Tissue distribution properties of technetium-99m-diamide-dimercaptide complexes and potential use as renal radiopharmaceuticals

Kasina, S.; Fritzberg, Alan R.; Johnson, Dennis L.; Eshima, Dennis

doi:10.1021/jm00160a023

Cited by 66 publications

(40 citation statements)

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“…This ligand system forms highly stable tetradentate complexes with Tc (CmTc-N2S2) at the +5 oxidation level (12). Studies of a large number of compounds containing the N2S2 donor group showed that high yields of "mTc complexes of the predicted structure were obtained (13). We have shown that other potential metal-binding groups, such as the carboxylate group present in the N2S2 ligands, do not participate in metal binding (14).…”

mentioning

confidence: 99%

Specific and stable labeling of antibodies with technetium-99m with a diamide dithiolate chelating agent.

Fritzberg¹,

Abrams²,

Beaumier³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

147

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Technetium-99m labeling of antibodies has been suboptimal because of low affinity adventitious binding, nonspecific labeling, and loss of immunoreactivity. The diamide dithiolate ligand system (N2S2) forms highly stable, well-defined tetradentate complexes with Tc(V). Antibodies and their fragments have been labeled by conjugation of preformed "mTc4,5-bis(thioacetamido)pentanoate active ester to protein amine groups to give a chemically known 99"Tc-N2S2 complex covalently linked to antibody. Evaluations of the "'Tc-N2S2-bound antibodies and their fragments have shown high stability and retained immunoreactivity.Successful targeting ofdiagnostic radionuclides to tumors not only provides a tool to diagnose and stage cancer but also demonstrates feasibility for therapy where ligand systems can be applied to therapy radionuclides. Early studies with radiolabeled antibodies utilized radioiodine (1231/1311) because of extensive experience in protein radioiodination, covalent attachment, and ready availability of the radionuclide (1,2). Improved tumor-to-nontumor ratios were achieved with 1"'In compared to 131I by using diethylenetriaminepentaacetate (DTPA) bifunctional chelating agent technology (3)(4)(5) MATERIALS AND METHODS Preparation of 99mTc-4,5-bis(thioacetamido)pentanoyl (N2S2)-Conjugated Anti-Melanoma 9.2.27 F(ab')2 Fragment. To a mixture of 25 1.l of 4,5-bis(benzoylthioacetamido)pentanoic acid (1.0 mg/ml solution in 90% CH3CN) and 100 ,ul of 1 M NaOH was added 100 mCi of sodium [99mTc]pertechnetate in 1.0 ml of saline (0.9% NaCl). Then 1.0 mg of sodium dithionite (0.10 ml of a freshly prepared 10 mg/ml solution) was added, and the mixture was heated at 750C for 15 min.The pH was brought to about 6 with 0.10 ml of 1 M HCI and 0.30 ml of 0.2 M sodium phosphate buffer (pH 6.0). Then 10.0 mg of 2,3,5,6-tetrafluorophenol (0.10 ml of a 100 mg/ml solution in 90% CH3CN) and 12.5 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.10 ml of a 125.0 mg/ml solution in 90% CH3CN) were added, and the solution was heated at 75°C for 30 min. The resulting tetrafluorophenyl active ester derivative of "mTc-4,5-bis(thioacetamido)pentanoate was purified by loading the reaction mixture on a conditioned C18 cartridge (J. T. Baker), washing with 2.0 ml of 20% (vol/vol) ethyl alcohol/0.01 M sodium phosphate, pH 7.0, eight times, and eluting with 100% CH3CN. The solvent was evaporated under a stream of N2. Then 0.5 ml of the 9.2.27 F(ab')2 fragment (16) at 2.5 mg/ml and 0.50 ml of 0.2 M sodium phosphate (pH 9.0) were added for conjugation. After 15 min at room temperature, 25 mg of lysine (0.25 ml of a 250-mg/ml solution at pH 9.0) was added to quench unreacted ester. The 99mTc-N2S2-9.2.27 F(ab')2 was purified by passage through a G-25 Sephadex column (Pharmacia) equilibrated with phosphate-buffered saline.Abbreviations: N2S2, diamide dithiolate chelating system; 99M Tc-N2S2-9.2.27 F(ab')2, 99mTc-4,5-bis(thioacetamido)pentanoyl-9.2.27 F(ab')2 fragments; DPTA, diethylenetriaminepentaacetate.

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mentioning

confidence: 99%

Specific and stable labeling of antibodies with technetium-99m with a diamide dithiolate chelating agent.

Fritzberg¹,

Abrams²,

Beaumier³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

147

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“…As., Argentina) [34,35]. Images were taken five to ten minutes after intravenous injection of the tracer, in anesthetized mice at multiple time points following Unx or Stx2 administration.…”

Section: Methodsmentioning

confidence: 99%

Compensatory renal growth protects mice against Shiga toxin 2-induced toxicity

et al. 2006

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Uninephrectomy (Unx) is followed by the compensatory renal growth (CRG) of the remaining kidney. Previous evidence has shown that during CRG, renal tissue is resistant to a variety of pathologies. We tested the hypothesis that the functional changes that take place during CRG could attenuate Shiga toxin (Stx) toxicity in a mouse model of Stx2-induced hemolytic uremic syndrome (HUS). The participation of nitric oxide (NO) was analyzed. After CRG induction with Unx, mice were exposed to a lethal dose of Stx2, and the degree of renal damage and mortality was measured. Stx2 effects on the growth, renal blood flow (RBF) and NO synthase (NOS) intrarenal expression in the remaining kidney were then studied. The induction of CRG strongly prevented Stx2-mediated mortality and renal damage. Administration of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) during CRG partially impaired the protection. Both Stx2 and L-NAME interfered with the hypertrophic and hyperplastic responses to Unx, as well as with the increase in RBF. In intact mice, Stx2 decreased renal perfusion, inhibited endothelial NOS basal expression and enhanced inducible NOS expression; all of these effects were attenuated by prior Unx. It is concluded that during CRG mice are highly protected against Stx2 toxicity and lethality. The protective capacity of CRG could be related to the enhancement of renal perfusion and preservation of eNOS renal expression, counterbalancing two major pathogenic mechanisms of Stx2.

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“…Fritzberg et al [157] synthesized about twenty diamide dimercaptide N2S2 derivatives in order to develop a Tc-99m radiopharmaceutical to replace radioiodinated hippuran. In addition to radiopharmaceutical potential, N2S2 ligands might offer access to produce Tc-99m complexes of desirable structures and properties with high stability [158,159].…”

Section: Sulfur Containing Ligandsmentioning

confidence: 99%