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US 8,691,761 B2Granted
Somatostatin receptor 2 antagonists
OwnerJean E. F. Rivier, Judit Erchegyi +2inventors
InventorsJean E. F. Rivier, Judit Erchegyi, Jean Claude Reubi, Helmut R. Maecke
Life of this patent
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Abstract
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.
Claims10
A somatostatin antagonist that binds to SSTR2;
- is not significantly internalized into cells expressing SSTR2, and reduces octreotide-induced internalization of SSTR2, wherein the antagonist is a cyclic somatostatin (SRIF) peptide antagonist comprising the amino acid sequence (cyclo 3-14) Xaa1-Xaa2-D-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15;
- Xaa1 is des-Xaa;
- Xaa2 is Trp(A), Phe(B), Nal or Tyr, wherein A is H, Cl, F, Br, Me, NO2, OMe or N-formyl and B is H, halogen, CH3, NO2 or OCH3;
- D-Xaa3 is D-Cys, D-Pen, D-HCys or another D-isomer α-amino acid having an SH-side chain;
- Xaa4, Xaa5 and Xaa6 are des-Xaa;
- Xaa7 is Aph(Q1), Tyr, ITyr, Ala(thienyl) or Trp(A) where Q1 is Cbm, OH—Cbm, CH3-Cbm, OCH3-Cbm, OEt-Cbm, Cbm-Et(OEt)2 or Hor;
- Xaa8 is D-Trp(A), Trp(A), Tyr, D-Tyr, Phe(B), D-Phe(B), L or D-BzlHis,
- L or D-(DNP)His, L or D-Aph(Cbm);
- Xaa9 is Lys, NαMeLys, hLys, NαMehLys, Orn or NαMeOrn;
- Xaa10 is Thr, Ser or Val;
- Xaa11, Xaa12 and Xaa13 are des-Xaa;
- Xaa14 is Cys, Pen, hCys or another L-isomer α-amino acid having an SH side chain;
- Xaa15 is 2Nal, D-2Nal, Aph(Q2), D-Aph(Q2), (R1)Cha, (R1)D-Cha, (R1)Leu, (R1)D-Leu, Tyr, D-Tyr, Trp, D-Trp or des-Xaa;
- wherein R1 is H or CαMe, and Q2 is Cbm, OH-Cbm, CH3-Cbm, OCH3-Cbm or OEt-Cbm;
- and Xaa15 is optionally amidated or is C-terminated with Gly-OH group.
12 more elements
A kit for the diagnostic radioimaging of cancer, wherein the cells of said cancer have functional somatostatin receptors, comprising:
- (a) a somatostatin antagonist in a suitable container, wherein the somatostatin antagonist is either:
- (i) labeled with at least one radionuclide;
- (ii) unlabeled and provided with at least one radionuclide in a suitable container for labeling;
- or
- (iii) unlabeled and capable of being subsequently labeled with at least one radionuclide;
- and
- (b) instructions for use:
- and wherein;
- the somatostatin antagonist selectively binds to SSTR2:
- cells of said cancer have functional SSTR2 receptors;
- and
- the somatostatin antagonist is a cyclic somatostatin peptide antagonist comprising the amino acid sequence (cyclo 3-14) Xaa1-Xaa2-D-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15,
- Xaa1 is des-Xaa;
- Xaa2 is Trp(A), Phe(B), Nal or Tyr, wherein A is H, Cl, F, Br, Me, NO2, OMe or N-formyl and B is H, halogen, CH3, NO2 or OCH3;
- D-Xaa3 is D-Cys, D-Pen, D-HCys or another D-isomer α-amino acid having an SH-side chain;
- Xaa4, Xaa5 and Xaa6 are des-Xaa;
- Xaa7 is Aph(Q1), Tyr, ITyr, Ala(thienyl) or Trp(A) where Q1 is Cbm, OH-Cbm, CH3-Cbm, OCH3-Cbm, OEt-Cbm, Cbm-Et(OEt)2 or Hor;
- Xaa8 is D-Trp(A), Trp(A), Tyr, D-Tyr, Phe(B), D-Phe(B), L or D-BzlHis, L or D-(DNP)His, L or D-Aph(Cbm);
- Xaa9 is Lys, NαMeLys, hLys, NαMehLys, Orn or NαMeOrn;
- Xaa10 is Thr, Ser or Val;
- Xaa11, Xaa12 and Xaa13 are des-Xaa;
- Xaa14 is Cys, Pen, hCys or another L-isomer α-amino acid having an SH side chain;
- Xaa15 is 2Nal, D-2Nal, Aph(Q2 ), D-Aph(Q2 ), (R1)Cha, (R1)D-Cha, (R1)Leu, (R1)D-Leu, Tyr, D-Tyr, Trp, D-Trp or des-Xaa;
- wherein R1 is H or CαMe, and Q2 is Cbm, OH-Cbm, CH3-Cbm, OCH3-Cbm or OEt-Cbm;
- and Xaa15 is optionally amidated or is C-terminated with Gly-OH group.
