WO2006114324A1 - Composes comprenant des peptides cyclises se liant aux recepteurs de la somatostatine - Google Patents

Composes comprenant des peptides cyclises se liant aux recepteurs de la somatostatine Download PDF

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Publication number
WO2006114324A1
WO2006114324A1 PCT/EP2006/003994 EP2006003994W WO2006114324A1 WO 2006114324 A1 WO2006114324 A1 WO 2006114324A1 EP 2006003994 W EP2006003994 W EP 2006003994W WO 2006114324 A1 WO2006114324 A1 WO 2006114324A1
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thr
phe
lys
amino acid
cys
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PCT/EP2006/003994
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English (en)
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Ananth Srinivasan
Leonard G. Luyt
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Schering Ag
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Priority claimed from EP05009361A external-priority patent/EP1717247A1/fr
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Publication of WO2006114324A1 publication Critical patent/WO2006114324A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • C07K14/6555—Somatostatins at least 1 amino acid in D-form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention concerns compounds comprising novel cyclized peptides with increased selectivity towards binding to the somatostatin receptor 5 (SSTR 5 ) its production and use in the diagnosis and treatment of somatostatin-responsive diseases or diseases characterized by up-regulation of somatostatin receptors, in particular proliferative diseases.
  • SSTR 5 somatostatin receptor 5
  • Cancer is the leading cause of morbidity and mortality in developed countries. For example, approximately 1.4 million new cases and more than 0.5 million cancer deaths were reported in the U.S. in 1996. In 1995, the total annual cost of cancer care in the U.S., including direct and indirect costs, was estimated to be more than $ 96 billion. A great need exists for improved diagnostic and therapeutic tools to allow early detection and safe, cost-effective treatment of cancer.
  • SSTRs somatostatin receptors
  • neurons of nervous system tumors such as astrocytomas und meningeomas display SSTRs on their surfaces.
  • SSTR expression has also been found in human breast tu- mors, malignant lymphomas and renal cell carcinomas.
  • some prostate tumors may be characterized by SSTR expression.
  • SSTRi-s SSTR subtypes
  • Octreotide (Sandostatin ® ) binds to SSTR 2 , SSTR 3 and SSTR 5 and is marketed in the U.S. and Europe for treatment of acromegaly and control of symptoms associated with vipomas and metastatic 49.393 carcinoid tumors.
  • Lanreotide (SomatulineTM) has a SSTR subtype profile similar to that of Octreotide and is approved in several European countries for the same indications as Octreotide.
  • a radiolabelled form of Octreotide, m In-pentetreotide ( i ⁇ In-DTP A-D-Phe 1 -Octreotide or " 'In-OctreoScan 18 ') has been approved in the U.S. and in Europe for imaging neuroendo- crine tumors. Recently, the U.S. FDA approved a new radio pharmaceutical, NeoTectTM, a 99m Tc-labelled form of the novel somatostatin analogue depreotide (P829), for sale as an imaging agent. Bloom, et al. (1999), Chest. 115: 224-232, describes the use of 99m Tc-depreotide for evaluation of solitary pulmonary nodules of the lung. 99m Tc-labelled depreotide has also been studied as an imaging agent for other somatostatin-receptor bearing tumors. Depreotide is described in WO 95/00553 and WO 95/33497.
  • somatostatin analogues do, thus, not exhibit a significant selectivity for either SSTR 2 or SSTR 5 and only a limited number of ligands have been found to impart preferential binding to one of the somatostatin subtypes.
  • agonists for each of the five subtypes were reported (Rohrer, S.P. et al. (1998) Science 282: 737-740).
  • a back- bone-cyclic somatostatin analogue has also been reported to have some SSTR 5 selectivity (Gilon, C. (1998) J. Med. Chem. 41: 919-929).
  • the present inventors have now surprisingly identified new constrained backbone-cyclized peptides which improved binding to somatostatin receptor subtype 5 and which simultaneously show a de- creased somatostatin subtype 2 binding activity, i.e. which have an increased specificity to SSTR 5 , if compared to the somatostatin receptor agonist ReP2045.
  • the novel compounds are therefore somatostatin analgoues with an improved selectivity towards somatostatin receptor subtype 5.
  • X 3 is selected from the group consisting of diphenyl-Ala, (I)NaI, (2)Nal, (4)Pal, Phe(4-F),
  • X 4 is selected from the group consisting of ⁇ Ala(cyclopropyl), diaminopropanoic acid
  • X 5 is an amino acid containing a side-chain, capable of forming a direct or indirect bond to a metal chelating residue, a polypeptide, a drug or a dye; a natural amino acid; or an unnatural amino acid, X 6 an amino acid containing a side-chain, capable of forming a direct or indirect bond to a metal chelating residue, a therapeutic or a dye; a natural amino acid; or an unnatural amino acid under the proviso that X 5 is cysteine, homo-cystein or methionine, when X 3 has the meaning Tyr and X 4 has the meaning Thr.
