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Title: Development of more efficacious Tc-99m organ imaging agents for use in nuclear medicine by analytical characterization of radiopharmaceutical mixtures. Progress report, May 1, 1981-April 30, 1982

Abstract

The objectives of this year's research were to develop a method for rapidly determining TcO/sub 4//sup -/ in /sup 99/Mo//sup 99m/Tc generator eluates, to improve the ability to chromatographically determine individual Tc-HEDP complexes in radiopharmaceuticals, and to investigate the effects of TcO/sub 4//sup -/ concentration and electrochemical reduction on the types and relative amounts of Tc-HEDP complexes present in a radiopharmaceutical formulation. A rapid and sensitive high performance liquid chromatographic (HPLC) method for the quantitative determination of pertechnetate (TcO/sub 4//sup -/) was developed. This HPLC-based analysis may be of considerable utility in assessing the history and function of /sup 99/MO/sup 99m/Tc generators as well as in the routine analysis of reduced technetium radiopharmaceuticals for the presence of undesired TcO/sub 4//sup -/. Encouraging results were obtained on a dimethyl amine column using aqueous (NH/sub 4/)/sub 2/SO/sub 4/ as the mobile phase. The preparation of Tc(NaBH/sub 4/) HEDP radiopharmaceutical analogues using varying concentrations of total TcO/sub 4//sup -/ shows a dramatic effect in the number and distribution of Tc-HEDP complexes over a TcO/sub 4//sup -/ concentration range of 10/sup -2/ to 10/sup -8/M. These results suggest that total TcO/sub 4//sup -/ concentration is an important parameter to be considered in the preparationmore » of a specific Tc-HEDP complex to improve skeletal imaging. The preparation of Tc(electrode) HEDP radiopharmaceutical analogues by using electrochemical reduction was explored. The resulting solutions contain Tc-HEDP complexes that are tentatively identified as being the same complexes formed by NaBH/sub 4/ reduction, although the relative concentrations of these complexes are quite different with the two modes of reduction. Thus, electrochemical reduction shows promise as a viable route to the preparation of specific Tc-HEDP complexes for improved skeletal imaging.« less

Authors:
;
Publication Date:
Research Org.:
Cincinnati Univ., OH (USA)
OSTI Identifier:
5611055
Report Number(s):
DOE/EV/10380-2
ON: DE82006895; TRN: 82-008139
DOE Contract Number:
AC02-80EV10380
Resource Type:
Technical Report
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; 62 RADIOLOGY AND NUCLEAR MEDICINE; RADIOPHARMACEUTICALS; CHEMICAL PREPARATION; SKELETON; SCINTISCANNING; TECHNETIUM 99; RADIOISOTOPE GENERATORS; TECHNETIUM COMPLEXES; LIQUID COLUMN CHROMATOGRAPHY; COMPARATIVE EVALUATIONS; ELECTROCHEMISTRY; ISOMERIC NUCLEI; MOLYBDENUM 99; PATIENTS; PERTECHNETATES; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; BODY; CHEMISTRY; CHROMATOGRAPHY; COMPLEXES; COUNTING TECHNIQUES; DAYS LIVING RADIOISOTOPES; DIAGNOSTIC TECHNIQUES; DRUGS; EVEN-ODD NUCLEI; HOURS LIVING RADIOISOTOPES; INTERMEDIATE MASS NUCLEI; ISOMERIC TRANSITION ISOTOPES; ISOTOPES; LABELLED COMPOUNDS; MOLYBDENUM ISOTOPES; NUCLEI; ODD-EVEN NUCLEI; ORGANS; OXYGEN COMPOUNDS; RADIOISOTOPE SCANNING; RADIOISOTOPES; SEPARATION PROCESSES; SYNTHESIS; TECHNETIUM COMPOUNDS; TECHNETIUM ISOTOPES; TRANSITION ELEMENT COMPLEXES; TRANSITION ELEMENT COMPOUNDS; YEARS LIVING RADIOISOTOPES; 400702* - Radiochemistry & Nuclear Chemistry- Properties of Radioactive Materials; 550601 - Medicine- Unsealed Radionuclides in Diagnostics

