The Salk Institute for Biological Studies

Other

University of Bern

Universitât Bern

Piramal Imaging Sa

University Hospital Basel

Universitatsspital Basel

Universitaet Bern

Universitaetsspital Basel

Advanced Accelerator Applications Usa, Inc.

Universitat Bern Verwaltungsdirektion

Jean Claude Reubi

Jean E F Rivier

Judit Erchegyi

Helmut R Maecke

Helmut Robert Maecke

Hans Rink

Klaus-Peter Eisenwiener

Roland Riek

Helmut Maecke

Rosalba Mansi

Mihaela Ginj

Jean EF Rivier

To provide a diagnostic and therapeutic medicament, a bombesin analog peptide antagonist conjugate is provided which has general Formula (I), wherein A is a metal chelator comprising at least one radionuclide metal, B is a spacer linked to N-terminal of C or a covalent bond and C is a bombesin analog peptide antagonist having a sequence as claimed, where further x is an integer from 1 to 3 and n is an integer from 1 to 6.[A-(B)]&#x2014;C&#x2003;&#x2003;(I)

Bombesin analog peptide antagonist conjugates

The invention is directed to somatostatin analogs which are receptor antagonists of the somatostatin receptor, including receptor-selective antagonists, especially sst2-selective antagonists. Related compounds and compositions are included, including antagonists complexed with or conjugated to radioactive nuclides. The antagonists of the invention are useful in diagnosing and treating neoplastic and non-neoplastic mammalian diseases; such methods, and kits, are encompassed.

Somatostatin receptor 2 antagonists

SRIF peptide antagonists, which are selective for SSTR2 in contrast to the other cloned SRIF receptors and which bind with high affinity to the cloned human receptor SSTR2 but do not activate the receptor, have many useful functions. Because they do not bind with significant affinity to SSTR1, SSTR3, SSTR4 or SSTR5, their administration avoids potential undesirable side effects. By incorporating radioiodine or the like in these SSTR2-selective SRIF antagonists, a labeled compound useful in drug-screening methods is provided. Alternatively, for use in therapy, highly radioactive moieties can be N-terminally coupled, complexed or chelated thereto. Because they block the receptor function, they can be used therapeutically to block certain physiological effects which SSTR2 mediates.

Receptor(SSTR2)-selective somatostatin antagonists

SRIF peptide antagonists, which are selective for SSTR2 in contrast to the other cloned SRIF receptors and which bind with high affinity to the cloned human receptor SSTR2 but do not activate the receptor, have many useful functions. Because they do not bind with significant affinity to SSTR1, SSTR3, SSTR4 or SSTR5, their administration avoids potential undesirable side effects. Because they block the receptor function, they can be used therapeutically to block certain physiological effects which SSTR2 mediates. By incorporating radioiodine or the like in these SSTR2-selective SRIF antagonists, a labeled compound useful in drug-screening methods is provided. Alternatively, for use in therapy, highly radioactive moieties can be N-terminally coupled, complexed or chelated thereto.

In one embodiment, a method for treating a cancerous disease is provided which includes characterizing a disease by an overexpression of one or more somatostatin receptors, and exposing the one or more somatostatin receptors to a pharmaceutical composition comprising a somatostatin analogue which binds to the one or more somatostatin receptors. In one example, the somatostatin analogue may have the general formula: wherein Z is optionally present or absent and when present is selected from the group consisting of DOTA-based chelators, DTPA-based chelators, NOTA-based chelators, carbonyl compounds, hydrazino nicotinamide, N4-chelators, desferrioxamine, NS-chelators, tyrosine for halogenation, a fluorescent dye, and biotin; L is optionally present or absent and when present is a linker molecule; X1 is a symmetric or asymmetric diamino acid containing 3 or 4 consecutive carbon atoms; X2 is a positively charged natural or unnatural amino acid, an arginine mimic, citrulline, or a neutral amino acid; X3 is phenylalanine, Ala-[3-(2-thienyl)], &#x3b1;-naphthylalanine, or &#x3b2;-naphthylalanine; X4 is an aromatic amino acid; X5 is threonine or serine; and X6 is phenylalanine, Ala-[3-(2-thienyl)], &#x3b1;-naphthylalanine, or &#x3b2;-naphthylalanine.

Treatment process using somatostatin analogues

Analogs of SRIF which are selective for SSTR4 in contrast to the other cloned SRIF receptors are useful in determining tissue and cellular expression of the receptor SSTR4 and its biological role in regulating tumor growth. SRIF analog peptides, such as des-AA[Ala]-SRIF; des-AA[Aph]-SRIF, des-AA[Aph]Cbm-SRIF; des-AA[Tyr,Ala]-Cbm-SRIF, and des-AA[Tyr,CMe-L-2Nal]-SRIF, and counterparts incorporating D-Cysand/or D-Trpand/or Ala, bind with high affinity to the cloned human receptor SSTR4 and activate the receptor, but they do not bind with significant affinity to human SSTR1, SSTR2, SSTR3 or SSTR5. By incorporating an iodinated tyrosine in position-2 in these SSTR4-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. Alternatively, for use in therapy, cytotoxins or highly radioactive elements can be N-terminally coupled or complexed thereto.

Receptor(SSTR4)-selective somatostatin analogs

In one embodiment, a composition of somatostatin analogues having the general formula: is provided wherein Z may be absent or present and when present is selected from DOTA- and DTPA-based chelators, NOTA-based chelators, carbonyl compounds, hydrazino nicotinamide, N-chelators, desferrioxamine, NS-chelators, optionally complexed or labeled with a radioisotope, tyrosine for halogenation, a fluorescent dye, or biotin. The composition further provides that L may or may not be present and when present is a linker molecule, X1 is glutamic acid or a symmetric or asymmetric diamino acid containing 3 or 4 consecutive C atoms, X2 is a positively charged natural or unnatural amino acid, an arginine mimic, citrulline, or a neutral amino acid, X3 is phenylalanine, Ala-[3-(2-thienyl)], &#x3b1;-naphthylalanine, or &#x3b2;-naphthylalanine, X4 is an aromatic amino acid, X5 is threonine or serine, and X6 is phenylalanine, Ala-[3-(2-thienyl)], &#x3b1;-naphthylalanine, or &#x3b2;-naphthylalanine.

Compositions of somatostatin analogues

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-AA[D-Trp, NMeIAmp, Tyr]-SRIF and counterparts incorporating Cbm at the N-terminus and/or NSer, 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.

SSTR1-selective analogs

Analogs of SRIF which are selective for SSTR3 in contrast to the other cloned SRIF receptors. These analogs are useful in determining the tissue and cellular expression of the receptor SSTR3 and its biological role in the endocrine, exocrine and nervous system, as well as in regulating tumor growth. SRIF analog peptides, such as des-AA &lsqb;N MeD-Agl (2-naphthoyl) &rsqb;-SRIF and counterparts incorporating D-Cys and/or Tyr , inhibit the binding of a universal SRIF radioligand to the cloned human receptor SSTR3, but they do not bind with significant affinity to human SSTR1, SSTR2, SSTR4 or SSTR5. By incorporating an iodinated tyrosine in position-2 or in position-11 in these SSTR3-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. Because the N-terminus accommodates bulky moieties without loss of selectivity, a cytotoxin or a complexing agent to accept a radioactive nuclide may be present at the N-terminus. Alternatively, the binding affinity may be improved without detriment to the selectivity by adding a carbamoyl moiety at the N-terminus and/or replacing Phe with Aph or substituted Aph.

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Berne, Switzerland

Jean Claude Reubi