SSTR1-selective analogs

Abstract

Analogs of SRIF which are selective for SSTR1 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR1 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA1,2,5[D-Trp8, IAmp9, Tyr11]-SRIF and counterparts incorporating Cbm at the N-terminus, as well as radioiodinated versions thereof, inhibit the binding of a universal SRIF radioligand to the cloned human receptor SSTR1, but they do not bind with significant affinity to human SSTR2, SSTR3, SSTR4 or SSTR5. By incorporating an iodinated tyrosine in position-2 or in position-11 in these SSTR1-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. The N-terminus accommodates bulky moieties without loss of selectivity, and a carbamoyl moiety or a conjugating agent that will accept a radioactive nuclide or will link to a cytotoxin may be present at the N-terminus.

Description

[0001] This application is a division of U.S. Ser. No. 10 / 099,240, filed Mar. 15, 2002, which claims priority from U.S. Ser. No. 60 / 276,871, filed Mar. 16, 2001, the subject matter of both applications is incorporated herein by reference.[0002] This invention was made with Government support under Grant No. 5R01 DK50124 awarded by the National Institutes of Health. The Government has certain rights in this invention.[0003] This invention is directed to peptides related to somatostatin and to methods for pharmaceutical treatment of mammals using such peptides. More specifically, the invention relates to shortened receptor-selective somatostatin analogs and the inclusion of amino acid substitutions in such analogs and optional modification of the N-terminus that confer thereto receptor-selectivity and / or increased affinity to the receptor, to pharmaceutical compositions containing such peptides, to such peptides complexed with radioactive nuclides or conjugated to cytotoxins, to metho...

AI Technical Summary

Benefits of technology

The patent describes the creation of new peptides that can bind to a specific receptor in the body, called SSTR1. These peptides are more selective and have greater binding strength than previously known. They can be used to locate tumors that express SSTR1 receptors and can also be used as therapeutic agents to treat conditions mediated by SSTR1. The peptides can be labeled with radioactive materials and used for scintigraphy or radionuclide therapy. Overall, these peptides have improved properties for targeting and treating certain tumors.

Problems solved by technology

Interventional treatment to the arterial system, such as angioplasty or bypass surgery, can be damaging to the vessel wall.

However, if cell proliferation and matrix deposition continue, they lead to a pathological condition known as intimal hyperplasia (IH).

Apart from intravascular stents and anticoagulation, which appear effective in limiting restenosis in the short term, no other interventions have been successful in halting the development of IH; however, there is now evidence that SRIF may have an effect upon IH.

Clinical trials using angiopeptin to inhibit IH-causing restenosis, however, have been inconclusive.