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Four new acyclic ligands, Bn-[H.sub.3]nonapa (3), [H.sub.3]nonapa (4), pN[O.sub.2]-Bn-[H.sub.3]nonapa (10), and Bn[H.sub.3]trenpa (7), were synthesized and studied with nonradioactive [In.sup.3+] and with radioactive [sup.111][In.sup.3+]. The coordination of these ligands to [In.sup.3+] was confirmed by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Radiolabeling experiments were performed with [sup.111][In.sup.3+]; these demonstrated [H.sub.3]nonapa (4) to be the best indium ligand of those studied herein, achieving radiochemical yields of ~97% in 10 min at ambient temperature, and stability to transchelation in mouse serum of 44.5% ± 25.9% after 24 h. Although the radiolabeling kinetics of [H.sub.3]nonapa (4) were excellent, serum stability results were inferior to the previously studied ligands DOTA, DTPA, and [H.sub.4]octapa, suggesting that the presented ligands may find their optimum radiopharmaceutical applications with isotopes other than [sup.111]In. Owing to the high denticity of these ligands (9-10 coordinate), they may realize their potential with large ion isotopes such as [sup.177]Lu, [sup.86/90]Y, and [sup.225]Ac. Key words: radiopharmaceuticals, coordination chemistry, radiometals, multidentate ligands, picolinates. Quatre nouveaux ligands acycliques Bn-[H.sub.3]nonapa (3), [H.sub.3]nonapa (4), p-N[O.sub.2]-Bn[H.sub.3]nonapa (10) et Bn-[H.sub.3]trenpa (7) ont ete synthetises et etudies a l'aide de l'ion [In.sup.3+], non radioactif, et de l'ion [sup.111][In.sup.3+], radioactif. La coordination de ces ligands avec l'ion [In.sup.3+] a ete confirmee par spectrometrie de masse de haute resolution et spectroscopie de resonance magnetique nucleaire. Des experiences de radiomarquage avec l'ion [sup.111][In.sup.3+] ont ete realisees et ont montre que [H.sub.3]nonapa (4) etait le plus performant des quatre ligands etudies, de par son rendement chimique (environ 97%, apres 10 minutes et a la temperature ambiante) et sa stabilite a l'egard de la transchelation dans du serum de souris (44,5% [+ or-] 25,9% des ligands intacts apres 24 h). Bien que la cinetique du radiomarquage de [H.sub.3]nonapa (4) fut excellente, les resultats de la stabilite de ce dernier dans le serum ont ete inferieurs a ceux obtenus pour les ligands precedemment etudies (DOTA, DTPA et [H.sub.4]octapa), ce qui signifie que les ligands etudies ici pourraient etre utilises de facon optimale dans le domaine pharmaceutique avec des isotopes autres que l'indium [sup.111]In. En raison de la denticite elevee de ces ligands (coordinence de 9 a 10), ils pourraient atteindre tout leur potentiel avec des isotopes ioniques lourds tels que [sup.177]Lu, [sup.86/90]Y et [sup.225]Ac. [Traduit par la Redaction] Mots-cles : radiopharmaceutiques, chimie de coordination, radiometaux, ligands multidentates, picolinates., Introduction The radiometal [sup.111]In is a versatile isotope that has been commonly used for single photon emission computed tomography (SPECT) and Auger electron/[β.sup.-] therapy, typically withtargeting vectors such as peptides, [...]

A detailed study was conducted to obtain a novel bifunctional chelate alternatives to the aminocarboxylate macrocycles NOTA ([N.sub.3][O.sub.3]) or DOTA [N.sub.4][O.sub.4]) for application of radioisotopes of Ga to diagnostic nuclear medicine. The results from the complete syntheses, characterizations, labeling studies, and biodistribution profiles of the linear [N.sub.4][O.sub.2] chelate [H.sub.2]dedpa which coordinates [super 67]Ga quantitatively to form [[super 67]Ga(dedpa)](+) after 10 min at RT represents the new platform chelates with higher stability than that of DOTA.

The design, synthesis, and preliminary radiolabeling evaluation of new N,N,O-type pyridyl-tert-nitrogen-phenol ligands for the [[M[(CO).sub.3]].sup.3+] core, where (M = Tc, Re) are described. The radiolabeled complexes formed with [[Tc[(CO).sub.3]].sup.3+] are stable even in the presence of a large excess of competitive chelators and could find potential use for radiopharmaceutical applications.

Ferrocenyl carbohydrate conjugates were syntesized and investigated as potential antimalarial agents targeting the high glucose utilization of the parasite that causes malaria. In vitro antiplasmodial and cytotoxicity studies of several ferrocenyl complexes showed that most of them have moderate antimalarial activity against both chloroquine-sensitive and -resistant strains of the parasite and low toxicity to a human cell line.

