Tc HIDA

ACS Symposium Series American Chemical Society Washington, DC, 1980. 

Attempts to design Tc-radiopharmaceuticals of this type in the past have all failed. The past failures were due, at least in part, to the lack of information on the chemistry of Tc. The availability of new knowledge on the chemistry of Tc (such as that in the chapters by Davison and Deutsch) greatly increases the likelihood that new bifunctional Tc-radiopharmaceuticals will be developed. 

Transition metal complexes containing radioactive isotopes have found widespread use as radiopharmaceuticals in diagnostic nuclear medicine. The most useful transition metal nuclide is technetium-99m and there are many examples of the successful applications of complexes of Tc-99m in both structural and functional studies of patients. Limitations on the design of additional more useful and better technetium radiopharmaceuticals include a) a very incomplete knowledge of the chemistry and structure of technetium compounds and b) inadequate information on the factors which influence the biodistribution and interaction with biomolecules, such as receptors, of transition metal complexes. These factors are discussed in terms of the need for additional metalloradiophannaceuticals. 

This work was supported in part by USPHS Grant GM 10548 and by Grant HL 17655. 

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Several studies of the relationship between structure and biodistribution have been carried out on the "Tc-HIDA derivatives and related compounds. The more hydrophilic agents, such... 

Costello CE, Brodack JW, Jones AG, Davison A, Johnson DL, Kasina S, Fritzberg AR (1983) The investigation of radiopharmaceutical components by fast atom bombardment mass spectroscopy the identification of Tc-HIDA and the epimers of TC-CO2DADS. J Nucl Med 24 353-355... 

Loberg MD, Fields AT (1978) Chemical structure of technetium-99m-labeled N-(2,6-dimethyl-phe-nylcarbamoylmethyl)-iminodiacetic acid ( Tc-HIDA). Int J Appl Radiat Isot 29 167-173 March A, Garuti P, Duatti A et al (1990) Synthesis of technetium(V)-nitrido complexes with chelating amines a novel class of monocationic, octahedral complexes containing the [Tc = N] core. Crystal structures of [TcN(en)2Cl] (en = ethylenediamine) and [TcN(tad)Cl] (tad = 1,5,8,12-tet-raazadodecane). Inorg Chem 29 2091-2096... 

Nunn AD, Schramm E (1981) Analysis of Tc-HIDAs and factors affecting their labeling rate, purity, and stability. J Nucl Med 22-.P52... 

Substitution of the ortho positions also promoted urinary as opposed to biliary excretion of 99mTc-iabelled HIDA derivatives. The radiochemical purity of the " Tc-HIDA formulations was found to be dependent upon the preparative conditions used. At least two components were identified in formulations with (21c) and the pH of the preparative medium and the pKa of the complexing agent appear to be important factors affecting radiochemical purity. ... 

Tc-dihydrothioctic acid, Tc-HIDA, Tc-isomercaptobutyric acid and Tc-pyridoxylideneglutamate... 

From there, " Tc(HIDA)2 was excreted into the bile and eventually into the intestines. Loberg also prepared C-labeled HIDA and determined its biodistribution. In marked contrast to 99" Tc(HIDA)2, C-HIDA is excreted rapidly and almost exclusively by the kidneys (7 ). The difference in distribution between HIDA and the Tc-complex of HIDA demonstrates that 5 Tc is not functioning as a tag for HIDA and illustrates some of the difficulties encountered when trying to design Tc-radiopharmaceuti-cals based on small molecules (i.e. Molecular weight < 1000). 

Figure 3. Proposed structure of hepatobiliary agent Tc(HIDA h...

A HIDA scan assesses the patency and function of the biliary tree. A radiolabelled isotope, technetium-99m ( Tc), is injected intravenously... 

Ru chloride containing Ru and Ru was found to exhibit similar biological behaviour to that of "Tc with two derivatives of HIDA. This suggests that Ru agents may be developed for use in delayed scintigraphic studies of the liver, where "Tc might be unsuitable. 

AT-(2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid (HIDA) and several ether derivatives have been evaluated as ligands for complexation, producing Tc complexes suitable as hepatobiliary agents. Tc-IDA complexes have a negative charge (Loberg and Fields 1978). Two molecules of ligand are coordinated to one Tc(III)-core (Nunn et al. 1983) (Fig. 2.1.17). 

MDP methylenediphosphonate, HSA human serum albumin, DMSA dimercaptosuccinic acid, DTPA diethylene triamine pentaacetate, HIDA hepatoiminodiacetic acid, EC ethylene dicysteine, HSA human serum albumin, MIBI monodentate methoxyisobutyl isocyanide, MAG3 mercaptoacetyltrigly-cine, ECO ethylene dicysteine dimer, HMPAO hexamethylpropylene amine oxime a eluate (370 MBq), Tc is not considered... 

Ponto JA, Swanson DP, Freitas JE (1987) Clinical manifestations of radiopharmaceutical formulation problems. In Hladik WB III, Saha GB, Study KT (eds) Essentials of nuclear medicine science. Williams Wilkins, Baltimore, pp 268-279 Ryan J, Cooper MD, Loberg MD (1977) Technetium-99m-labeled N-(2,6-dimethylphenylcarbamoyl-methyl)iminodiacetic acid (Tc-99m-HIDA) a new radiopharmaceutical for hepatobiliary imaging studies. J Nucl Med 18 997-1004... 

United States Pharmacopeial Convention (2005) Official Monographs USP 28, technetium Tc 99m disofenin injection, technetium Tc 99m lidofenin injection, technetium Tc 99m mebrofenin injection. United States Pharmacopeia (USP) 28-national formulary (NF) 23, pp 1854-1857 Weissmann HS, Frank MS, Bernstein LH, Freeman LM (1979) Rapid and accurate diagnosis of acute cholecystitis with Tc-99m-HIDA cholescintigraphy. Am J Roentg 132 523-528... 

The structure of HIDA is shown in Figure 2. This compound was originally synthesized by Loberg(7 ) as a lidocaine analog capable of complexing Tc. When the ""Tc-complex of HIDA was prepared and its biodistribution determined in mice, it was found to rapidly leave the circulation and accumulate in the liver. 

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