WO2002020610A2 - Peptides marques contraints par conformation, destines a l'imagerie ou a usage therapeutique - Google Patents

Peptides marques contraints par conformation, destines a l'imagerie ou a usage therapeutique Download PDF

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Publication number
WO2002020610A2
WO2002020610A2 PCT/US2001/027708 US0127708W WO0220610A2 WO 2002020610 A2 WO2002020610 A2 WO 2002020610A2 US 0127708 W US0127708 W US 0127708W WO 0220610 A2 WO0220610 A2 WO 0220610A2
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Prior art keywords
peptide
hydrogen
group
acid
linear
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PCT/US2001/027708
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English (en)
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WO2002020610A3 (fr
Inventor
Michelle A. Schmidt
Jack L. Erion
Ananthachari Srinivasan
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Biosynthema Inc.
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Priority to US10/363,977 priority Critical patent/US20040106548A1/en
Priority to AU2001288847A priority patent/AU2001288847A1/en
Publication of WO2002020610A2 publication Critical patent/WO2002020610A2/fr
Publication of WO2002020610A3 publication Critical patent/WO2002020610A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6425—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a receptor, e.g. CD4, a cell surface antigen, i.e. not a peptide ligand targeting the antigen, or a cell surface determinant, i.e. a part of the surface of a cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • 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
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to conformationally constrained receptor targeted radiolabeled peptides which are amenable to positioning of a chelating moiety (henceforth referred to as "CM") and/or diagnostic or therapeutic isotopes.
  • CM chelating moiety
  • the methodology is applicable to several families of peptides including but not limited to: somatostatin, gastrin, gastrin releasing peptide, bombesin and bombesin antagonists, gastrin releasing peptides, adhesion peptides, cholecystokinin, neurotensins, neuropeptide Y, vasoactive intestinal peptides, thyroid stimulating hormone, angiotensin, pancreatic adenylate cyclase activating peptide, and substance P.
  • chelating moieties containing diagnostic and therapeutic isotopes can be attached at the same position.
  • other therapeutic agents such as physiologically acceptable drugs can be attached at the same position.
  • Conformational constraints in diagnostic and therapeutic agents in peptides have been introduced by means of disulfide bonds and amide cyclizations. These constraints are responsible for altering the stability and specificity of these receptor-targeted agents. Conformationally constrained peptides containing secondary and primary amines, ethers, thioethers, amidines, esters and other functionalities have been synthesized. Methods are disclosed which provide means for incorporating multiple features of the above functionalities in the macrocyclic ring of the peptides.
  • moieties may be attached to the macrocyclic ring.
  • Such other moieties include, but are not limited to, dyes which are useful for detection such as for diagnostic purposes and drugs which can be used for therapeutic purposes.
  • Such a modification may also render rigidity to the ring resulting in an inactive compound.
  • Inco oration of varying ring sizes (macrocyclic chain) between the side chains of amino acids renders different three-dimensional conformations of the peptide chain. These features can impose different specificities for the peptide.
  • the incorporation of O, S or NH alters flexibility of the macrocyclic chain, while amines (endocyclic and exocyclic) can also be utilized for incorporation of diagnostic and therapeutic entities (radiolabeled chelating groups, dyes and chemotherapeutic drugs).
  • Incorporation of esters (lactones) allows temporary serum-stability and imparts specificity to the peptide, while aiding metabolism in the excretionary organs.
  • olefin metathesis is a carbon skeleton redistribution in which new unsaturated carbon-carbon bonds are formed in the presence of metal catalysts.
  • the ring closing metathesis of a diene involves an alternating type of propagation reaction. An intermolecular metathesis reaction with the carbene complex is followed by an intramolecular metathesis reaction. The ease of occurrence of both these steps varies, and the stereoselectivity of the cyclization step varies with the catalyst. The optimum condition for a given ring closing metathesis must be found by trial and error.
  • the substrate concentration plays a major role in the success of any ring closing metathesis reaction.
  • Dilute solution favors the intramolecular reaction. Since a protected peptide attached to a solid phase can be considered a pseudo-dilute solution, ring closing metathesis typically favors intramolecular cyclization. The success of the reaction depends on several factors. If there are chiral centers between two reacting multiple bonds, then the ring closing metathesis of one diastereomer may be favored over the other.