  • the absolute affinity to SSTR5 is important for increasing the targeting of SSTR5 and on the other hand the relative ratios of affinity towards SSTR2 versus affinity towards SSTR5.
  • the cyclized peptides of the present invention show an IC 50 in nM towards SSTR5 of less than 50, preferably less than 45, more preferably of less than 40, less than 35, less than 30, less than 25, less than 20, less than 15, less than 10.
  • the IC 50 in nM towards SSTR2 is larger than 0.1, larger than 0.2, larger than 0.4, larger than 0.5, larger than 0.6, larger than 0.7, larger than 0.8, larger than 0.9, larger than 1.0, larger than 1.5, larger than 2.0, larger than 2.5, larger than 3.0, larger than 3.5, larger than 4.0 and larger than 5.0.
  • the ratio of SSTR2 to SSTR5 affinity in % is 0.014 (ratio 2/5 in %) for ReP2045, i.e. the binding affinity of ReP2045 to SSTR5 is only 0.014% of its binding affinity to SSTR2.
  • the cyclized peptides of the present invention show at least a 5-fold improvement of that ratio.
  • the ratio of the IC50 of SSTR2/SSTR5 in % is at least 0.2, 0,3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, .1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100, i.e.
  • the cyclized peptides have a binding affinity to SSTR5, which is equal to SSTR2.
  • the binding affinity to SSTR5 is higher than to SSTR2, e.g. preferably 150%, 200%, 250%, 300%, or 350%.
  • At least one of the amino acids of X 3 , X 4 , X 5 , or X 6 preferentially at least one of the amino acid of X 5 or X 6 comprise at least one halogen moiety, preferably attached to a side chain.
  • X 3 is selected from the group consisting of Tyr and (I)NaI. It is further preferred that X 4 is selected from the group consisting of Thr and VaI and it is particular preferred that X 3 has the meaning Tyr or (I)NaI and X 4 has the meaning Thr and VaI.
  • reactive groups are thio, hydroxy, carboxy or amino residues.
  • the side-chain comprises at least one thio group and, therefore, particular preferred amino acids cysteine, homo-cysteine and methionine and in particular methionine.
  • a further preferred amino acid is Lys(GlyMeDOTA).
  • direct bond in this context and as used throughout the specification means a covalent bond to a further residue, i.e. a direct bond to a metal chelating residue, a polypeptide, a drug or a dye
  • indirect bond means that one or more additional chemical residues, which are attached via covalent or non-covalent bonds are located between the amino acid X 5 and/or X 6 and the metal chelating residue, the polypeptide, the drug or the dye.
  • These one or more additional chemical residues can also be termed "spacer”.
  • a spacer can, e.g. provide a spatial separation between the constrained backbone cyclized peptides of the present invention and the further functionality of the compound which is coupled to the compound through the amino acid containing a side-chain, capable of forming a direct or indirect bond.
  • X 5 and/or X 6 can mean any naturally occurring amino acids. These amino acids may be referenced herein in abbreviated form, using standard one-letter or three-letter codes (which can be found, for example, in G. Zubay, Biochemistry (2d. ed.), 1988 (MacMillen Publishing: New York) p.33).
  • the following amino acids and amino acid analogues are intended to be represented by the following abbreviations: Hey is homocysteine; Hhc is homohomocysteine (3-mercaptopropylglycine); Pen is penicillamine; Aib is aminoisobutyric acid; NaI is 2-naphthylalanine; Aca is 6- aminocaproic acid; Ain is 2-aminoindan-2-carboxylic acid; HIy is homolysine; Achxa is 4- amino-cyclohexylalanine; Amf is 4-aminomethyl-phenylalanine; Aec is S-(2- aminoethyl)cysteine; Ape is S-(3-aminopropyl) cysteine; Aes is O-(2-aminoethyl)serine; Aps is O-(3-aminopropyl)serine; Abu is 2-aminobutyric acid; Nva is nor
  • (I)NaI is 1 -Naphtylalanine, also written as 3 -(1-Naphtyl)- AIa-OH, as disclosed also in Advanced ChemTech, Handbook of Combinatorial & Peptide Chemistry, 2003-2004.
  • (2)Nal is 2-Naphtylalanine, also written as 3 -(2-Naphtyl)- AIa-OH as disclosed also in Advanced ChemTech, Handbook of Combinatorial & Peptide Chemistry, 2003-2004.
  • (4)Pal is 4-Pyridylalanine, also written as 3 -(4-Pyridyl)- AIa-OH as disclosed also in Ad- vanced ChemTech, Handbook of Combinatorial & Peptide Chemistry, 2003-2004.
  • a "substituted derivative" of an amino acid includes such substitutions as amino, hydroxyl, N-alkyl wherein alkyl represents Ci to C 4 alkyl, N- aryl, N-acyl, O-alkyl wherein alkyl represents Ci to C 4 alkyl, O-aryl, O-acyl, S-alkyl wherein alkyl represents Ci to C 4 alkyl, S-aryl.
