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

[0013] Certain modifications have now been discovered which are effective to create peptide analogs of SRIF that are more selective for SSTR1 in contrast to the other cloned human SRIF receptors and / or have greater binding strength than those disclosed in the '499 patent. The basic original modification substituted an optionally alkylated amino-methyl Phe into the 9-position of a SRIF analog that otherwise binds to SSTR1, and it has now been found that the selectivity and / or the binding strength of such analogs can be enhanced by modifying the N-terminus and / or the residue in the 11-position and also by Nαmethylating the alkylated 9-position residue. As a result, peptides have now been created that bind strongly and selectively to cloned SSTR1. Analogs of these peptides can be iodinated or otherwise radiolabeled while not only retaining their desirable biological properties, but certain iodinated Tyr-containing analogs show further increased binding strength. These novel peptides 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 certain pharmacological functions without the accompanying side effects heretofore characteristic of administering SRIF. These long-acting SRIF analog peptides, when radiolabeled, can be used in scintigraphy in order to locate, i.e. localize, tumors expressing these receptors, either in vitro or in vivo; other labeling as well known in this art, e.g. fluorescent, can alternatively be used. With an appropriate chelated radioligand, these analogs can be turned into radiopharmaceuticals which are suitable for radionuclide therapy in treatment of such tumors; alternatively, they can be covalently joined to a cytotoxic moiety using an appropriate covalent conjugating agent, e.g. glutaraldehyde or one which binds via a disulfide linkage.

[0015] These SRIF analogs not only selectively bind to SSTR1, but they bind thereto with high affinity. By selectively binding is meant that they exhibit a KD or an IC50 with SSTR1 which is at least about one-tenth or less of that with respect to at least 3 of the other five SRIF receptors. The greater the differential, the more preferred it is. It is believed the four residues located centrally within the ring structure, i.e. at positions 7-10 of the native molecule, are primarily responsible for receptor binding and biological activity; however, as herein shown both the N-terminus and the 11-position residue, along with these four residues, can have a significant effect thereupon. These SRIF analogs can also be readily labeled and effectively used in drug screening methods and in radionuclide and cytotoxic therapy. For example, these analogs are useful in localizing such receptor in the body and in diagnosing the locations of tumors, particularly prostate cancers, sarcomas and neuroendocrine tumors. As radionuclide therapeutic agents, they are considered to be particularly useful in destroying tumors expressing SSTR1 receptors.

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.