  • Dab is diaminobutyric acid
  • AGly is ⁇ -allylglycine
  • All is allyl
  • Dde is l-(4,4-dimethyl-2,6-dioxocyclohexylidine)-ethyl
  • Ph 3 P is triphenylphosphine
  • DEAD is diethylazodicarboxylate
  • NBS is o-nitrobenzenesulfonyl
  • HOBt is N-hydroxybenzotriazole
  • HBTU 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate
  • DBU is diazabicycloundecane
  • MeOtBu is methyl- t-butyl ether
  • TFA trifluoroacetic acid.
  • Common amino acids are given their common three letter codes. Unless otherwise stated, the amino acids have the L-configuration at the chiral center.
  • Resin-bound, protected AGly 2 ,Ser(OAll) 7 -Octreotate and Ser(OAU) 2 ' 7 -Octreotate were cyclized to the unsaturated compound in the presence of Grubbs' catalyst. After the introduction of the chelating moiety, deprotection and reduction yielded the macrocyclic peptide.
  • Macrocyclic peptides are ideal candidates for Tc-99m chelation chemistry because of the absence of reducible groups, such as_disulf ⁇ de. Methods developed here are amenable to the preparation of a large number of peptides and peptidomimetics by combinatorial chemistry. I. Endocyclic amines containin-g a chelating moiety
  • E is a group of formula COOR 4 , CH 2 OR 5 , CON(R ⁇ OH or CON(R 7 )(R 8 ) wherein R 4 is hydrogen or C 1 -C 5 linear or branched chain alkyl groups, R 5 is hydrogen or physiologically acceptable, physiologically hydrolyzable ester,
  • R 6 is hydrogen or C ⁇ -C 5 linear or branched chain alkyl groups
  • R 7 ⁇ R 8 is hydrogen or C 1 -C 5 linear or branched chain alkyl groups or taken together form a cyclic alkyl group C 3 -C ⁇ 0 ;
  • CM is a dye, a therapeutic agent, or a chelating moiety or metal binding site wherein the chelating moiety is labeled with a metal isotope selected from 99m Tc, 203 Pb, 67 Ga, In, 97 Ru, 62 Cu, 64 Cu, 186 Re, 188 Re, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu or a radioactive halogen isotope on the understanding that i) if the label is a metal isotope, CM represents a chelating group suitable for the metal and ii) if the label is a radioactive halogen isotope, the halogen is attached to an aromatic ring, wherein the CM is attached directly or through a spacing group to the peptide, said
  • CM being attached to the amine through an amide or urea bond or by any other modification which allows attachment of a chelate and which modifications are known to those of skill in the art, wherein the chelating group is preferably derived from ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), cyclohexyl 1,2-diamine tetraacetic acid (CDTA), ethyleneglycol-O,O'-bis(2-aminoethyl)-N,N,N',N'-diacetic acid
  • EDTA ethylene diamine tetraacetic acid
  • DTPA diethylene triamine pentaacetic acid
  • CDTA cyclohexyl 1,2-diamine tetraacetic acid
  • HBED triethylene tetraamine hexaacetic acid
  • TTHA triethylene tetraamine hexaacetic acid
  • N,N',N",N m -tetraacetic acid (DOT A), l,4,7-triazacyclononane-N,N',N"-triacetic acid
  • NOTA 1,4,8,1 l-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid
  • TETA 1,4,8,1 l-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid
  • PG is a sulfur protecting group selected from alkanoyl, arylcarbonyl, arylalkanoyl, acetamidomethyl, tetrahydropyranyl and tetrahydrofuranyl, i Y', Y", and Y'" are hydrogen or oxygen with the proviso that at least one of them is an
  • Ri and R 2 are hydrogen or alkyl (C ⁇ -C 3 ),
  • X NH or S with the proviso that Y'" is hydrogen when X is S,
  • Z is PG ifX is S
  • Z is hydroxyalkyl, aminoalkyl or carboxyalkyl.
