targeting of Human Carbonic Anhydrase IX. D.Can, B. Spingler, P. Schmutz, F. Mendes, P. Raposinho, C. Fernandes, F. Carta, A. Innocenti, I. Santos, C. T. Supuran and R. Alberto (2012): Angew. Chem. Int. Ed., 51, 3354-3357
• Cyclopentadienyl-Based Amino Acids (Cp-aa) As Phenylalanine Analogues for Tumor Targeting: Syntheses and Biological Propertiesof [(Cp-aa)M(CO)3](M = Mn, Re, 99mTc). S. Sulieman, D. Can, J. Mertens, H. W. Peindy N’Dongo, Y.  Liu, P. Schmutz, M. Bauwens, B. Spingler, and R. Alberto (2012): Organometallics, (2012) 31, 6880−6886
• Cyclopentadienyl Chemistry in Water: Synthesis and Properties of Bifunctionalized [(η⁵-C₅H₃{COOR}₂)M(CO)₃] (M=Re and ^99mTc) Complexes. S. Ursillo, D. Can, H. W. Peindy N’Dongo, P. Schmutz, B. Spingler and R. Alberto (2014): Organometallics, (2014), 33, 6945–6952