Citation Formats

Heineman, W.R., and Deutsch, E.A. Development of more efficacious Tc-99m organ imaging agents for use in nuclear medicine by analytical characterization of radiopharmaceutical mixtures. Progress report, May 1, 1981-April 30, 1982. United States: N. p., 1981. Web. doi:10.2172/5611055.
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Heineman, W.R., & Deutsch, E.A. Development of more efficacious Tc-99m organ imaging agents for use in nuclear medicine by analytical characterization of radiopharmaceutical mixtures. Progress report, May 1, 1981-April 30, 1982. United States. doi:10.2172/5611055.
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Heineman, W.R., and Deutsch, E.A. Tue . "Development of more efficacious Tc-99m organ imaging agents for use in nuclear medicine by analytical characterization of radiopharmaceutical mixtures. Progress report, May 1, 1981-April 30, 1982". United States. doi:10.2172/5611055. https://www.osti.gov/servlets/purl/5611055.
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@article{osti_5611055,
title = {Development of more efficacious Tc-99m organ imaging agents for use in nuclear medicine by analytical characterization of radiopharmaceutical mixtures. Progress report, May 1, 1981-April 30, 1982},
author = {Heineman, W.R. and Deutsch, E.A.},
abstractNote = {The objectives of this year's research were to develop a method for rapidly determining TcO/sub 4//sup -/ in /sup 99/Mo//sup 99m/Tc generator eluates, to improve the ability to chromatographically determine individual Tc-HEDP complexes in radiopharmaceuticals, and to investigate the effects of TcO/sub 4//sup -/ concentration and electrochemical reduction on the types and relative amounts of Tc-HEDP complexes present in a radiopharmaceutical formulation. A rapid and sensitive high performance liquid chromatographic (HPLC) method for the quantitative determination of pertechnetate (TcO/sub 4//sup -/) was developed. This HPLC-based analysis may be of considerable utility in assessing the history and function of /sup 99/MO/sup 99m/Tc generators as well as in the routine analysis of reduced technetium radiopharmaceuticals for the presence of undesired TcO/sub 4//sup -/. Encouraging results were obtained on a dimethyl amine column using aqueous (NH/sub 4/)/sub 2/SO/sub 4/ as the mobile phase. The preparation of Tc(NaBH/sub 4/) HEDP radiopharmaceutical analogues using varying concentrations of total TcO/sub 4//sup -/ shows a dramatic effect in the number and distribution of Tc-HEDP complexes over a TcO/sub 4//sup -/ concentration range of 10/sup -2/ to 10/sup -8/M. These results suggest that total TcO/sub 4//sup -/ concentration is an important parameter to be considered in the preparation of a specific Tc-HEDP complex to improve skeletal imaging. The preparation of Tc(electrode) HEDP radiopharmaceutical analogues by using electrochemical reduction was explored. The resulting solutions contain Tc-HEDP complexes that are tentatively identified as being the same complexes formed by NaBH/sub 4/ reduction, although the relative concentrations of these complexes are quite different with the two modes of reduction. Thus, electrochemical reduction shows promise as a viable route to the preparation of specific Tc-HEDP complexes for improved skeletal imaging.},
doi = {10.2172/5611055},
journal = {},
number = ,
volume = ,
place = {United States},
year = {Tue Dec 01 00:00:00 EST 1981},
month = {Tue Dec 01 00:00:00 EST 1981}
}
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Technical Report:
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DOI:  10.2172/5611055
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  • ;
    High performance liquid chromatography (HPLC) was used to efficiently separate and detect the individual components in a radiopharmaceutical mixture. A procedure for separating Tc(NaBH/sub 4/)HEDP radiopharmaceutical analogues by anion exchange HPLC with uv-visible and ..gamma.. detection was developed. Such preparations consist of as many as 7 Tc-containing components, the relative quantities of which are highly dependent on the conditions during preparation and subsequent handling. The in vivo distributions of 3 of the isolated Tc-HEDP species were evaluated as skeletal imaging agents in normal rats. The chromatographically separated Tc-HEDP components exhibit distinctly different biodistributions which are related to the chromatographic characteristicsmore » of the individual components. These same Tc-HEDP components were evaluated for uptake in myocardial infarcts using the isoproterenol-induced necrosis model in the rat. The relative uptake of the various components in the infarcted heart parallels the skeletal uptake. An optically transparent thin layer electrochemical flow cell was developed and characterized. This cell enables optical and electrochemical measurements to be made simultaneously on individual Tc-HEDP complexes as they elute from the HPLC. These results demonstrate the potential presence of numerous technetium complexes in radiopharmaceuticals and the efficacy of HPLC as a mode of separation and detection of these complexes. One particular component in the Tc(NaBH/sub 4/)HEDP radiopharmaceutical analogue is more effective than the others for both skeletal and myocardial infarct uptake. This is strongly suggestive that a more efficacious radiopharmaceutical would result from the administration of this single component.« less