  • E is a group of formula COOR 4 , CH 2 OR 5 , CON(R 6 )OH or CON(R 7 )(R 8 ) wherein
  • R 4 is hydrogen or C 1 -C 5 linear or branched chain alkyl groups
  • R 5 is hydrogen or physiologically acceptable, physiologically hydrolyzable ester
  • R 6 is hydrogen or C 1 -C 5 linear or branched chain alkyl groups
  • R j R 8 is hydrogen or C 1 -C 5 linear or branched chain alkyl groups or taken together form a cyclic alkyl group C 3 -C ⁇ o;
  • t CM is a dye, a therapeutic agent, or a chelating moiety or metal binding site wherein the chelating moiety is labeled with a metal isotope selected from 99m Tc, 03 Pb, 67 Ga, ⁇ In, 97 Ru, 62 Cu, 64 Cu, 186 Re, 188 Re, 90 Yr 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu or a radioactive halogen isotope on the understanding that i) if the label is a metal isotope, CM represents a chelating group suitable for the metal and ii) if the label is a radioactive halogen isotope, the halogen is attached to an aromatic ring, wherein the CM is attached directly or through a spacing group
  • CM being attached to the amine through an amide or urea bond or by any other modification which allows attachment of a chelate and which modifications are known to those of skill in the art, wherein the chelating group is preferably derived from ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), cyclohexyl 1,2-diamine tetraacetic acid (CDTA), ethyleneglycol-O,O'-bis(2-aminoethyl)-N,N,N',N'-diacetic acid
  • EDTA ethylene diamine tetraacetic acid
  • DTPA diethylene triamine pentaacetic acid
  • CDTA cyclohexyl 1,2-diamine tetraacetic acid
  • HBED triethylene tetraamine hexaacetic acid
  • TTHA triethylene tetraamine hexaacetic acid
  • N,N',N",N'"-tetraacetic acid (DOTA), l,4,7-triazacyclononane-N,N',N"-triacetic acid
  • NOTA 1,4,8,1 l-tetraazacyclotetradecane-N,N*,N",N'"-tetraacetic acid
  • TETA 1,4,8,1 l-tetraazacyclotetradecane-N,N*,N",N'"-tetraacetic acid
  • PG is a sulfur protecting group selected from alkanoyl, arylcarbonyl, arylalkanoyl, acetamidomethyl, tetrahydropyranyl and tetrahydrofuranyl, Y', Y", and Y" 1 are hydrogen or oxygen with the proviso that at least one of them is an
  • E is a group offormula COOR 4 , CH 2 OR 5 , CON(R 6 )OH or CON(R 7 )(R 8 ) wherein .
  • R is hydrogen or C 1 -C 5 linear or branched chain alkyl groups,
  • R 5 is hydrogen or physiologically acceptable, physiologically hydrolyzable ester
  • R 6 is hydrogen or C ⁇ -C 5 linear or branched chain alkyl groups
  • R 7j R 8 is hydrogen or C ⁇ -C 5 linear or branched chain alkyl groups or taken together form a cyclic alkyl group C 3 -C ⁇ 0 ;
  • CM is a dye, a therapeutic agent, or a chelating moiety or metal binding site wherein the chelating moiety is labeled with a metal isotope selected from 99m Tc, 203 Pb, 67 Ga, In, 97 Ru, 62 Cu, 64 Cu, 186 Re, 188 Re, 90 Y, 121 Sn, 16I Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu or a radioactive halogen isotope on the understanding that i) if the label is a metal isotope, CM represents a chelating group suitable for the metal and ii) if the label is a radioactive halogen isotope, the halogen is attached to an aromatic ring, wherein the CM is attached directly or through a spacing group to the
  • HBED triethylene tetraamine hexaacetic acid
  • TTHA triethylene tetraamine hexaacetic acid
  • N,N',N",N'"-tetraacetic acid (DOTA), l,4,7-triazacyclononane-N,N',N"-triacetic acid
  • NOTA 1,4,8,1 l-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid
  • TETA 1,4,8,1 l-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid
  • PG is a sulfur protecting group selected from alkanoyl, arylcarbonyl, arylalkanoyl, acetamidornethyl, tetrahydropyranyl and tetrahydrofuranyl,
  • Y', Y", and Y'" are hydrogen or oxygen with the proviso that at least one of them is an O,
  • Ri and R 2 are hydrogen or alkyl (C 1 -C3),
  • X NH or S with the proviso that Y"' is hydrogen when X is S,
  • Z is PG ifX is S
  • Z is hydroxyalkyl, aminoalkyl or carboxyalkyl.
