Enhanced receptor selectivity: carbonic anhydrase inhibitors are relevant for both cancer diagnosis and therapy. Combining non-radioactive Re compounds with their radioactive (99m)Tc homologs enables the use of identical molecules for therapy and imaging (theragnostic). The syntheses and in vitro evaluation of [(Cp-R)M(CO)(3)] (Cp=cyclopentadienyl, M=Re, (99m)Tc) with R being a highly potent carbonic-anhydrase-targeting vector is reported.

Verbesserte Rezeptorselektivität: Carboanhydrase‐Hemmstoffe sind wichtig für die Krebsdiagnostik und ‐therapie. Mit einer Kombination aus nicht radioaktiven Re‐Verbindungen und ihren radioaktiven 99mTc‐Homologen sind Therapie und Bildgebung (Theragnostik) möglich. Die Synthese und In‐vitro‐Untersuchung des Komplexes [(Cp‐R)M(CO)3] (Cp=Cyclopentadienyl; M=Re, 99mTc), der einen Carboanhydrase‐Zielvektor R trägt, werden vorgestellt (siehe Bild).

Due to an enhanced demand for amino acids, the l-type amino acid transporter 1 (LAT1) is overexpressed in many tumor cell lines. LAT1 represents therefore an attractive target for cancer therapy and diagnosis. On the basis of our reported aqueous synthesis of [(Cp-R)99mTc(CO)3]-type complexes, − we describe the preparation of unnatural amino acid analogues [(Cp-CH2CH(NH2)COOH)Mn(CO)3] and [(Cp-CH(NH2)COOH)M(CO)3] (M = Mn, Re, 99mTc). Starting from fully protected HC5H5-aa (aa = amino acid), [(Cp-aa)99mTc(CO)3] complexes are accessible in quantitative yields and in a one-step synthesis from [99mTcO4]−. The rhenium and manganese analogues were prepared and structurally characterized to confirm the authenticity of the 99mTc complex. The inhibition constant of natural phenylalanine (phe) for LAT1 is in the range 70 ± 10 μM. The K i value of [(Cp-CH(NH2)COOH)Mn(CO)3] (1a) is 53 ± 11 μM, whereas K i for the “true” phe analogue [(Cp-CH2CH(NH2)COOH)Mn(CO)3] (2) was surprisingly high at 277 ± 37 μM. Complex 1a caused efflux when exposed to cells, underlining its active transport by LAT1 into the cell. 99mTc analogues of small biological lead structures such as amino acids are generally not recognized anymore by their targets, in particular by trans-membrane transporters. The bioorganometallic analogues presented here are, however, actively transported and corroborate the importance of organometallic complexes as mimics of organic lead structures in life sciences.

Complexes of the [(η 5 -C 5 H 4 COOR)M(CO) 3 ] type (M = 99m Tc, Re; R = targeting function) are basic bioorganometallic structures with the potential of combining molecular imaging ( 99m Tc) with therapy (cold Re or 186/188 Re). So far, the single carboxylate group on the cyclopentadienyl ring (Cp − ) limited targeting to one function. The concept of Cp − as a scaffold for attaching biological molecules could be extended substantially with two or more functionalities bound to the Cp − ligand. Accordingly, the rarely studied bis-substituted cyclopentadienyl ligands [C 5 H 3 (1,2-COOMe) 2 ] − and [C 5 H 3 (1,3-COOMe) 2 ] − were synthesized and their coordination to the fac-{M(CO) 3 } + moiety was studied in water. Both ligands are deprotonated at physiological pH and do not undergo Diels−Alder reactions. In water, they react directly with [Re(OH 2 ) 3 (CO) 3 ] + to form [(η 5 -C 5 H 3 {1,2-COOMe} 2 )Re(CO) 3 ] and [(η 5 -C 5 H 3 {1,3-COOMe} 2 )Re(CO) 3 ]. Controlled hydrolysis at neutral to alkaline pH gives the monoesters and fully hydrolyzed [(η 5 -C 5 H 3 {1,2-COOH} 2 )Re(CO) 3 ] and [(η 5 -C 5 H 3 {1,3-COOH} 2 )Re(CO) 3 ]. Thermal treatment leads to decarboxylation and formation of [(η 5 -C 5 H 4 COOH)Re(CO) 3 ]. The corresponding 99m Tc homologues are directly accessible under slightly acidic conditions from [ 99m TcO 4 ] − in high yields. In the presented strategy, the Cp − ring acts as a scaffold for attaching multiple targeting agents or pharmacophores at the same time. ■ INTRODUCTIONThe evaluation of new molecular imaging agents and medicinal inorganic compounds for therapy is a driving force in bioorganometallic chemistry. 1 Metal-based imaging agents and metal complexes currently used for therapy generally do not have much in common and have very distinct structures. A recent extension to the concept of imaging and therapy is theranostics in which both, diagnosis and therapy, are combined in one single compound, typically a nanomaterial. 2,3 Homologous complexes of two elements, one suited for diagnosis and one for therapy, represent an attractive molecular alternative to nanomaterial-based theranostics. 2,4−6 Technetium and rhenium represent such a "matched-pair", in that they form isostructural and highly robust complexes in low oxidation states. As structural mimics of pharmaceutical lead compounds, the cold (or hot 186 Re and 188 Re) rhenium complexes are therapeutically active, while the 99m Tc homologues are the imaging congener. According to this theranostic concept, a metal complex is an integral part of a lead structure; consequently, the complex must be small. The "innocent" cyclopentadienyl (Cp − ) ligand is, therefore, attractive as [(Cp-R) 99m Tc(CO) 3 ] can be integrated into lead structures and mimic phenyl rings, for example. 7−11 Cyclopentadienyl complexes are robust, and targeting functionalities can be attached, as has been shown with many bioconjugates of ferrocene. 9,12−16 We previously reported studies on the preparation of [(Cp-R) 99m Tc(CO) 3 ] and its rhenium homologues. 10,11,...

Starting from asymmetric Thiele's acid derivatives, two different imaging probes [(99m)Tc(CO)(3)(CpR)] (R=potential targeting vector) are generated simultaneously in one-pot and from one substrate. This extends the previously introduced labeling strategy of metal-mediated retro-Diels-Alder reaction with HCp-R dimers. We demonstrate that chemically active functionalities such as hydroxamic acids are not following this labeling strategy. Adopting the principle of replacing phenyl rings by [Re(CO)(3)(Cp)] entities, potent histone deacetylase (HDAC)-inhibiting Re analogs of suberoylanlilide hydroxamic acid (SAHA; N-hydroxy-N'-phenyloctanediamide) were synthesized and characterized. Cytotoxic evaluation on different tumor cell lines revealed low IC(50) values [μM] for these compounds, comparable to their purely organic congeners.