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Cystic fibrosis (CF) is caused by mutations in the gene that encodes the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to almost total absence of CFTR at the plasma membrane, a defect potentially corrected via drug-based therapies. Herein, we report the first proof-of-principle study of a noninvasive imaging probe able to detect CFTR at the plasma membrane. We radiolabeled the CFTR inhibitor, CFTRinh -172a, with technetium-99m via a pyrazolyl-diamine chelating unit, yielding a novel 99m Tc(CO)3 complex. A non-radioactive surrogate showed that the structural modifications introduced in the inhibitor did not affect its activity. The radioactive complex was able to detect plasma membrane CFTR, shown by its significantly higher uptake in wild-type versus mutated cells. Furthermore, assessment of F508del CFTR pharmacological correction in human cells using the radioactive complex revealed differences in corrector versus control uptake, recapitulating the biochemical correction observed for the protein.

The lack of selectivity for cancer cells and the resulting\ud negative impact on healthy tissue is a severe drawback of actual\ud cancer chemotherapy. Tethering of cytotoxic drugs to targeting\ud vectors such as peptides, which recognize receptors overexpressed\ud on the surface of tumor cells, is one possible strategy to overcome\ud such a problem. The pentapeptide cyc(RGDfK) targets the integrin\ud receptor αvβ3, important for tumor growth and metastasis formation.\ud In this work, two terpyridine based Ru(II) complexes were prepared\ud and for the first time conjugated to cyc(RGDfK) via amide bond\ud formation resulting in a monomeric and a dimeric bioconjugate. Both\ud Ru(II) complexes bind strongly and selectively to integrin αvβ3, with\ud the dimeric molecule displaying a 20-fold higher affinity to the\ud receptor than the monomeric one. However, the cytotoxicity of the\ud complexes and related bioconjugates against human A549 and\ud SKOV-3 cell lines is still not sufficient for application as anticancer\ud agents. Nevertheless, considering the high selectivity for integrin\ud receptor αvβ3, the synthesis of Ru-based bioconjugates with\ud cyc(RGDfK) paves a promising way towards the design of effective\ud targeted anticancer agents.

In order to target platinum complexes to cancer cells, trans-Pt(II) or trans-Pt(IV) complexes were bioconjugated to the cyclic peptide cRGDfK (cRGD), with affinity for αvβ3 integrin receptors, through their 4-picolinic acid spectator ligands. To tackle this goal, the Pt(II) and Pt(IV) precursors were activated at their carboxylic acid function and futher reacted with the cRGDfK peptide, to afford the bioconjugates Pt(II)-cRGD and Pt(IV)-cRGD, respectively. Pt(II)-cRGD was studied by 195Pt-NMR that confirmed the presence of the Pt(II) center. In contrast, the characterization of Pt(IV)-cRGD was not possible due to the tendency of this complex to undergo reduction to Pt(II) in solution. Thus, only the Pt(II)-cRGD complex was used for further biological studies, and it exhibited some cytotoxic activity against the HUVEC cell line, with the highest levels of αvβ3 expression. However, no improved effects were observed with respect to the Pt(II)-pic precursor. Studies by ICP-MS showed enhanced intracellular accumulation for Pt(II)-cRGD with respect to Pt(II)-pic in cancer cells. Overall, these results show that while Pt(II) bioconjugation enhances compound's uptake, it did not translate into an increase in cytotoxicity.

We describe the synthesis and biological evaluation of the cationic (99m)Tc-tricarbonyl complex fac-[(99m)Tc(CO)3 (κ(3) -L1)](+) (Tc1) anchored by a pyrazole-diamine-methylbenzylguanidine-based ligand (L1), as potentially useful for myocardial imaging. The rhenium complex fac-[Re(CO)3 (κ(3)-L1)](+) (Re1) was prepared and characterized as a 'cold' surrogate of the radioactive complex. Cell uptake studies in a neuroblastoma cell line suggest that Tc1 uptake mechanism is related to the norepinephrine transporter (NET). Tissue distribution studies in CD1 mice showed that Tc1 presents high initial heart uptake and a slow washout from the heart (7.8 ± 1.3% injected dose per gram (ID/g), 30-min post-injection (p.i.); 6.3 ± 1.3% ID/g, 60-min p.i.), with heart to blood ratios of 11.8 and 9.0 at 30- and 60-min p.i., respectively. The uptake mechanism of Tc1 appears to be similar to that of metaiodobenzylguanidine (MIBG), as it can be reduced by coinjection with nonradioactive MIBG. The biodistribution profile of Tc2, where the benzylguanidine pharmacophore is absent, corroborates the fact that Tc1 does not accumulate in the heart by a simple diffusion mechanism but rather by a NET-mediated mechanism. The results confirm those obtained in the cell assays. Despite the persistent heart uptake found for Tc1, the high hepatic and renal uptake remains to be improved.