22 more elements
A kit for the treatment of cancer, wherein the cells of said cancer have functional somatostatin receptors, comprising
- (a) a somatostatin antagonist in a suitable container, wherein, upon radionuclide labeling of the somatostatin antagonist, the antagonist is present in a therapeutically effective amount for cancer treatment, and wherein the somatostatin antagonist is either:
- (i) labeled with at least one radionuclide,
- (ii) unlabeled, and provided with at least one radionuclide in a suitable container for labeling, or
- (iii) unlabeled, and capable of being subsequently labeled with at least one radionuclide;
- and
- (b) instructions for use;
- and
- wherein:
- the somatostatin antagonist selectively binds to SSTR2:
- cells of said cancer have functional SSTR2 receptors;
- and
- the somatostatin antagonist is a cyclic somatostatin peptide antagonist comprising the amino acid sequence (cyclo 3-14) Xaa1-Xaa2-D-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15,
- Xaa1 is des-Xaa;
- Xaa2 is Trp(A), Phe(B), Nal or Tyr, wherein A is H, Cl, F, Br, Me, NO2, OMe or N-formyl and B is H, halogen, CH3, NO2 or OCH3;
- D-Xaa3 is D-Cys, D-Pen, D-HCys or another D-isomer α-amino acid having an SH-side chain;
- Xaa4, Xaa5 and Xaa6 are des-Xaa;
- Xaa7 is Aph(Q1), Tyr, ITyr, Ala(thienyl) or Trp(A) where Q1 is Cbm, OH-Cbm, CH3-Cbm, OCH3-Cbm, OEt-Cbm, Cbm-Et(OEt)2 or Hor;
- Xaa8 is D-Trp(A), Trp(A), Tyr, D-Tyr, Phe(B), D-Phe(B), L or D-zlHis, L or D-(DNP)His, L or D-Aph(Cbm);
- Xaa9 is Lys, NαMeLys, hLys, NαMehLys, Orn or NαMeOrn;
- Xaa10 is Thr, Ser or Val;
- Xaa11, Xaa12 and Xaa13are des-Xaa;
- Xaa14 is Cys, Pen, hCys or another L-isomer α-amino acid having an SH side chain;
- Xaa15 is 2Nal, D-2Nal, Aph(Q2), D-Aph(Q2), (R1)Cha, (R1)D-Cha, (R1)Leu, (R1)D-Leu, Tyr, D-Tyr, Trp, D-Trp or des-Xaa;
- wherein R1 is H or CαMe, and Q2 is Cbm, OH-Cbm, CH3-Cbm, OCH3-Cbm or OEt-Cbm;
- and Xaa15 is optionally amidated or is C-terminated with Gly-OH group.