  • the dyes and therapeutics which can be used for CM include, but are not limited to, the following: Visible dyes:
  • (AA) a is Phe, Tyr, an isomer of Tyr, polyhydroxylated Phe, or aromatic amino acids, wherein the amino acid can have an L- or D- configuration; k is 1, 2 or 3;
  • 1 is 1, 2 or 3;
  • AA 2 is Phe, Tyr, an isomer of Tyr, polyhydroxylated Phe, or aromatic amino acids, wherein the amino acid can have an L- or D- configuration;
  • (AA) m is a dipeptide sequence consisting of DTrp-Lys, DTrp-Om, DTrp-Dab, DTrp- 4-piperidinylglycine, DTrp-4-piperidinylalanine, DTrp-4-aminomethylcyclohexylalanine, DTrp-4-aminomethylcyclohexylglycine, DTrp-4-aminocyclohexylalanine, DTrp-4- aminocyclohexylglycine.
  • DTrp can be substituted by L-Trp;
  • AA 3 is any amino acid
  • (AA)b is none, serine or threonine;
  • R is hydrogen or C 1 -C 5 linear or branched chain alkyl groups bearing -OH at any location;
  • E is COOH, CH 2 -OH, CONH 2 , COOR or CONHOH wherein R 4 is hydrogen or Ci-
  • n 1, 2 or 3;
  • P is none, O or S; n' is 1-7; p is 1-6; p' is 1-6; p" is 1-6;
  • CM is a dye, a therapeutic agent, or a chelating moiety or metal binding site wherein the chelating moiety is labeled with a metal isotope selected from 99m Tc, 203 Pb, 67 Ga, l u In, 97 Ru, 62 Cu, 64 Cu, 186 Re, 188 Re, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu or a radioactive halogen isotope on the understanding that i) if the label is a metal isotope, CM represents a chelating group suitable for the metal and ii) if the label is a radioactive halogen isotope, the halogen is attached to an aromatic ring, wherein the CM is attached directly or through a spacing group to the peptide, said CM being attached to the amine through an amide or urea bond or by any other modification which allows attachment of a chelate and
  • PG is a sulfur protecting group selected from alkanoyl, arylcarbonyl, arylalkanoyl, acetamidomethyl, tetrahydropyranyl and tetrahydrofuranyl,
  • Y', Y", and Y'" are hydrogen or oxygen with the proviso that at least one of them is an O,
  • Ri and R 2 are hydrogen or alkyl (C ⁇ -C 3 ),
  • X NH or S with the proviso that Y'" is hydrogen when X is S,
  • Z is PG ifX is S
  • Z is hydroxyalkyl, aminoalkyl or carboxyalkyl.
  • Step 1 The protected peptide was assembled in an automated synthesizer according to the
  • Step 2 The resin, tBoc-DPhe 1 ,AGly 2 ,Tyr 3 ,Dab 7 ( ⁇ -o-NBS)-Octreotate-Resin (55 mg, 10 ⁇ mol peptide content, 0.18 mmol/g) was suspended in a solution of 1 mL of methylene chloride CH 2 C1 2 containing 52 mg of triphenyl phosphine (Ph 3 P) (0.2 mmol; 20 Xs.) 34 ⁇ L of diethylazodicarboxylate (DEAD) (0.2 mmol; 20 Xs.). After vigorous shaking for a few minutes, allyl alcohol (20 fold excess) was added.
  • Ph 3 P triphenyl phosphine
  • DEAD diethylazodicarboxylate
  • the resin was filtered, washed with 5 mL of methylene chloride and dried.
  • the resin-bound peptide was alkylated with 3-butenol, 4-pentenol, 5-hexenol or allyloxyethanol. In each case, a small amount of the peptide was cleaved from the resin and assayed to ensure complete alkylation.
