Bio-organometallic Chemistry DOI: 10.1002/anie.201107333 [(Cp-R)M(CO) 3 ] (M = Re or 99m Tc) Arylsulfonamide, Arylsulfamide, and Arylsulfamate Conjugates for Selective Targeting of Human Carbonic Anhydrase IX** Daniel Can, Bernhard Spingler, Paul Schmutz, Filipa Mendes, Paula Raposinho, CØlia Fernandes, Fabrizio Carta, Alessio Innocenti, Isabel Santos, ClaudiuT. Supuran, and Roger Alberto* Diagnosis and treatment of diseases requires molecules designed for targeting specific receptors. Since nature has developed a realm of functionally and structurally similar receptors, selectivity for a specific target is a key criterion for inhibitors. [1] Inhibitors are typically organic but Meggers et al. showed that high selectivity does not only depend on intermolecular interactions but also on a directed 3D arrange- ment of different functionalities as exemplified with organo- metallic protein kinase inhibitors. [2–4] Inert complexes offer the opportunity to populate biologically relevant space. Thus, bio-organometallic complexes are versatile chemical probes [2, 5–8] as pioneered by for example, Jaouen and co- workers who developed ferrocene-based, selective estrogen receptor inhibitors. [9–11] Replacing a phenyl ring in for example, tamoxifen by [(Cp-R)Re(CO) 3 ] (CP = cyclopenta- dienyl) resulted in retention of high affinity for the estrogen receptor. [12] These organometallic compounds have therapeu- tic potential but their use for in vivo diagnosis is limited since radionuclides such as 18 F for PET (positron emission tomog- raphy) cannot be introduced without alteration of chemical authenticity. Given that Cp-based complexes can replace phenyl rings without affecting the bioactivity, identical compounds for combined therapy and noninvasive diagnosis are desirable for theragnostics. [13, 14] Rhenium and technetium belong to the same triad. Whereas Re-based compounds can be used for therapy, their 99m Tc homologous serve as imaging agents in single photon emission computed tomography (SPECT). [15–17] We recently introduced a strategy for the aqueous syntheses of [(Cp-R) 99m Tc(CO) 3 ] (“R” = target-specific moiety). In this report, we present Re bio-organometallic carbonic anhydrase inhibitors (CAI) with nanomolar affinities for specific CA subtypes. The 99m Tc complexes have been prepared and complement the Re congeners as identical, diagnostic agents. Carbonic anhydrases (CAs) are Zn enzymes catalyzing the formation of carbonic acid from CO 2 and water. [18] In mammals, 16 different membrane-bound, cytosolic or mito- chondrial isozymes are known. [18, 19] CAs are attractive from a pharmaceutical point of view because of hypoxia-induced overexpression of hCA IX and hCA XII (hCA = human carbonic anhydrase) in many malignancies, including cancer. [18, 20–23] Therefore, CAs are targets for cancer diagnosis and therapy. However, the large number of isozymes and diffuse localization impede selective accumulation of inhib- itors. [19] Several fluorescent sulfonamide- or sulfamate-based CAIs, radio-iodinated monoclonal antibodies [24–27] but only one 99m Tc-labeled inhibitor have been reported. [28] Following the concept of extended 3D space population, we synthesized four new arylsulfonamide, -sulfamide, and -sulfamate based CAIs with the [(Cp-R)M(CO) 3 ]-motif (M = Re or 99m Tc) and evaluated their affinity to CA isoforms (Scheme 1). Compounds 2 and 3 were structurally character- ized (see the Supporting Information). Binding studies of complexes 1–4 with 12 CA isozymes showed inhibition constants in the low nanomolar range for some of the isoforms (Table 1). Such low K i values are uncommonly rare for bio-organometallic compounds. [30] The hCA II, VI, VII, IX, XII, and XIII are considered as sulfonamide- and sulfamate-avid isoforms [18] which is consis- Scheme 1. Structures of cyclopentadienyl-based CAIs. [*] D. Can, Priv.-Doz.Dr. B. Spingler, Dr. P. Schmutz, Prof. Dr. R. Alberto Institute of Inorganic Chemistry, University of Zurich Winterthurerstrasse 190, 8057 Zurich (Switzerland) E-mail: ariel@aci.uzh.ch Dr. F. Mendes, Dr. P. Raposinho, Dr. C. Fernandes, Prof. Dr. I. Santos Instituto Tecnológico e Nuclear Estrada Nacional 10, 2686-953 SacavØm (Portugal) F. Carta, A. Innocenti, Prof. Dr. C. T. Supuran Universita degli Studi di Firenze, Polo Scientifico Laboratorio di ChimiCABioinorganica 50019 Sesto Fiorentino, Florence (Italy) [**] We thank the University of Zurich and the SLS for providing beamtime. Work by the Supuran lab was financed by an EU FP7 grant (Metoxia). Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201107333. . Angewandte Communications 3354  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2012, 51, 3354 –3357