  • the term When applied to amino acids that contain a side chain aromatic ring, the term also encompasses o-, m-, and p-substitutions including but not limited to o-amino, m-amino, p-amino, amino, o-hydroxyl, m-hydroxyl, p-hydroxyl, and the like.
  • Particularly preferred natural or unnatural amino acids which can constitute X 5 or X 6 , and which preferably constitute X 6 are alanine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, proline, arginine, serine, threonine, tryptophane, valine, tyrosine, tert-butyl glycine, N-methyl phenylalanine (NMe)Phe, Hey, Hhc, Pen, Aib, NaI, Aca, Ain, HIy, Achxa, Amf, Aec, Ape, Aes, Aps, Abu, Nva, FD, WD, YD, Cpa, Thp, D-NaI, Dpg, NIe, (I)NaI, (2)Nal, (N-CH 3 )CyS, (N-CH 3
  • NMe amino acids
  • Phe and Tpi amino acids
  • An increased binding to SSTR 5 has been observed when X 6 is selected from the group consisting of (NMe)Phe, Phe and Tpi.
  • X 5 is selected from the group consisting of cysteine, homo-cysteine, methionine and Lys(GlyMeDOTA).
  • the metal chelating residue which is connected through a direct or indirect bond to either the amino acid side-chain of X 5 or X 6 , preferentially to the amino acid side chain of X 5 , is selected from the group consisting of:
  • V is H or a CO link to X 5 or X 6
  • R 3 is H or covalent link to X 5 or X 6 ;
  • each R 4 is independently H, Ci to C 4 alkyl, or aryl and one R 4 is linked to X 5 or X 6 ;
  • each R 5 is independently H, Ci to C 4 alkyl, or aryl and one R 5 is cova- lently linked to X 5 or X 6 ;
  • n'" is an integer that is 2 or 3 and where each R is independently H, Ci to C 4 alkyl, or aryl and one R 6 is covalently linked to X 5 or X 6 ;
  • a 2 is H, HOOC-, H 2 NOC-, -NHOC-, -OOC-, R 2 'NOC-, X 2 -NH0C-, X 2 -
  • B 2 is H, SH, -NHR 10 , -N(R 10 )-, X 2 -NR 10 - or R 9 ;
  • Z 2 is H or R 10 ;
  • X 2 is SH, -NHR 10 , -N(R 10 )-, X 2 -NR 10 - or R 7 ;
  • R 8 , R 9 and R 10 are independently H, straight chain CpC 8 alkyl, e.g.
  • n is O, 1 or 2;
  • R 11 is CpC 4 alkyl, an amino acid, or a peptide comprising 2 to about 10 amino acids; and: (1) where B 2 is -NHR 10 , X-NR 10 - or -N(R 10 )-, X 2 is SH and n" is 1 or 2; (2) where X 2 is -NHR 10 , X 2 -NR 10 -, or -N(R 10 )-, B 2 is SH and n" is 1 or 2; (3) where B 2 is H or R9, A 2 is HOOC-, H 2 NOC-, X-NHOC-, X-OOC-, -NHOC-, or -00C-,
  • X 2 is SH and n" is O or 1; (4) where A 2 is H or R 9 , then where B 2 is SH, X 2 is - NHR 10 , X 2 -NR 10 -, or -N(R 10 )- and where X 2 is SH, B 2 is -NHR 14 , X 2 -NR 10 - or - N(R 10 ) and n" is 1 or 2; (5) where X 2 is H or R 10 , A 2 is HOOC-, H 2 NOC-, - NHOC-, -00C-, X 2 -NHOC- or X 2 -00C- and B 2 is SH; and (6) where Z 2 is mmeetthhyyll,, XX 22 iiss mmeetthhyyll,, AA 22 iiss HHO0O0CC-, H 2 NOC-, -NHOC-, -OOC-, X 2 -NHOC- or
  • a particularly preferred chelator which can be directly or indirectly bound to a cyclized peptide of the present invention is a substance according to formula (X)
  • Xaa is an L- ⁇ -amino acid
  • Zaa is an ⁇ -amino acid, an ⁇ -amino acid amide, an aminoethylether, a ⁇ -aminol, or a peptide containing from two to ten ⁇ -amino acids, said peptide having a carboxyl terminal ⁇ -amino acid, ⁇ -amino acid amide, aminoethylether, or ⁇ -aminol
  • A is the amino or carboxyl group of the amino acid, or a protected amino or carboxyl group.
  • this metal chela- tor is bound via the amino or carboxyl group to the cyclized peptides of the present invention. Homologs of ⁇ -Dap may also be employed in the compounds of the present invention.
  • Suitable L- ⁇ -amino acids for substitution as Xaa in the preferred chelators of the invention include naturally occurring amino acids such as asparagine, glutamine, threonine, serine, ar- ginine, histidine, lysine, ornithine, phenylalanine, tyrosine, and, in addition, synthetic amino acids containing hydrophilic substituents.