  • Step3 50 mg of the resin (25 ⁇ mole peptide) was suspended in 5 mL of methylene chloride containing 20 mg of Grubbs' catalyst. The mixture was heated at 40°C for 10-15 hours. At the end of the reaction, the resin was removed by filtration and washed with methylene chloride and THF (tetrahydrofuran).
  • Step 4 The resin (250 mg; 0.18 mmol/g) containing the previously made peptide of step 3 was suspended in 3 mL of DMF (dimethylformamide). To this suspension, 200 ⁇ L of DBU and 200 ⁇ L of mercaptoethanol was added and shaken for 7 hours.
  • DMF dimethylformamide
  • Step 5 A solution of tri-t-butyl-DTPA anhydride (56 mg; 0.1 mmol) in 200 ⁇ L of DMF was activated with 0.5 mL of HOBt-HBTU (200 mM) solution for 1 hour and added to 140 mg (50 ⁇ mol of the peptide) of the above resin. The suspension was shaken for overnight and filtered. The resin was washed with DMF and 10 mL of THF.
  • Step 6 The resin was deprotected using 250 ⁇ L of TFA:phenol:thioanisole:water (85:5:5:5) overnight. The crude peptide was precipitated using 10 mL of MeOtBu. After centrifugation, the mixture was washed with 4 X 10 mL of dissolved in MeOtBu. The mixture was taken up in 2 mL of 2:3 acetonitrile: water, shaken in a vortex mixer and the resin was removed by filtration. The filtrate was lyophilized to obtain the peptide.
  • Step 7 The compound ( ⁇ 6 mg) was dissolved in 8 mL of MeOH:H 2 O (0.001 M HC1) (1 :1).
  • the solution was hydrogenated in the presence of 1-2 mg of PtO 2 (Adams' catalyst) for 10-12 hours. Catalyst was filtered and the solution was evaporated to dryness. The residue was dissolved in 1-2 mL of water and evaporated and the process was repeated two more times. The residue was dissolved in water and lyophilized to obtained the product.
  • PtO 2 Adams' catalyst
  • (AA) a is Phe, Tyr, an isomer of Tyr, polyhydroxylated Phe or aromatic amino acids, wherein the amino acid can have an L- or D- configuration;
  • NH-CM k is 1, 2 or 3;
  • 1 is 1, 2 or 3;
  • AA 2 is Phe, Tyr, an isomer of Tyr, polyhydroxylated Phe or aromatic amino acids, wherein the amino acid can have an L- or D- configuration;
  • (AA) m is a dipeptide sequence consisting of DTrp-Lys, DTrp-Orn, DTrp-Dab, DTrp-
  • DTrp-4-aminomethylcyclohexylglycine, DTrp-4-aminocyclohexylalanine, DTrp-4- aminocyclohexylglycine and DTrp can be substituted by L-Trp;
  • AA 3 is any amino acid; _ . (AA) b is none, serine or threonine;
  • R is hydrogen or C ⁇ -C 5 linear or branched chain alkyl groups bearing -OH at any location;
  • E is COOH, CH 2 -OH, CONH 2, COOR or CONHOH wherein R4 is hydrogen or d-
  • n 1, 2 or 3;
  • CM is a dye, a therapeutic agent, or a chelating moiety or metal binding site wherein the chelating moiety is labeled with a metal isotope selected from 99m Tc, 203 Pb, 67 Ga, n ⁇ In, 97 Ru, 62 Cu, 64 Cu, 186 Re, 188 Re, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu or a radioactive halogen isotope on the understanding that i) if the label is a metal isotope, CM represents a chelating group suitable for the metal and ii) if the label is a radioactive halogen isotope, the halogen is attached to an aromatic ring, wherein the CM is attached directly or through a spacing group to the peptide, said CM being attached to
  • N,N',N",N'"-tetraacetic acid (DOTA), l,4,7-triazacyclononane-N,N',N"-triacetic acid
  • NOTA 1,4,8,1 l-tetraazacyclotetradecane-N,N l ,N",N'"-tetraacetic acid
  • TETA 1,4,8,1 l-tetraazacyclotetradecane-N,N l ,N",N'"-tetraacetic acid
  • t 1,4,8,1 l-tetraazacyclotetradecane-N,N l ,N",N'"-tetraacetic acid
  • PG is a sulfur protecting group selected from alkanoyl, arylcarbonyl, arylalkanoyl, acetamidomethyl, tetrahydropyranyl and tetrahydrofuranyl,
  • Y', Y", and Y'" are hydrogen or oxygen with the proviso that at least one of them is an O,
  • Ri and R 2 are hydrogen or alkyl (C ⁇ -C 3 ),
  • X NH or S with the proviso that Y'" is hydrogen when X is S,
  • Z is PG ifX is S
  • Z is hydroxyalkyl, aminoalkyl or carboxyalkyl.
