Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1994-07-29
1997-02-11
Hollinden, Gary E.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
424 936, 424 9361, 534 14, 556 26, 568 8, A61K 5104
Patent
active
056018002
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The metal compounds formed are easily prepared, generally producing a single species, in high yields which are highly stable. .sup.99m Tc compounds have potential for diagnostic imaging applications. The beta-emitting transition metal radionuclides (e.g. .sup.186 Re/.sup.188 Re, .sup.109 Pd, etc.) hold potential for therapeutic applications. Chelates of these ligands with paramagnetic metal ions hold potential as MRI contrast agents.
BACKGROUND OF THE INVENTION
Radiotherapeutic Agents
Radiotherapy using "non-sealed sources" by way of radiolabeled pharmaceuticals has been employed for several decades [1-3]. Less than a handful of therapeutic pharmaceuticals are currently in routine use in the United States and approved by FDA. Recently, there has been renewed interest in developing new agents due to the emergence of more sophisticated molecular carriers, such as monoclonal antibodies, more capable of selective targeting of cancerous lesions. In addition, the identification of different radionuclides [4-7] with different chemical properties that have physical decay properties that are desirable for therapeutic application has further spurred development of new agents.
Although there has been some success in treatment of specific malignant diseases, many problems remain to be solved in this area. For example, in most cancers, it has been difficult to provide acceptable selectivity in radiation doses delivered to target tissues relative to normal tissues. Successful development of new therapeutic radiopharmaceuticals will require improved localization of these agents in target tissues and increasing rates of clearance from non-target tissues. In both of these situations, it is imperative that the therapeutic radionuclide remain firmly associated with the radioactive drug in vivo for extended periods of from a few hours up to several days. The length of time required will depend upon the pharmacokinetic and physical half-life of the radionuclide. No single radionuclide will be appropriate in formulating therapeutic agents since different half-lives and the energy of emitted particles will be required for different applications [4-7], making it essential that radiopharmaceuticals with different radionuclides be made available.
It is expected that therapeutic agents will be primarily labeled with beta-particle emitting radionuclides for the near future. Several different chelating structures have been employed to maintain the association of these beta emitters with the drug [8-12]. Many of the chelating structures are not sufficiently stable and most, if not all, do not provide appropriate routes or rates of clearance of radioactivity from non-target tissues [13,14]. This results in delivery of high radiation doses to normal tissues and reduces the therapeutic ratio which in turn lowers the amount of radiation dose that can be safely delivered to target tissues, such as tumors or micrometastases. Development of new radionuclide chelates that link the radioactive metal to the radiopharmaceutical is presently necessary. These complexes must be highly stable in vivo while attached to the biomolecules and have improved clearance characteristics from normal tissues after catabolism of the antibody.
Diethyltriaminepentaacetic acid (DTPA) forms a rather stable chelate with a variety of metals and is exemplary of prior art chelating moieties. However, coupling of this ligand to monoclonal antibodies by one of its five carboxyl groups resulted in unacceptable in vivo stability with a variety of radionuclides [15]. Linking of DTPA by a side group attached to one of the carbon atoms on an ethylene bridging group provides improved in vitro and in vivo stability [16]. However, the stability characteristics are not ideal and clearance activity from certain organs such as kidney and liver, are poor [17].
Chelating agents based on the diamidodithiol (DADT) and triamidomonothiol (TAMT) backbones are another example of chelating agents that are used for forming small and stable hydrophilic complexes with .su
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Katti Kattesh V.
Ketring Alan R.
Singh Prahlad R.
Volkert Wynn A.
Curators of the University of Missouri
Hartley Michael G.
Hollinden Gary E.
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