  • ;
    A procedure based on high performance liquid chromatography (HPLC) has been developed for separating individual Tc-diphosphonate complexes in skeletal-imaging radiopharmaceuticals prepared by reduction of TcO/sub 4//sup -/ with NaBH/sub 4/ in the presence of methylene diphosphonate (MDP). Seven different Tc-MDP complexes have been detected and isolated in pure form. Significant differences in skeletal uptake and blood clearance are exhibited by the three complexes tested thus far by biodistribution studies in test animals. The relative quantities of these complexes present in a radiopharmaceutical preparation are dramatically influenced by the pH of the reaction mixture. Thus, control of pH is a simplemore » means of forming in high yield the single, most efficacious Tc-MDP complex for skeletal imaginG. An HPLC method with electrochemical detection has been developed for the analytical determination of total TcO/sub 4//sup -/ (/sup 99m/Tc + /sup 99/Tc). Concentrations of TcO/sub 4//sup -/ as low as 9 x 10/sup -9/ M can be detected. The method is being evaluated for monitoring total TcO/sub 4//sup -/ in /sup 99/Mo//sup 99m/Tc generators.« less

  • Anion exchange high performance liquid chromatography (HPLC) has been used to separate components of /sup 99m/Tc(NaBH/sub 4/) - DMAD formulations prepared as a function of pH, the presence or absence of air, and the time post reaction. The formulation pH is an effective variable for controlling the generation and interconversion of /sup 99m/Tc-DMAD components, and for allowing the preparation of large quantities of specific /sup 99m/Tc-DMAD complexes for biological evaluation. Individual components of /sup 99m/Tc(NaBH/sub 4/)-DMAD mixtures, separated by anion exchange HPLC, have been evaluated as skeletal imaging agents in rats. Biodistribution data show that the evaluated exhibit markedly differentmore » bone uptake and soft tissue localization. Comparison of the Tc(NaBH/sub 4/)-DMAD complex exhibiting the most favorable biological distribution with Osteoscan using an osteogenic rat model showed the DMAD complex to be slightly more efficacious. The total concentration of technetium in the eluants of commercially available /sup 99/Mo//sup 99m/Tc radionuclide generators has been determined by five different analytical procedures using four analytical techniques. Liquid scintillation beta counting, gas flow proportional beta counting, ionization chamber beta counting and high performance liquid chromatography with ultraviolet detection were used to track /sup 99/TcO/sub 4//sup -/ in the eluants of clinically used generators from each of the four domestic (USA) manufactures. The relative merits and disadvantages of the five procedures for the analysis of total technetium in the eluants of commercially available generators have been evaluated. 9 references, 3 figures.« less

  • It has been demonstrated that formulation variables (pH, TcO/sub 4//sup -/ concentration, and ligand-to-metal ratio) influence the chromatographic distribution of the components of a Tc-hydroxyethylidene diphosphonate (HEDP) mixture prepared by the NaBH/sub 4/ reduction of TcO/sub 4//sup -/ in the presence of HEDP. The use of alternate reductants for TcO/sub 4//sup -/ (i.e., SnCl/sub 2/, and electrode) not only alters the relative proportion of the Tc-HEDP components formed, but produces new complexes not previously seen (based on chromatographic retention time data). Thus, a systematic evaluation has been undertaken of the SnCl/sub 2/ and electrochemical reduction preparations that is similar tomore » that conducted for Tc(NaBH/sub 4/)-HEDP mixtures. High performance liquid chromatography with electrochemical detection has been utilized to separate components of a Tc(NaBH4)-methylene diphosphonate mixture. All Tc components of the mixture are reducible at a mercury electrode and hydrodynamic voltammetric data is being generated. Stripping chronocoulometry has been developed as a novel variation of anodic stripping voltammetry in order to increase precision in the analytical determination of TcO/sub 4//sup -/ in aqueous solution. Pilot studies to evaluate the operating parameters of /sup 99/Mo//sup 99m/Tc/ generators and to investigate two new diphosphonate ligands in the preparation of technetium skeletal imaging radiopharmaceutical analogs have been initiated.« less

  • The formation of many different technetium complexes in the Tc(NaBH4)-HEDP, Tc(NaBH4)-MDP, and Tc(NaBH4)-DMAD systems has been clearly demonstrated by HPLC-separation of reaction mixtures. The dramatically different biodistributions exhibited by the various complexes strongly suggests that an improved skeletal radiopharmaceutical would result if the single technetium complex which exhibits the optimum biodistribution properties is administered to the patient. The influence of pH, time, concentrations of TcO4 and ligand, and the nature of reductant on the relative amounts of the different complexes formed were investigated. Electrochemical reduction offers a means of possibly generating a desired complex in very high yield due tomore » the precision with which redox potential can be controlled. Additionally, we have developed HPLC methods with uv and electrochemical detection for the determination of total TcO4 in eluents from the ZZMo//sup 99m/Tc radionuclide generator. The inadequacy of current theory to accurately predict total TcO4 in generator eluents was demonstrated in that the concentration of total TcO4 is a major factor determining the yield of individual Tc-diphosphonate complexes. Spectroelectrochemistry proved an effective technique to study the redox properties of Tc-complexes. 18 refs., 10 figs., 1 tab.« less