  • Exemplary synthetic amino acids include, without limitation, diaminopropionic acid; diaminobutyric acid; substituted tyrosines such as haloty- rosine; hydroxyltyrosine; aminotyrosine; substituted phenylalanines such as o-, m- or p- halophenylalanine; o-, m- or p-aminophenylalanine, wherein the amino substitutent may be a primary, secondary, or tertiary amine; o-, m- or p-hydroxylphenylalanine; o-, m- or p-O- alkylphenyalanine wherein alkyl represents Ci to C 4 alkyl; o-, m- or p-O-acylphenylalanine; o-, m- or p-S-alkylphenylalanine wherein alkyl represents Ci to C 4 alkyl; and the like.
  • Xaa is an L- ⁇ -amino acid such as serine, diaminobutyric acid, arginine, histidine, tyrosine, or a substituted phenylalanine. More preferably, Xaa is an aromatic an L- ⁇ -amino acid such as tyrosine, a substituted tyrosine residue such as iodotyrosine, bromotyrosine, chlorotyrosine, O-alkyl -tyrosine where alkyl represents Ci to C 8 alkyl, hydroxyltyrosine, aminotyrosine, and the like, or a substituted phenylalanine residue.
  • substituted phenylalanine residues include 4-fluorophenylalanine, 4- chlorophenylalanine, 4-bromophenylalanine, 4-iodophenylalanine, 4-nitrophenylalanine, 4- aminophenylalanine, N 4 -R 12 -4-aminophenyl alanine, N 4 -R 12 , N 4 -R 13 -4-aminophenylalanine, or 3- R 13 -4-aminophenylalanine where R 12 is Ci to C 4 alkyl and R 13 is selected from the group consisting of H, Ci to C 4 alkyl amino, hydroxyl, NH-alkyl wherein alkyl represents Ci to C 4 alkyl, NH-acyl, O-alkyl wherein alkyl represents Ci to C 4 alkyl, O-acyl, S-alkyl wherein alkyl represents Ci to C 4 alkyl, SO-alkyl and SO 2 -alkyl wherein al
  • R 14 and R 15 are each independently H, a straight chain Ci to C 4 alkyl group, a branched chain Ci to C 4 alkyl group, or an aryl group and Hal is F, Cl , Br or I.
  • the carboxyl terminal amino acid of the chelators may be in carboxylic acid form or in amidated form, or alternatively, in the form of a .beta.-aminol.
  • the chelating moieties mentioned above and in particular the preferred peptide based chelating moieties can optionally comprise one or more protected side-chain residues.
  • the side- chains are protected during the synthesis of the compound comprising a cyclized peptide and a metal chelating residue to avoid coupling and/or derivatisation of side-chain functional groups.
  • the preferred chelating moieties optionally comprise one or more protected side-chain residues, if required.
  • the side chain residue of X 5 and/or X 6 may be linked to a metal chelator.
  • a metal chelator Preferably through a side chain nitrogen, sulfur, or oxygen atom.
  • linkage may be direct or indirect through intervening atoms or amino acid residues.
  • the linkage is through -CH 2 CO-.
  • Such linkages may be accomplished via the alkylation of these atoms with moieties containing reactive electro- philes such as alkyl halides. These atoms may also be reacted with chelators containing isocy- anates, isothiocyanates, or activated carboxylic esters.
  • An appropriately protected X 5 and/or X 6 residue may also be linked to a metal chelator through a side chain carbon by forming a Wittig or Emmons-Horner reagent on the side chain and reacting this with an aldehydo func- tionality on an appropriately protected chelator.
  • the resulting double bond linkage can be left as is or subsequently reduced to yield saturated hydrocarbon linkage.
  • a wide variety of metals which can be employed in radiotherapeu- tic or radiodiagnostic approaches are known in the art and comprise without limitation 186 Re, 188 ⁇ R>e, 212 B D i-, 213r B>i-, 90- Yw-, 153 S ⁇ -m, 47 ⁇ S.c, (,I n Ga, Mm ⁇ Tc, 99m ⁇ Tc, (,I n Cu, l l l ⁇ In, 166 ⁇ H ⁇ o, 223 D Ra, and j 22 5 A . c.
  • the compound of the present invention (with or without a metal chelator attached) can also be labelled with covalently coupled radioisotopes, including halogens and in particular 18 F, 125 I, 131 I, 123 I and 211 At.
  • radioisotopes are coupled through a covalent bond to the compounds of the present invention.
  • the radioisotope can be coupled to any moiety within the compound, which is capable of forming a bond to the respective radioisotope. It is, however, preferred that such compounds are coupled to amino acids.
  • the amino acid can be part of the amino acids forming the constrained backbone cyclized peptides or can be one of the to further groups which are coupled to X 5 and/or X 6 .
