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The rotational orientation of cyclopentadienyl rings, their effect on d-orbital energy levels and splitting in transition metal complexes are described. The possibility of using sterically imposed ligand rotation as a means of spin-state manipulation makes indenyl compounds a potentially rich source of magnetically adjustable molecules.

Pu L3 W-ray near edge absorption spectra for Pu(0-VII) for more than 60 chalcogenides, chlorides, hydrates, hydroxides, nitrates, carbonates, oxy-hydroxides and other compounds both as solids and in solution are reported.

Research has been conducted on tris(bis(trimethylsilyl)amido)samarium. The study of this compound has been carried out via the use of density functional theory and X-ray crystallography, and the results have demonstrated that the structure features positional disorder of the metal atom above and below the plane defined by three N donor atoms.

The reaction intermediates of an organic reaction mediated by samarium(II) is isolated and analyzed by H NMR and X-ray crystallography. Analyses of the intermediates by X-ray diffraction and GC/MS have provided a clear understanding of the multiple roles of the samarium reagent in nitro reduction chemistry.

The synthesis, structural characterization and the interaction with the heavy group 2 metals are presented and the preparation of complexes with general formula (Me2P(Fl)2)(AeI(thf))(sub n), and the isolation and the crystallographic characterization of uncomplexed phosphonium diylide [Me2P(FI)2](super -) is described. It is seen that despite strong electrostatic attraction that usually drives metal-ligand binding in highly ionic systems, calcium and barium ions preferred to remain solvated with neutral oxygen donor ligands, rather than coordinate to the anionic diylide.

Background: Human epidermal growth factor receptor-2 (HER-2) and tumor-associated glycoprotein 72 (TAG-72) have proven to be excellent molecular targets for cancer imaging and therapy. Trastuzumab, which binds to HER-2, is effective in the treatment of disseminated intraperitoneal disease when labeled with (213)Bi or (212)Pb. (213)Bi-humanized CC49 monoclonal antibody (HuCC49DeltaCH2), which binds to TAG-72, inhibits the growth of subcutaneous xenografts. A next logical step to improve therapeutic benefit would be to target tumors with both molecules simultaneously.Methods: Athymic mice bearing intraperitoneal human colon carcinoma xenografts were treated with a combination of trastuzumab and HuCC49DeltaCH2 labeled with (213)Bi administered through an intraperitoneal route. The sequence of administration also was examined.Results: Before combining the 2 monoclonal antibodies, the effective doses of (213)Bi-CC49DeltaCH2 and (213)Bi-trastuzumab for the treatment of peritoneal disease were determined to be 500 muCi for each labeled antibody. Treatment with (213)Bi-HuCC49DeltaCH2 resulted in a median survival of 45 days and was comparable to the median survival achieved with (213)Bi-trastuzumab. Each combination provided greater therapeutic efficacy than either of the agents given alone. However, the greatest therapeutic benefit was achieved when (213)Bi-HuCC49DeltaCH2 and (213)Bi-trastuzumab were coinjected, and a median survival of 147 days was obtained.Conclusions: Dual targeting of 2 distinct molecules in tumors such as TAG-72 and HER-2 with alpha-particle radiation resulted in an enhanced, additive, therapeutic benefit. The authors also observed that this radioimmunotherapeutic strategy was well tolerated. [ABSTRACT FROM AUTHOR]

Examines the samarium (Sm)-mediated reduction of aryl nitro compounds. Use of nuclear magnetic resonance and X-ray crystallography; Conversion of aryl and alkyl nitro compounds into amine; Reaction of Sm with nitroso compounds.

Investigates the interaction of noncoordinated phosphonium diylide with heavy group metals. Relation between organometallic compounds of the heavy group two elements and ligands; Examples of group two elements; Synthesis of heavy metals.

