Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1998-01-21
1999-12-28
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
424 111, 424 165, 424 91, 530300, 530311, 530324, 206223, 206569, A61K 5100, A61M 3614
Patent
active
060077921
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to radiotherapeutic agents and peptides, radiodiagnostic agents and peptides, and methods for producing such labeled radiodiagnostic and radiotherapeutic agents. Specifically, the invention relates to receptor-binding vasoactive intestinal peptides (including native vasoactive intestinal peptide (VIP) and fragments, derivatives, analogues and mimetics thereof), and embodiments of such compounds labeled with gamma-radiation emitting isotopes such as technetium-99m (Tc-99m), as well as methods and kits for making, radiolabeling and using such peptides to image sites in a mammalian body. The invention also relates to receptor binding vasoactive intestinal peptides and derivatives, analogues and mimetics thereof, labeled with cytotoxic radioisotopes such as rhenium-186 (.sup.188 Re) and rhenium-188 (.sup.188 Re), and methods and kits for making, radiolabeling and using such compounds therapeutically in a mammalian body.
2. Description of the Prior Art
Native vasoactive intestinal peptide (VIP) is a 28 amino acid peptide that was first isolated from hog upper small intestine (Said and Mutt. 1970, Science 169: 1217-1218). This peptide belongs to a family of structurally-related, small peptides that includes helodermin, secretin, the somatostatins, and glucagon. The peptide has the formula: Biochemistry 2d ed., 1988. MacMillan Publishing: New York, p. 33).
The biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cyclic adenosine monophosphate signalling system. VIP regulates a variety of different biological activities in tissues and organs. It modulates cellular metabolic activities and regulates exocrine and endocrine secretions. It also induces relaxation of smooth muscle and causes vasodilatory effects. VIP is also involved in the regulation of cellular proliferation and survival in a number of different cell types, including keratinocytes, smooth muscle cells, sympathetic neuroblasts, hippocampal cells and, in vitro, NIH 3T3 cells.
VIP receptors are widely distributed throughout the gastrointestinal tract and are also found in various other cell types. Large numbers of VIP receptors are expressed in rumor cells of, for example, adenocarcinomas, breast cancers, melanomas, neuroblastomas and pancreatic carcinomas. In fact, expression of high affinity binding sites for VIP (comprising the VIP receptor protein) is a marker for these tumor cells. Specific binding of VIP to these cells can be exploited as a marker to locate and identify such tumor cells in vivo.
A variety of radionuclides are known to be useful for radioimaging, including .sup.67 Ga, .sup.99m Tc (hereinafter Tc-99m), .sup.111 In, .sup.123 I, .sup.125 I, .sup.169 Yb or .sup.186 Re. A number of factors must be considered for optimal radioimaging in humans. To maximize the efficiency of detection, a radionuclide that emits gamma energy in the 200 to 200 keV range is preferred. To minimize the absorbed radiation dose to the patient, the physical half-life of the radionuclide must be as short as the imaging procedure will allow. To allow for examinations to be performed on any day and at any time of the day, it is advantageous to have a source of the radionuclide always available at the clinical site.
Methods for radioiodinating VIP analogues at tyrosine residues in the VIP sequence (Tyr.sup.10 or Tyr.sup.22) using .sup.123 I or .sup.125 I are known in the prior art. These radioiodinated species have also been used to assess VIP binding to receptors on tumor cells.
Boissard et al., 1986, Cancer Res. 46: 4406-4413 describe radioiodination of VIP and binding to human colon adenocarcinoma cells.
El Battari et al., 1988, J. Biol. Chem. 263: 17685-17689 describe raioiodination of VIP and binding to human colon adenocarcinoma cells.
Shaffer et al., 1987, Peptides 8: 1101-1106 disclose radioiodination of VIP and binding to human small cell and non-small cell carcinoma cells.
Svoboda et al., 1988, Eur. J. B
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Civitello Edgar R.
Dean Richard T.
Lister-James John
Pearson Daniel A.
Dees Jos,e G.
Diatide, Inc.
Jones Dameron
McDaniels Patricia A.
Noonan Kevin E.
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