  • a particular pre- ferred amino acid for the coupling of radioisotopes is tyrosine.
  • a polypeptide chain e.g. a metal chelating polypeptide, attached to either X 5 and/or X 6 is modified by the introduction of 18 F, 125 I, 131 I, 123 I and/or 21 1 At.
  • X 3 , X 4 , X 5 and X 6 have the preferred meaning as indicated above, i.e. cyclo[lNal-DTrp-Lys-Thr-Met-(NMe)Phe]; cyclo[Trp-DTrp-Lys- Thr-Met-(NMe)Phe]; cyclo[lNal-DTrp-Lys-Val-Met-(NMe)Phe]; cyclo[Phe(4-F)-DTrp-Lys- Thr-Met-(NMe)Phe]; cyclo[Tyr-DT ⁇ -Lys-Val-Met-(NMe)Phe]; cyclo[lNal-DTr ⁇ -Lys-Thr- Lys(GlyMeDOT A)-(NMe)Phe] ; cyclo[Tyr-DT ⁇ -Lys-Thr-Met-(NMe)Phe] ; cyclo[2Nal-DTrp-L
  • the metal chelating residue has the preferred meanings as outlined above under a) through k) and even more preferred that the metal chelating moiety has the meaning - ⁇ Dap-Xaa-Cys-Zaa-A, wherein Xaa, Zaa and A have the meaning as outlined above.
  • the compounds of the invention may also be complexed with non-radioactive metals such as rhenium, using methods similar to those set forth below.
  • Compounds of the invention complexed to metals can be formed according to known methods. For example, a salt of 98m Tc pertechnetate, 188 Re perrhenate or 186 Re perenate may be reacted with a compound in the presence of a reducing agent such as dithionite ions, stannous ions or ferrous ions.
  • a reducing agent such as dithionite ions, stannous ions or ferrous ions.
  • a particu- lar preferred reducing agent is stannous chloride.
  • complexes and chelats may be formed by ligand exchange, wherein the compound of the invention is reacted with the preformed labile complex of 99m Tc, 188 Re or 186 Re and another compound known as a transfer ligand.
  • any transfer ligand may be used, for example, tartrate, citrate, gluconate, glucoheptonate, manitole, and the like.
  • Exemplary methods for complexes and the com- pounds of the invention with 99m Tc and 188 Re are set forth in example 4.
  • an appropriate quantity of a compound of the invention is introduced into a vial containing a reducing agent, such as stannous chloride, in an amount sufficient to label the agent with 99m Tc, 188 Re or 186 Re.
  • a reducing agent such as stannous chloride
  • more reducing agent is required to effect labelling with 188 Re or 186 Re than is required to effect labelling with 99m Tc.
  • cytostatic or cytotoxic drugs have been successfully employed in the therapy of various tumor diseases and are, thus, particularly preferred: ofacediasulfone, aclarubicine, ambazone, aminoglutethimide, L- asparaginase, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, carpecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flav
  • the compound comprising the cyclized peptide fur- ther comprises a polypeptide which is either linked directly or indirectly through X 5 and/or X 6 , preferably through X 5 to the cyclized peptide.
  • polypeptide is used to refer to polyamino acids with two or more amino acid residues and, thus, includes peptides, a term which is often used to refer to polyamino acids with two to 100 amino acids and proteins, a term which is often used to refer to polyamino acids with more than 100 amino acids.
  • a poly- peptide component can comprise naturally and non-naturally occurring amino acids, in particular alanine, asparagine, cysteine, asparagine, aspartic acid, glutamine, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, proline, arginine, serine, threonine, tryptophane, valine, tyrosine, tert-butyl glycine, N-methyl phenylalanine, lysine(GlyMeDOTA), Hey, Hhc, Pen, Aib, NaI, Aca, Ain, HIy, Achxa, Amf, Aec, Ape, Aes, Aps, Abu, Nva, FD, WD, YD, Cpa, Thp, D-NaI, Dpg, Dab, NIe, (N-CH 3 )CyS, Om, (
  • antibody comprises without limitation fully human, humanized, chimeric and xenogenic antibodies.
  • the binding fragment of an antibody is preferably an antibody binding domain fragment, e.g. Fv, Fab, Fab', F(ab') 2 , Fabc, Facb.
  • single chain antibody comprises, e.g. single chain Fvs, (scFvs) and diabodies.
  • the compound of the present invention can comprise a dye.
  • a dye in the context of a somatostatin receptor specific binding component, i.e. the cyclized peptide of the present invention can, for example, allow to label tumor cells in vivo and, thus, facilitate the determination of the perimeter of a tumour during a surgical procedure or can be used in imaging techniques employing light of various wave lengths like, e.g. laser imaging.
  • the term "dye" within the meaning of the present invention encompasses substances which are capable of adsorbing light in the visible or invisible light spectrum and which are preferably capable to emit light in the visible or invisible spectrum.