Aiming to develop new strategies for the labeling of hydroxyl-containing biomolecules with the organometallic core fac-[99mTc(CO)3]+, we have prepared a new model bifunctional chelator, L4 (ethyl hydrogen (2-{[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]amino}ethyl)phosphonate), combining a pyrazolyl-amine chelating group and a monophosphonate ethyl ester function (–P(O)OHOEt). The phosphonate group allows metal stabilization, and, simultaneously, can be considered as a potential attachment site for a biomolecule. Reaction of L4 with the precursor [99mTc(H2O)3(CO)3]+ gave the model radiocomplex [99mTc(CO)3(k3-L4)] (6a). This radiocomplex was identified by comparing its chromatographic profile with that of the corresponding Re analog (6) under the same conditions, also prepared and fully characterized by the usual analytical techniques. Radiocomplex 6a is moderately lipophilic (log Po/w = 1.07), presenting high stability in vitro without any measurable decomposition or ligand exchange, even in the presence of strong competing chelators such as histidine and cysteine (37°C, 24 h). Biodistribution studies of the complex in CD-1 mice indicated a rapid blood clearance, and a rapid clearance from main organs, occurring primarily through the hepatobiliary pathway. Complex 6a presents also a high robustness in vivo, demonstrated by its resistance to metabolic degradation in blood, and intact excretion into the urine, after RP-HPLC analysis of blood and urine samples. Copyright © 2007 John Wiley & Sons, Ltd.

The rhenium oxides Re2O7 and ReO3 react with hydrogen peroxide solutions yielding peroxo complexes that efficiently catalyze the oxidation of olefins, aromatics, and certain organometallic compounds. In contrast, related oxides of molybdenum (MoO3) and vanadium (V2O5) do not activate H2O2 under comparable conditions. The active rhenium peroxo complex was isolated from the system Re2O7/H2O2: the crystalline red-orange, explosive compound of formula H4Re2O13 is the most oxygen rich rhenium compound isolated to date. Its structure resembles a “peroxo perrhenic acid”. The binuclear compound could be isolated in the form of a diglyme adduct, structurally defined as two corner-sharing pentagonal bipyramids with apical oxo and aquo ligands; the equatorial positions are occupied by the bridging oxygen and by n2-peroxo groups (two [O2]2− ligands per rhenium). In contrast to the known complex [CH3ReO(O2)2].H2O, the new peroxo species [O{ReO(O2)2.H2O}2] decomposes hydrolytically during the catalytic cycle and can thus not compete in terms of catalytic activity in oxidation reactions involving H2O2. Hydrolysis yields “perrhenic acid” Re2O7.2H2O, the diglyme adduct of which compound was also characterized by means of an X-ray diffraction analysis.

Mixed — ligand model complexes, [99mTc(O)(PNX)(SPh)] (XO (1a), S (2a)), were synthesized from [99mTcO4]−. These compounds were characterized by comparing their radioactive HPLC profiles with the UV profiles of the analytically pure Re compounds 1 and 2. Based on stability studies, undertaken in aqueous solutions and in glutathione challenge experiments, 2a was chosen for biodistribution studies in rats. Using this approach, the labelling of a 5-HT1A receptor ligand (derivatized aryl-piperazine) with 99mTc was also performed using the PNS chelate.

The organometallic fac-[99mTc(OH2)3(CO)3]+ reacts with heterofunctionalized phosphines with an amide group, of the general formula HPN2, H2PNO, HPNR (R = 4-(3-Aminopropyl)-1-(methoxyphenyl)piperazine), leading to the complexes [99mTc(k3-PN2)(CO)3] (3a), [99mTc(k2-H2PNO)X(CO)3] (4a) and [99mTc(k2-HPNR)X(CO)3] (5a). The characterization of 3a-5a was based on the HPLC characteristics of the corresponding Re surrogates (3–5). Under the tested experimental conditions, the more stable compounds are 4a and 5a, in which the chelate is neutral and bidentate through the phosphorus and the oxygen of the amide function. The binding affinity and selectivity of 5 for the 5HT1A receptor were determined.

This paper presents an overview of progress involving group 7 elements and actinides with scorpionate ligands. This includes oxides, polyhydrides and carbonyls of group 7 elements and any type of compounds of actinides (III) and (IV). Synthetic procedures, reactivity and structural data are reviewed.