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Technetium Radiopharmaceuticals

#3246


Fatty Acids Labeled with 99mTc. Influence of the Lipophilicity of the Chelating Core on the Biodistribution

Tech Area / Field

  • CHE-RAD/Photo and Radiation Chemistry/Chemistry
  • BIO-CHM/Biochemistry/Biotechnology

Status
3 Approved without Funding

Registration date
07.04.2005

Leading Institute
Khlopin Radium Institute, Russia, St Petersburg

Collaborators

  • Pacific Northwest National Laboratory, USA, WA, Richland\nCentral Manchester and Manchester Children's University Hospitals, UK, Manchester\nNational Centre for Scientific Research "Demokritos" / Institute of Radioisotopes & Radiodiagnostic Products, Greece, Athens\nUniversità di Ferrara / Department of Radiological Sciences, Italy, Ferrara\nInstituto Technology Nuclear, Portugal, Sacavem

Project summary

The aim of our proposal is to develop novel 99mTc-labeled fatty acids and to evaluate their potential use as myocardial imaging agents. This project involves the study of uptake of the bioconjugates synthesized in heart as influenced by the lipophilicity of the chelating core and structure of the fatty acid. Fatty acids with a long hydrocarbon chain are an energy source for normoxic myocardium. Study of their metabolism and retention on the surface of myocardium tissues furnishes important information about the state of the cardiovascular system and hypoxic areas in heart. Fatty acids labeled with 123I, 19F, and 11C are widely used today in the clinical practice. However, as these nuclides are produced on cyclotrons, labeled preparations based on them are very expensive, and the application site should be located at a short distance from the production site. We propose to consider the possibility of using 99mTc as radioactive tracer. This is a relatively cheap nuclide with favorable, from the viewpoint of nuclear diagnostics, decay parameters. Furthermore, this nuclide is produced with a 99mTc generator operating for several weeks, which allows considerable expansion of the territory in which radiopharmaceuticals can be applied. However, the technetium ion is a “foreign” ion for biomolecules, and therefore is alters their native behavior much more strongly compared to the compounds labeled with “nonmetalic” nuclides. Tethering of a technetium ion to biomolecules requires a bulky chelating core containing several polar groups. Such groups will exert an unpredictable effect on the behavior of a biologically active molecule, primarily because of formation of additional hydrogen bonds and strong dipole–dipole interactions. The tricarbonyltechnetium(I) ion, Tc(CO)3+, seems to be more promising in this respect than complexes of high-valence technetium(V, IV, III) traditionally used in nuclear medicine. The Tc(CO)3+ ion is sufficiently stable and forms water-soluble species; it contains technetium in the low-valence state and has only three free coordination vacancies arranged in the fac-positions.

We believe that one of the factors significantly affecting the behavior of a biomolecule is the lipophilicity of the chelating core. The most widely used chelating cores contain on their periphery polar groups such as, e.g., amino and carboxy groups capable of hydrogen bonding. In this connection, it seems urgent to prepare lipophilic chelating cores and systematically study the influence of their hydrophilic and lipophilic properties on the biological behavior of active biomolecules. In this project, we intend to study how the lipophilicity of the chelating core affects accumulation of fatty acids in the myocardium, with the aim to develop technetium radiopharmaceuticals for diagnostics of heart metabolism.

To accomplish this goal, we intend:

  • to prepare tridentate and “2+1” chelators of different lipophilicities [tripyrazolylborate, bis(pyrazol-1-yl)acetate, “2+1” system dithiocarbamate–isonitrile;
  • to prepare complexes of these chelators with the organometallic fragments M(CO)3+ (M = Tc, Re) and to evaluate their lipophilicity;
  • to study complexation of Tc(CO)3+ with these ligands in aqueous solutions by 99Tc NMR spectroscopy;
  • to evaluate the kinetic stability of the complexes in the interligand exchange with histidine and their stability in vitro;
  • to develop procedures for linking the chelating cores to model fatty acids (in the first step, to valeric acid), to measure the lipophilicity of the model bioconjugates, and to study biodistribution of 99mTc-labeled fatty acids in laboratory animals (mice, rabbits) and reveal the influence of the lipophilicity of the chelating core;
  • to develop procedures for linking the most promising chelating cores to fatty acids of various structures, to study the biodistribution of the resulting bioconjugates, and to determine how the structure of the acids affects their metabolism in the myocardium;
  • to formulate recommendations on synthesis of new radiopharmaceuticals based on 99mTc and fatty acids; to develop procedures for linking the most promising chelating cores through a spacer with model amino acids.

Implementation of the project should result in development of procedures for preparing chelating cores of various lipophilicities, ensuring strong binding of the Tc(CO)3+ fragment; in evaluation of the lipophilicities of their Tc(CO)3+ complexes; in development of procedures for conjugation of these chelating cores with fatty acids; in evaluation of the accumulation of 99mTc-labeled fatty acids in myocardium depending on the lipophilicity of the chelating core and structure of the fatty acid; and in development of procedures for conjugation of technetium complexes with amino acids via hydrocarbon spacer.


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