Glucosamine and 1,3,4,6-tetra-O-acetyl glucosamine are conjugated to the cyclopentadienylrhenium(I) and technetium(I) cores and the X-ray structure is determined for the free glucosamine conjugate. The structure is ascertained to be a high-affinity inhibitor of the glucose metabolism enzyme, hexokinase.

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We have investigated novel bifunctional chelate alternatives to the arninocarboxylate macrocycles NOTA (N3O3) or DOTA (N4O4) for application of radloisotopes of Ga to diagnostic nuclear medicine and have found that the linear N4O2 chelate H2dedpa coordinates 67Ga quantitatively to form [67Ga(dedpa)]+ after 10 min at RT. Concentration-dependent coordination to H2dedpa of either 68Ga or 67Ga showed quantitative conversion to the desired products with ligand concentrations as low as 10-7 M. With 68Ga, specific activities as high as 9.8 mCi nmol-1 were obtained without purification. In a 2 h competition experiment against human apo-transferrin, [67Ga(dedpa)]+ showed no decomposition. Two bifunctional versions of H2dedpa are also described, and these both coordinate to 67Ga at RT within 10 min. Complete syntheses, characterizations, labeling studies, and biodistribution profiles of the 67Ga complexes are presented for the new platform chelates. The stability of these platform chelates is higher than that of DOTA. [ABSTRACT FROM AUTHOR]

PurposeImproved bifunctional chelates (BFCs) are needed to facilitate efficient 64Cu radiolabeling of monoclonal antibodies (mAbs) under mild conditions and to yield stable, target-specific agents. The utility of two novel BFCs, 1-Oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid (p-SCN-Bn-Oxo-DO3A) and 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (p-SCN-Bn-PCTA), for mAb imaging with 64Cu were compared to the commonly used S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (p-SCN-Bn-DOTA).MethodsThe BFCs were conjugated to trastuzumab, which targets the HER2/neu receptor. 64Cu radiolabeling of the conjugates was optimized. Receptor binding was analyzed using flow cytometry and radioassays. Finally, PET imaging and biodistribution studies were done in mice bearing either HER2/neu-positive or HER2/neu-negative tumors.Results64Cu-Oxo-DO3A- and PCTA-trastuzumab were prepared at room temperature in >95% radiochemical yield (RCY) in <30 min, compared to only 88% RCY after 2 h for the preparation of 64Cu-DOTA-trastuzumab under the same conditions. Cell studies confirmed that the immunoreactivity of the mAb was retained for each of the bioconjugates. In vivo studies showed that 64Cu-Oxo-DO3A- and PCTA-trastuzumab had higher uptake than the 64Cu-DOTA-trastuzumab at 24 h in HER2/neu-positive tumors, resulting in higher tumor to background ratios and better tumor images. By 40 h all three of the 64Cu-BFC-trastuzumab conjugates allowed for clear visualization of the HER2/neu-positive tumors but not the negative control tumor.ConclusionThe antibody conjugates of PCTA and Oxo-DO3A were shown to have superior 64Cu radiolabeling efficiency and stability compared to the analogous DOTA conjugate. In addition, 64Cu-PCTA and Oxo-DO3A antibody conjugates may facilitate earlier imaging with greater target to background ratios than the analogous 64Cu-DOTA antibody conjugates. [ABSTRACT FROM AUTHOR]

The design rationale, synthesis and radiolabeling evaluation of four glucosamine conjugated ligands for the [99mTc(CO)3]+core is described. The capability to bind the tricarbonyl core is initially demonstrated using the cold surrogate [Re(CO)3]+. The four compounds are competent chelates in binding [99mTc(CO)3]+as labeling studies show, with yields ranging from 79 to 96% and the resulting complexes showing stability in the presence of competing chelates for 24 h at 37 °C. The rhenium complexes were tested for hexokinase-catalysed phosphorylation, and the technetium complexes were tested for GLUT-1 mediated cell uptake - they showed a small amount of uptake but it was not glucose dependent, suggesting that it was not viathe GLUT-1 transporters. [ABSTRACT FROM AUTHOR]

This review will highlight recent advances in ligand design for innovative applications in medicinal inorganic chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy. Increasing the potency of therapeutic compounds, while limiting side-effects, is a common goal in medicinal chemistry. In an effort to achieve this goal, compounds are being developed that either target a disease site, or are activated by a disease specific biological process. Metal complexes containing targeting functions and/or bioactive ligands, as well as agents that are activated by specific enzymes, or changes in pH and pO2, provide new avenues for drug development. Radiodiagnostic compounds, magnetic resonance imaging agents, and optical probes containing transition metals offer versatility unavailable to organic imaging agents. In certain cases, dual modality agents have been developed, and will be highlighted. Finally, we will discuss targeted metal binding compounds for treatment of metal overload disorders, and the recent application to neurodegenerative disease.