  • Preferred dyes are fluorescent dyes.
  • a further aspect of the invention is a pharmaceutical composition, comprising a compound of the present invention further pharmaceutically acceptable materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, buffers, preservatives, carriers and/or excipients.
  • the pharmaceutical composition is supplied in the form of a pyrogen-free parenterally acceptable pharmaceutical form, which may be an aqueous solution or a lyophilizate for the reconstitution prior to administration.
  • the preparation of such a pharmaceutical composition having due regard to pH, isotonicity, stability and the like is within the skill in the art.
  • the pharmaceutical composition of the invention may include pharmaceutically acceptable diluents, such as, for example, sodium chloride injection and Ringer's injection.
  • the composition may be administered in autologous serum or plasma. Supplementary active compounds may also be co-administered with the compounds of the present invention in accordance with the invention.
  • compositions of the invention may optionally contain a stabilizer such as gentisic acid as set forth in U.S. 4,323,000; US 4,233,284; US 4,497,744; US 5,384,113 and/or ascorbic acid as disclosed in US 5,393,512 and US 5,011,676, in WO 97/28181 and in WO 98/33531.
  • a stabilizer such as gentisic acid as set forth in U.S. 4,323,000; US 4,233,284; US 4,497,744; US 5,384,113 and/or ascorbic acid as disclosed in US 5,393,512 and US 5,011,676, in WO 97/28181 and in WO 98/33531.
  • hydroquinone stabilizers such as so disclosed in US 4,229,427 may be added to the compounds of the invention.
  • the kit comprises a compound wherein X 3 , X 4 , X 5 and X 6 has the preferred meaning as indicated above in a) through n) and the metal chelating residue is one of the preferred metal chelating residues as indicated above in a) through k) or even more preferred the metal chelating residue according to formula (X)- ⁇ Dap-Xaa-Cys-Zaa-A, wherein Xaa, Zaa and A have the meaning as outlined above. It is even more preferred that the metal chelator according to formula (X) has the specific structure as indicated in a) to s). It is particular preferred that the reducing agents are chosen to facilitate labelling with 186 Re, 188 Re and m Tc.
  • Stabilizers such as gentisic acid and/or ascorbic acid or any of the stabilizers described above may also be included in kits intended for 188 Re or 186 Re radiolabelling.
  • An appropriate amount of a transfer ligand as described above can also be included in the kit.
  • the kit may also contain conventional pharmaceutical adjunct materials such as, for example, pharmaceutical ac- ceptable salts to adjust the osmotic pressure, buffers, preservatives, additional vials and the like.
  • the kit may also contain instructions for radio labelling.
  • the components of the kit may be in liquid, frozen or dry form. In a preferred embodiment, the kit components are provided in lyophilized form.
  • the kit of the invention may also be embodied in forms suitable for the diagnostic imaging or as a therapeutic agent using a radioisotope of a halogene, including 18 F, 211 At, 125 I, 131 I and preferably 123 I.
  • the kit comprises a sealed vial containing a predetermined quantity of a compound of the invention which is capable of being radiolabeled with a halo- gene isotope, preferably with 123 I.
  • a complex of ⁇ -emitting radionuclides such as 99m Tc and a compound of the invention are used to diagnose in SSTR-expressing tumors and subsequently a complex of a ⁇ -emitting radionuclide such as 188 Re or 186 Re and a compound of the present invention is used to treat the tumor.
  • a dye like, for example polymethine dyes in particular dicarbocyanine, tricarbocyanine, indotricarbocyanine, merocyanine, styryl, squarilium and oxanol dyes and rhodamine dyesphenoxazine or phe- nothiazin dyes can be used in the diagnosis of diseases followed by therapy with, e.g. a complex ⁇ -emitting radionucleotide or with a compound comprising a cyclized peptide and a cytostatic or cytotoxic drug.
  • Particular preferred dyes are cyanine dyes like dicarbocyanine, tricarbocyanine, indotricarbocyanine dyes.
  • 99m Tc-labeled compounds of the invention are administered in a single unit injectable dose.
  • the compounds, in partial- lar the 99m Tc-labeled compounds of the invention may be administered intravenously in any conventional medium for intravenous injection such medium comprise an aqueous saline medium or blood plasma comprising medium.
  • the unit dose to be administered has a radioactivity of about 0.01 mCi to about 100 mCi, preferably 1 mCi to 50 mCi.
  • the solution to be injected at unit dosage is from about 0.01 ml to about 10 ml.
  • imaging in vivo can take place in a matter of a few minutes. However, imaging can take place, if desired, hours or even longer after a dye labelled or radiolabeled compound of the invention is injected into a patient. In most instances, a sufficient amount of the administered dose will accumulate in the area to be imaged within about 0.1 of an hour to permit the taking of images, e.g. scintiphotos. Any conventional method of imaging for diagnostic purposes can be utilized in accordance with this invention.
  • the compound of the present invention is administered preferably parenteral, and more preferably intravenous.