  • Step 1 The protected peptide was assembled in an automated synthesizer according to the Fmoc-strategy.
  • the resin bound peptide was shaken with 2% hydrazine (2 mL per 50 mg resin) for 30 minutes to remove the Dde protecting group, followed by reaction with Fmoc-L- allylglycine activated ester (4 fold excess) to give the product.
  • Step 2 50 mg of the resin (25 ⁇ mole peptide) was suspended in 5 mL of methylene chloride containing 20 mg of Grubbs' catalyst. The mixture was heated at 40°C for 10-15 hours. At the end of the reaction, the resin was removed by filtration and washed with methylene chloride and THF.
  • Step 3 The resin was shaken with 1 :1 piperidine:DMF (1 mL per 50 mg resin) for 1 hour. After the resin was filtered it was washed with THF and dried. A solution of tri-t-butyl- DTPA anhydride (56 mg; 0.1 mmol) in 200 ⁇ L of DMF was activated with 0.5 mL of HOBt- HBTU (200 mM) solution for 1 hour and added to 140 mg (50 ⁇ mol of the peptide) of the above resin. The suspension was shaken for overnight and filtered. The resin was washed with DMF and 10 mL of THF.
  • Step 4 The resin was deprotected using 250 ⁇ L of TFA:phenol:thioanisole: water (85:5:5:5) overnight. The crude peptide was precipitated using 10 mL of MeOtBu. . After centrifugation, the mixture was washed with 4 X 10 mL of MeOtBu. The mixture was taken up in 2 mL of 2:3 acetonitrile:water, shaken in a vortex mixer and the resin was removed by filtration. The filtrate was lyophilized to obtain the peptide.
  • Step 5 The compound ( ⁇ 5 mg) was dissolved in 10 mL of MeOH:H 2 O (O.OOIM HCl) (1 :1).
  • R is hydrogen or C 1 -C 5 linear or branched chain alkyl groups bearing -OH at any location;
  • E is a group of formula COOR 4 , CH 2 OR 5 , CON(R 6 )OH, CON(R 7 )(R 8 ) wherein R4 is hydrogen or C 1 -C 5 linear or branched chain alkyl groups,
  • R 5 is hydrogen or physiologically acceptable, physiologically hydrolyzable ester
  • R$ is hydrogen or C 1 -C 5 linear or branched chain alkyl groups
  • R 7 ⁇ R 8 is hydrogen or C ⁇ -C 5 linear or branched chain alkyl groups or taken together form a cyclic alkyl group C 3 -C ⁇ 0 ;
  • CM is a dye, a therapeutic agent, or a chelating moiety or metal binding site wherein the chelating moiety is labeled with a metal isotope selected from 99m Tc, 203 Pb, 67 Ga, m In, 97 Ru, 62 Cu, 64 Cu, 186 Re, 188 Re, 90 Y, 121 Sn, 161 Tb, 153 Sm, 166 Ho, 105 Rh, 177 Lu or a radioactive halogen isotope on the understanding that i) if the label is a metal isotope, CM represents a chelating group suitable for the metal and ii) if the label is a radioactive halogen isotope, the halogen is attached to an aromatic ring, wherein the CM is attached directly or through a spacing group
  • the chelating group is preferably derived from ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), cyclohexyl 1,2-diamine tetraacetic acid (CDTA), ethyleneglycol-O,O'-bis(2-aminoethyl)-N,N,N , ,N'-diacetic acid (HBED), triethylene tetraamine hexaacetic acid (TTHA), 1, 4,7,10-tetraazacyclododecane-