22 more elements
A composition for radioimaging or treating tumor cells comprising an effective amount of a radionuclide coupled to a somatostatin antagonist;
- wherein the antagonist selectively binds to SSTR2, is not significantly internalized into cells expressing SSTR2;
- the antagonist reduces octreotide-induced internalization of SSTR2;
- and wherein cells of said cancer have functional SSTR2 receptors;
- the antagonist is a cyclic somatostatin (SRIF) peptide antagonist comprising the amino acid sequence (cyclo 3-14) Xaa1-Xaa2-D-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15,
- Xaa1 is des-Xaa;
- Xaa2 is Trp(A), Phe(B), Nal or Tyr, wherein A is H, Cl, F, Br, Me, NO2, OMe or N-formyl and B is H, halogen, CH3, NO2 or OCH3;
- D-Xaa3 is D-Cys, D-Pen, D-HCys or another D-isomer α-amino acid having an SH-side chain;
- Xaa4, Xaa5 and Xaa6 are des-Xaa;
- Xaa7 is Aph(Q1), Tyr, ITyr, Ala(thienyl) or Trp(A) where Q1 is Cbm, OH-Cbm, CH3-Cbm,
- OCH3-Cbm, OEt-Cbm, Cbm-Et(OEt)2 or Hor;
- Xaa8 is D-Trp(A), Trp(A), Tyr, D-Tyr, Phe(B), D-Phe(B), L or D-BzlHis, L or D-(DNP)His, L or D-Aph(Cbm);
- Xaa9 is Lys, NαMeLys, hLys, NαMehLys, Orn or NαMeOrn;
- Xaa10 is Thr, Ser or Val;
- Xaa11, Xaa12 and Xaa13are des-Xaa;
- Xaa14 is Cys, Pen, hCys or another L-isomer α-amino acid having an SH side chain;
- Xaa15 is 2Nal, D-2Nal, Aph(Q2), D-Aph(Q2), (R1)Cha, (R1)D-Cha, (R1)Leu, (R1)D-Leu, Tyr, D-Tyr, Trp, D-Trp or des-Xaa;
- wherein R1 is H or CαMe, and Q2 is Cbm, OH-Cbm, CH3-Cbm, OCH3-Cbm or OEt-Cbm;
- and Xaa15 is optionally amidated or is C-terminated with Gly-OH group.
15 more elements
A compound for radioimaging or treating tumor cells comprising an effective amount of a radionuclide coupled to a somatostatin antagonist;
- wherein said antagonist binds to SSTR2and is selected from the group consisting of:
- (i) DOTA-pNO2Phe-c[DCys-Tyr-DTrp-Lys-Thr-Cys]-DTyr-NH2;
- (iii) DOTA-pNO2Phe-c[DCys-Tyr-D Aph(Cbm)-Lys-Thr-Cys]-DTyr-NH2;
- (iii) H2N-pNO2Phe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-2Nal-NH2;
- (iv) DOTA-pNO2Phe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-2Nal-NH2;
- (v) H2N-pNO2Phe-c[DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys]-2Nal-NH2;
- (vi) H2N-Cpa-c[DCys-L-Agl(NMe.benzoyl)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (vii) H2N-Cpa-c[DCys-D-Agl(NMe.benzoyl)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (viii) H2N-Cpa-c[DCys-Leu-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (ix) H2N-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (x) Cbm-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (xi) DOTA-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (xii) DOTA-bAla-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (xiii) DOTA-Peg-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (xiv) H2N-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-NH2;
- (xv) H2N-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-Cha-NH2;
- (xvi) H2N-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-Aph(Hor)-NH2;
- (xvii) H2N-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-DAph(Cbm)-NH2;
- (xviii) H2N-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-Aph(Cbm)-NH2;
- (xix) H2N-Cpa-c[DCys-Aph(Cbm)-DTrp-Lys-Thr-Cys]-DAph(Cbm)-GlyOH;
- (xx) H2N-Cpa-c[DCys-Aph(CONH—OCH3)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (xxi) H2N-Cpa-c[DCys-Aph(CONH—OH)-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (xxii) H2N-Cpa-c[DCys-Aph(Cbm)-5F-DTrp-Lys-Thr-Cys]-2Nal-NH2;
- (xxiii) H2N-Cpa-c[DCys-Aph(Cbm)-5F-Trp-Lys-Thr-Cys]-2Nal-NH2;
- (xxiv) H2N-Cpa-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-2Nal-NH2;
- (xxv) DOTA-Cpa-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-2Nal-NH2;
- (xxvi) H2N-Cpa-c[DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys]-2Nal-NH2;
- (xxvii) DOTA-Cpa-c[DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys]-2Nal-NH2;
- (xxviii)DOTA-Cpa-c[DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2;
- and
- (xxix) DOTA-pNO2Phe-c[DCys-ITyr-DTrp-Lys-Thr-Cys]-DTyr-NH2.
28 more elements
Dependencies are inferred from the claim text.