  • the compounds of the invention preferably comprise a cytotoxic or cytostatic drug and/or a cytotoxic radioisotope, preferably 188 Re.
  • a therapeutically effective amount of a cytotoxic or cytostatic compound means the total amount of the active component of the pharmaceutical composition that is sufficient to show a meaningful patient benefit, i.e., a reduction in the incidence or severity of symptoms attributed to the somatostatin-responsive disease state, as compared to that expected for a comparable group of patients not receiving the compound of the invention.
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
  • therapy encompasses any therapeutic effect ranging from pain palliation to remission of symptoms associated with the particular somatostatin-responsive disease being treated.
  • therapy entails pain reduction, tumor ablation, tumor remission and tumor eradication.
  • a complex of the compound of the invention and a cytotoxic radioisotope is administered to a mammal, including a human patient, in need of treatment of a somatostatin-responsive disease.
  • the compound of the invention is a radiotherapeutic an amount of cytotoxic radioisotope from about 5 mCi to about 200 mCi may be administered via any suitable clinical route, preferably by intravenous injection or by intratumoral injection.
  • the radiotherapeutic complex of the invention may optionally be administered in combination with a chemotherapeutic drug such as tamoxifen, cisplatin, taxol, anti-angiogenic compounds, and others which were indicated above in the context of preferred drugs for coupling to X 5 and/or X 6 .
  • a chemotherapeutic drug such as tamoxifen, cisplatin, taxol, anti-angiogenic compounds, and others which were indicated above in the context of preferred drugs for coupling to X 5 and/or X 6 .
  • an unlabeled compound is used for therapy, e.g. comprising a cytotoxic or cytostatic drug
  • the amount of unlabeled compound administered for therapy of a somatostatin-responsive disease will depend upon the nature and severity of the condition being treated, and upon the nature of prior treatments which the patient has undergone.
  • the attending physi- cian will decide the amount of compound with which to treat each individual patient. Initially, the attending physician will administer low doses of the compound and observe the patient's response. Larger doses of the compound may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further.
  • the dosage of unlabeled compound administered in the therapeutic method of the invention should be in the range of about 0.1 ⁇ g to about 100 mg compound per kg body weight. More preferably, the dosage of unlabeled compound administered in the therapeutic method of the invention is in the range of about 0.1 ⁇ g to about 100 ⁇ g compound per kg body weight.
  • the unlabeled compound of the invention may also optionally be administered in combination with a chemotherapeutic drug.
  • the duration of therapy will vary, depending on the severity of the disease being treated and the condition and idiosyncratic response of each individual patient. It is contemplated that the duration of each administration of the compound of the invention will be in the range of about one to about 120 minutes of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the labelled or unlabeled compounds of the invention, whether administered alone or in combination with other drugs.
  • the N-Fmoc protected lysine is tethered to an insoluble, polymer based support via the side- chain amine, and has the carboxylic acid protected as an allyl ester.
  • the purity of the 99m Tc -labelled compound was determined by reverse-phase analytical HPLC using the following conditions: a Zorbax 300SB Cl 8, 4 ⁇ , 4.6 mm.times.250 mm analytical column was loaded with each radiolabeled compound, and the compound eluted at a solvent flow rate equal to 1.2 ml/min.
  • Radioactive components were detected in the HPLC method using an in-line radiometric detector linked to a computerized data collection and analysis system (Waters Millenium).
  • 99m Tc -glucoheptonate, 99m Tc -edetate, and 99m Tc -pertechnetate elute between one and four minutes under these conditions, whereas the 99m Tc -labeled compounds eluted after a much greater time.
  • the radiochemical purity (as determined by the % area of the main 99m Tc product peaks) was >80%.
  • the purity of the 99m Tc -labeled compound was also determined by TLC quality control analysis.
  • the radiolabeled peptide samples were spotted at the origin of each of two Gelman ITLC-SG strips. One strip each was developed in saturated saline (SAS) and 1 : 1 (v:v) methanol:! mol/1 ammonium acetate (MAM) and allowed to dry.
  • SAS strips were cut at R.sub.f 0.75 and the MAM strip was cut at R 040 .
  • the portions of the strips were counted for radioactivity in a dose calibrator, and the percent activity of the top and bottom portions of each strip calculated.
  • Radiolabeling binding assays were carried out as described in the prior art like, e.g. in museumsl S. et al (2002) J. Med. Chem. 45: 1665-1671.
  • the radioligand binding assays were carried out on membranes prepared from CHO-Kl cells stably expressing individually cloned somatostatin receptors 2 or 5 (SSTR2 or SSTR5).
  • Cells were grown for 2 days for almost confluence and were washed and scraped into 50 mM ice-cold Tris-HCl, pH 7.8, containing 1 mM EGTA, 5 mM MgCl 2 , 10 mg/mL leupeptin,200 mg/mL bacitracin, 0,1 mM PMSF, and 0,5 mg/mL aprotinin (buffer A) and were centrifuged at 10,000 rpm for 10 min at 4°C (in Sorvall RC 26 Plus ultracentrifuge, rotor SS-34).