The structurally novel bifunctional ligands C-NETA and C-NE3TA, each possessing both acyclic and macrocyclic moieties, were prepared and evaluated as potential chelates for radioimmunotherapy (RIT) and targeted magnetic resonance imaging (MRI). Heptadentate C-NE3TA was fortuitously discovered during the preparation of C-NETA. An optimized synthetic method to C-NETA and C-NE3TA including purification of the polar and tailing reaction intermediates, tert-butyl C-NETA (2) and tert-butyl C-NE3TA (3) using semiprep HPLC was developed. The new Gd(III) complexes of C-NETA and C-NE3TA were prepared as contrast enhancement agents for use in targeted MRI. The T 1 relaxivity data indicate that Gd(C-NETA) and Gd(C-NE3TA) possess higher relaxivity than Gd(C-DOTA), a bifunctional version of a commercially available MRI contrast agent; Gd(DOTA). C-NETA and C-NE3TA were radiolabeled with (177)Lu, (90)Y, (203)Pb, (205/6)Bi, and (153)Gd; and in vitro stability of the radiolabeled corresponding complexes was assessed in human serum. The in vitro studies indicate that the evaluated radiolabeled complexes were stable in serum for 11 days with the exception being the (203)Pb complexes of C-NETA and C-NE3TA, which dissociated in serum. C-NETA and C-NE3TA radiolabeled (177)Lu, (90)Y, or (153)Gd complexes were further evaluated for in vivo stability in athymic mice and possess excellent or acceptable in vivo biodistribution profile. (205/6)Bi- C-NE3TA exhibited extremely rapid blood clearance and low radioactivity level at the normal organs, while (205/6)Bi- C-NETA displayed low radioactivity level in the blood and all of the organs except for the kidney where relatively high renal uptake of radioactivity is observed. C-NETA and C-NE3TA were further modified for conjugation to the monoclonal antibody Trastuzumab.

An antibody-targeted radiation therapy (radioimmunotherapy, RIT) employs a bifunctional ligand that can effectively hold a cytotoxic metal with clinically acceptable complexation kinetics and stability while being attached to a tumor-specific antibody. Clinical exploration of the therapeutic potential of RIT has been challenged by the absence of adequate ligand, a critical component for enhancing the efficacy of the cancer therapy. To address this deficiency, the bifunctional ligand C-NETA in a unique structural class possessing both a macrocyclic cavity and a flexible acyclic moiety was designed. The practical, reproducible, and readily scalable synthetic route to C-NETA was developed, and its potential as the chelator of (212)Bi, (213)Bi, and (177)Lu for RIT was evaluated in vitro and in vivo. C-NETA rapidly binds both Lu(III) and Bi(III), and the respective metal complexes remain extremely stable in serum for 14 days. (177)Lu -C-NETA and (205/6)Bi -C-NETA possess an excellent or acceptable in vivo biodistribution profile.

These studies demonstrate the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using (212)Pb-labeled Herceptin as an in vivo generator of (212)Bi. In vitro studies compare the potential of the bismuth radioisotopes, (213)Bi and (212)Bi, to that of (212)Pb. Overall, (212)Pb results in a higher therapeutic index than either bismuth radioisotope, requiring lower radioactivity (microCi) for effective cytotoxic response. A pilot radioimmunotherapy (RIT) experiment treating mice bearing 5 d LS-174T intraperitoneally (i.p.) xenografts determined a maximum tolerated dose (MTD) of 20-40 microCi with i.p. administration. A specific dose response was observed and 10 microCi was selected as the effective operating dose for future experiments. Median survival of tumor-bearing mice receiving 10 microCi increased from 19 to 56 days (p = 0.008). The efficacy of (212)Pb-Herceptin was also assessed in a human pancreatic carcinoma xenograft (Shaw; i.p.) animal model previously reported as unresponsive to 213Bi-Herceptin (p = 0.002). Multiple dosing of (212)Pb-Herceptin was evaluated in both animal models. The median survival of mice bearing 3 d LS-174T i.p. xenografts increased to 110 days, with up to 3 doses of (212)Pb-Herceptin given at approximately monthly intervals; however, there was no evidence of a correlation with the second and third doses (p = 0.98). No improvement in median survival was noted with a similar regimen in the Shaw xenograft model.

Extract: Hybridoma/monoclonal antibody (mAb) technology as described in Kohler and Milstein's work resurrected Ehrlich's century old concept of "magic bullets." This seminal publication described fusion of a plasmacytoma (tumor of activated B lymphocytes) with spleen cells and subsequent isolation of hybrids that secreted mAb with pre-defined specificity. Generation of mouse mAbs against tumor-associated antigens became a focus in the 1980's. Pre-clinical studies provided proof-of-concept for the potential of mAbs for therapy although inherent limitations of these models demonstrated discordance in predictability of actual efficacy. Clinical investigations also illustrated deficiencies; foremost, an inevitable immune response, i.e., the production of human anti-murine immunoglobulin antibodies (HAMA). Other limitations included (1) inadequate tumor dose delivery; (2) insufficient activation of effector function(s); (3) slow blood clearance; (4) low affinity and avidity; (5) normal organ targeting; (6) tumor antigen heterogeneity; and (7) insufficient tumor penetration. Most of these were handled with genetic engineering or chemical modification, but some obstacles remained. HAMA production has been addressed by chimerization (combining portions of mouse and human antibodies) or complete humanization (grafting only the key antigen-binding portions of mouse antibody to a human antibody framework) of the mAb.