  • EDTA ethylene diamine tetraacetic acid
  • DTPA diethylene triamine pentaacetic acid
  • CDTA cyclohexyl 1,2-diamine tetraacetic acid
  • HBED ethyleneglycol-O,O'-bis(2-aminoethyl)-N,N,N , ,N'-diacetic acid
  • TTHA triethylene tetraamine
  • N,N',N",N"'-tetraacetic acid DAA
  • NOTA l,4,7-triazacyclononane-N,N',N"-triacetic acid
  • TETA 1,4,8,1 l-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid
  • PG is a sulfur protecting group selected from alkanoyl, arylcarbonyl, arylalkanoyl, acetamidomethyl, tetrahydropyranyl and tetrahydrofuranyl,
  • Y', Y", and Y"' are hydrogen or oxygen with the proviso that at least one of them is an O,
  • Ri and R 2 are hydrogen or alkyl (C 1 -C3),
  • X NH or S with the proviso that Y"' is hydrogen when X is S,
  • Z is PG ifX is S
  • Z is hydroxy alkyl, aminoalkyl or carboxy alkyl.
  • Step 1 500 mg of the resin (90 ⁇ mole peptide) was suspended in 22 mL of methylene chloride containing 90 mg of Grubbs' catalyst. The mixture was heated at 40°C for 10 hours.
  • the resin was removed by filtration and washed with methylene chloride and THF.
  • Step 2 The resin containing the cyclic product was treated with 5 mL of 1:1 piperidine:DMF for 30 minutes and filtered. The resin was washed with DMF and 10 mL of anhydrous THF and dried.
  • Step 3 A solution of tri-t-butyl-DTPA anhydride (112 mg; 0.2 mmol) in 200 ⁇ L of DMF was activated with 1 mL of HOBt-HBTU (200 mM) solution for 1 hour and added to 277 mg
  • Step 4 The resin (9 ⁇ mole; 50 mg; 0.18 mmol/g) was suspended in a solution of 1 mL of
  • Step 1 500 mg of the resin (90 ⁇ mole peptide) was suspended in 22 mL of methylene chloride containing 90 mg of Grubbs' catalyst. The mixture was heated at 40°C for 10 hours. At the end of the reaction, the resin was removed by filtration and washed with methylene chloride and THF.
  • Step 2 The resin containing the cyclic product was treated with 5 mL of 1 :1 piperidine:DMF for 30 minutes and filtered. The resin was washed with DMF and 10 mL of anhydrous THF and dried.
  • Step 3 The resin (9 ⁇ mole; 50 mg; 0.18 mmol/g) was suspended in a solution of 1 mL of

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Endocrinology (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Cell Biology (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Selon l'invention, des contrtaintes conformationnelles dans des agents diagnostiques et thérapeutiques, présents dans des peptides, ont été introduites par liaisons disulfure et cyclisations amides. Ces contraintes sont responsables de l'altération de la stabilité et de la spécificité de ces agents ciblant le récepteur. Des peptides contraints par conformation contenant des amines secondaires et primaires, des éthers, des thioéthers, des amidines, des esters et d'autres fonctionnalités ont été synthétisés. L'invention concerne des méthodes comportant plusieurs éléments de ces fonctionnalités dans le noyau macrocyclique des peptides.