  • the pellet was resuspended in buffer A and homogenized with a Polytron PT 1200 homogenizer (Kinematica AG, Switzerland) (setting 2, 3 strokes 10 s each). The homogenate was then centrifuged at 20 000 rpm for 20 min at 4°C. The pellet was resuspended in buffer A and homogenized using the Polytron homogenizer (setting 2, 3 strokes 5 s each). The protein content was determined by Bradford, and the membrane preparation was diluted in buffer A containing 1 mg/mL bovine serum albumin (BSA) to a final 0.2 or 0.4 mg/mL membrane protein (depending on the specific somatostatin receptor used).
  • BSA bovine serum albumin
  • the radioligand binding assay was performed in 96 well microtiter plates (Maxisorp plates, Nunc, Denmark). Cell membranes (10 or 20 mg protein) were incubated with the various cy- clized peptides indicated in Table 1 & 2, which comprised a lanthanide chelation unit, in a final volume of 250 ⁇ L, for 45 min. at room temperature in the presence or absence of competing peptides. Nonspecific binding was defined as the radioactivity remaining bound in the presence of 1 mM somatostatin.
  • reaction free radioligand was sepa- rated from bound Ligand by rapid filtration through UniFilter GF/C plates preincubated in a solution of 5g/L polyethyleneimine and 1 g/L BSA. The filtration was performed in Filter- Mate Cell Harvester (Packard Instrument Company, U.S.A.). After filtration, the filters were washed several times with cold buffer A containing 1 mg/mL BSA and allowed to dry overnight at room temperature. Then, bound radioactivity was counted. The binding assays were performed in triplicate wells. Data from radioligand binding were used to generate inhibition curves, and IC 50 values were determined for each of the tested peptides. The saturation binding data were analyzed by the method of Scatchard, and IC 50 values are expressed as mean ⁇ SEM (standard error of the mean).

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Abstract

L'invention concerne des composés comprenant de nouveaux peptides cyclisés à sélectivité accrue envers le récepteur 5 de la somatostatine (SSTR5), leur production et leur utilisation pour diagnostiquer et traiter les maladies sensibles à la somatostatine ou les maladies caractérisées par une régulation positive des récepteurs de la somatostatine, notamment, les maladies prolifératives.
PCT/EP2006/003994 2005-04-28 2006-04-28 Composes comprenant des peptides cyclises se liant aux recepteurs de la somatostatine WO2006114324A1 (fr)

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Cited By (1)

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WO1995000553A1 (fr) * 1993-06-23 1995-01-05 Diatech, Inc. Peptides radiomarques derives de la somatostatine et utilises dans des procedes d'imagerie et therapeutiques
WO1995031221A1 (fr) * 1994-05-12 1995-11-23 Diatech, Inc. Conjugues peptide-chelate metallique se liant a la somatostatine
WO1995033498A1 (fr) * 1994-06-03 1995-12-14 Diatech, Inc. Peptides marques au technetium-99m pour l'imagerie
WO1995033497A1 (fr) * 1994-06-03 1995-12-14 Diatech, Inc. Agents chelateurs metalliques a base de thiol, diamide et monoamine
WO1996004308A1 (fr) * 1994-07-29 1996-02-15 Diatech, Inc. Analogues de la somatostatine hexapeptidique cyclique
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US4612366A (en) * 1985-06-17 1986-09-16 Merck & Co., Inc. Cyclic hexapeptide somatostatin analogs
US5965694A (en) * 1992-09-01 1999-10-12 The Trustees Of The University Of Pennsylvania Somatostatin mimics and synthetic methods therefor
WO1995000553A1 (fr) * 1993-06-23 1995-01-05 Diatech, Inc. Peptides radiomarques derives de la somatostatine et utilises dans des procedes d'imagerie et therapeutiques
WO1995031221A1 (fr) * 1994-05-12 1995-11-23 Diatech, Inc. Conjugues peptide-chelate metallique se liant a la somatostatine
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WO1995033497A1 (fr) * 1994-06-03 1995-12-14 Diatech, Inc. Agents chelateurs metalliques a base de thiol, diamide et monoamine
WO1996004308A1 (fr) * 1994-07-29 1996-02-15 Diatech, Inc. Analogues de la somatostatine hexapeptidique cyclique
WO1996011954A1 (fr) * 1994-10-13 1996-04-25 Merck Frosst Canada Inc. Analogues de somatostatine radiomarques tc ou re
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7893042B2 (en) * 2008-12-19 2011-02-22 Pinnacle Pharmaceuticals, Inc. Phenazopyridine compounds
US8288365B2 (en) 2008-12-19 2012-10-16 Pinnacle Pharmaceuticals, Inc. Phenazopyridine compounds

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