PCT/US2001/027708 2000-09-07 2001-09-07 Peptides marques contraints par conformation, destines a l'imagerie ou a usage therapeutique WO2002020610A2 (fr)

Priority Applications (2)

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US10/363,977 US20040106548A1 (en) 2001-09-07 2001-09-07 Conformationally constrained labeled peptides for imaging and therapy
AU2001288847A AU2001288847A1 (en) 2000-09-07 2001-09-07 Conformationally constrained labeled peptides for imaging and therapy

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003006491A2 (fr) * 2001-07-10 2003-01-23 Amersham Health As Composes peptidiques
EP1494694A2 (fr) * 2002-03-26 2005-01-12 Peptor, Ltd. Analogues de la somatostatine photoactifs cyclises par le squelette pour therapie photodynamique et imagerie
WO2005012335A1 (fr) * 2003-07-30 2005-02-10 Amersham Health As Agents d'imagerie a peptide bicyclique
US6861236B2 (en) 2002-05-24 2005-03-01 Applied Nanosystems B.V. Export and modification of (poly)peptides in the lantibiotic way
WO2005030266A2 (fr) * 2003-09-29 2005-04-07 Amersham Health As Imagerie optique du cancer colorectal
WO2005084715A2 (fr) 2004-03-04 2005-09-15 Ge Healthcare As Composes pharmaceutiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997009344A2 (fr) * 1995-08-29 1997-03-13 Peptor Limited Banques de nouveaux analogues de peptides a squelette cyclise sur le squelette
WO1999065508A1 (fr) * 1998-06-19 1999-12-23 Peptor Ltd. Analogues de la somatostatine cyclises par squelette a contrainte de conformation

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1997009344A2 (fr) * 1995-08-29 1997-03-13 Peptor Limited Banques de nouveaux analogues de peptides a squelette cyclise sur le squelette
WO1999065508A1 (fr) * 1998-06-19 1999-12-23 Peptor Ltd. Analogues de la somatostatine cyclises par squelette a contrainte de conformation

Non-Patent Citations (1)

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Title
BASS LA ET AL.: "Identification of the Soluble in Vivo Metabolites of Indium-111-Diethylenetriaminepentaacetic Acid-D-Phe-1-Octreotide" BIOCONJUGATE JOURNAL, vol. 9, 14 February 1998 (1998-02-14), pages 192-200, XP002216302 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003006491A3 (fr) * 2001-07-10 2003-12-24 Amersham Health As Composes peptidiques
US8299030B2 (en) 2001-07-10 2012-10-30 Ge Healthcare Limited Peptide-based compounds
WO2003006491A2 (fr) * 2001-07-10 2003-01-23 Amersham Health As Composes peptidiques
US7994134B2 (en) 2001-07-10 2011-08-09 Ge Healthcare As Peptide-based compounds
EP2347771A1 (fr) * 2001-07-10 2011-07-27 Ge Healthcare As Composés peptidiques pour imagerie ciblée.
US7521419B2 (en) 2001-07-10 2009-04-21 Ge Healthcare As Peptide-based compounds
EP1494694A4 (fr) * 2002-03-26 2006-08-16 Develogen Israel Ltd Analogues de la somatostatine photoactifs cyclises par le squelette pour therapie photodynamique et imagerie
EP1494694A2 (fr) * 2002-03-26 2005-01-12 Peptor, Ltd. Analogues de la somatostatine photoactifs cyclises par le squelette pour therapie photodynamique et imagerie
US7700717B2 (en) * 2002-03-26 2010-04-20 Develogen Israel Ltd. Photo-active backbone cyclized somatostatin analogs for photodynamic therapy and imaging
US6861236B2 (en) 2002-05-24 2005-03-01 Applied Nanosystems B.V. Export and modification of (poly)peptides in the lantibiotic way
US7410943B2 (en) 2003-07-30 2008-08-12 Ge Healthcare As Imaging agents
US7811551B2 (en) 2003-07-30 2010-10-12 Ge Healthcare As Imaging agents
WO2005012335A1 (fr) * 2003-07-30 2005-02-10 Amersham Health As Agents d'imagerie a peptide bicyclique
WO2005030266A3 (fr) * 2003-09-29 2005-06-16 Amersham Health As Imagerie optique du cancer colorectal
WO2005030266A2 (fr) * 2003-09-29 2005-04-07 Amersham Health As Imagerie optique du cancer colorectal
WO2005084715A3 (fr) * 2004-03-04 2006-06-15 Amersham Health As Composes pharmaceutiques
WO2005084715A2 (fr) 2004-03-04 2005-09-15 Ge Healthcare As Composes pharmaceutiques
US7763234B2 (en) 2004-03-04 2010-07-27 Ge Healthcare As Pharmaceutical compounds

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