EP1007106A1 - Kombinatorische bibliothek - Google Patents

Kombinatorische bibliothek

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Publication number
EP1007106A1
EP1007106A1 EP98940025A EP98940025A EP1007106A1 EP 1007106 A1 EP1007106 A1 EP 1007106A1 EP 98940025 A EP98940025 A EP 98940025A EP 98940025 A EP98940025 A EP 98940025A EP 1007106 A1 EP1007106 A1 EP 1007106A1
Authority
EP
European Patent Office
Prior art keywords
metal
group
mixture
polyamino
chelator
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98940025A
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English (en)
French (fr)
Inventor
Alfred Pollak
John Thornback
David Roe
Ernest Wong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Resolution Pharmaceuticals Inc
Original Assignee
Resolution Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Resolution Pharmaceuticals Inc filed Critical Resolution Pharmaceuticals Inc
Publication of EP1007106A1 publication Critical patent/EP1007106A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
    • A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/14—Peptides, e.g. proteins
    • 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
    • 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
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • 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
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C07K1/047—Simultaneous synthesis of different peptide species; Peptide libraries

Definitions

  • the present invention relates to a combinatorial library. More particularly, the present invention relates to a combinatorial library useful for identifying targeting molecules which bind to selected ligands.
  • contrasting agents that in binding or localizing a site selectively within the body, help to resolve the image of diagnostic interest.
  • 67 Gallium salts for example, have an affinity for tumours and infected tissue and, with the aid of scanning tomography, can reveal afflicted body regions to the physician.
  • Other contrasting agents include the metal radionuclides such as 99m technetium and 186188 rhenium, and these have been used to label targeting molecules, such as proteins, peptides and antibodies that localize at desired regions of the human body.
  • Metal ions such as Gd are useful in diagnostic imaging as contrasting agents in magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • MRI is a currently used technique for the in vivo imaging of biological processes and offers non-ionizing radiation, modest magnetic fields, and is noninvasive. In addition, it offers superb spatial resolution (of the order of 1-3mm).
  • agents are used to improve the signal to noise ratio for the purpose of imaging designated areas or processes of the body. These are known as MRI contrast agents and have the potential to allow aquisition of data over shorter time periods and the ability to image regions that currently have poor image contrast.
  • Metal complexes have applications in the treatment, management or diagnosis of diseases. 1" 9 Examples include the use of Pt complexes in cancer therapy, 4"7 the use of Au complexes in rheumatoid arthritis therapy and the applications of Ga, In, Tc, Re, and Sm complexes in nuclear medicine. 3, 15"17
  • chelating agent Candidates for use as chelators are those compounds that bind tightly to the chosen metal radionuclide and also have a reactive functional group for conjugation with the targeting molecule.
  • Combinatorial chemistry is a methodology by which large numbers of compounds or libraries can be prepared and screened rapidly and concurrently in an efficient manner.
  • bifunctional chelators permits control of the type of metal coordination, the oxidation state of the coordinated metal, the stability and the conformation of the resulting metal complex.
  • a variety of bifunctional chelators are available. Examples of bifunctional chelators include polyamino polycarboxylates, polyamino polyphenolates, polyaza macrocycies with or without pendent coordination groups, tetradentate N X S 4 .
  • the present invention provides combinatorial library compounds which are effective for binding to a biological target in a rapid and cost effective manner, as well as a method of synthesizing the compounds
  • the present invention provides a combinatorial library of targeting agents that are labelled with a metal or radionuclide metal complexed to a chelating agent. A large number of labelled targeting agents can be quickly screened for their ability to bind to a biological target.
  • the present invention provides a combinatorial library of targeting compounds which have attached non-radioactive metal complexes which are isostructural with radiactive compounds for imaging applications or reactive Re complexes for radiotherapy.
  • a library comprising one or more sets of compounds, each set comprising a mixture of compounds of formula (1):
  • A-(B) n -C (1) wherein: A is a chelator moiety capable of complexing a metal;
  • B is a spacer group; n is selected from the integers 0 and 1 ; and C comprises one of a plurality of potential targeting molecules.
  • a library comprising one or more sets of compounds, each set comprising a mixture of compounds of formula (11):
  • W is selected from a group comprising: a) a metal binding moiety; b) a chelator moiety capable of binding a metal selected from polyamino polycarboxylates, polyamino polyphenolates, polyazamacrocycles with or without pendent coordination groups, tetradentate N x S 4 x ligands, polyamino polysulfides, polyamino polyphosphates, polyamino polyheterocyclics and derivatives or combinations of the above; c) a metal chelator of the general formula;
  • X is a linear or branched, saturated or unsaturated C ⁇ alkyl chain that is optionally interrupted by one or two heteroatoms selected from N, O, and S; and is optionally substituted by at least one group selected from hydroxyl, amino, carboxyl, C,. 6 alkyl, aryl and C(O)Z;
  • Y is H or a substituent defined by X;
  • R 1 through R 4 are selected independently from H; carboxyl; C ⁇ alkyl; C ⁇ alkyl substituted with a group selected from hydroxyl, amino, sulfhydryl, halogen, carboxyl, C ⁇ alkoxycarbonyl and aminocarbonyl; an alpha carbon side chain of a D- or L- amino acid other than proline; and C(O)Z;
  • R 5 is selected from H and a sulphur protecting group; and T is carbonyl or CH 2 .
  • a metal chelator selected from N,N-dimethyglycine-ser- cys-gly or N,N-dimethylglycine-tertbutylglycine-cys-gly; and e) a chelator complexed to a metal or metal radionuclide;
  • X is a multiple chelator binding moiety capable of coupling to at least one metal binding moiety;
  • Y is a spacer group is selected from the integers 0 and 1 ;
  • Z comprises a mixture of potential targeting moieties; m is greater than or equal to 1; and n is selected from the integers 0 and 1.
  • A-(B) n -C (1) wherein: A is a chelator moiety capable of complexing a metal; B is a spacer group, n is selected from the integers 0 and 1 ; and
  • C comprises one of a plurality of potential targeting molecules, comprising of the steps of:
  • a method for the synthesis of a library comprising one or more sets of compounds, each set comprising a mixture of compounds of formula (1):
  • A-(B) n -C (1) wherein: A is a chelator moiety capable of complexing a metal; B is a spacer group; n is selected from the integers 0 and 1 ; and C comprises one of a plurality of potential targeting molecules, comprising the steps of: I) Preparing a mixture of potential targeting molecules using combinatorial synthesis; and
  • a method of obtaining a compound having a desired targeting property comprising the steps of:
  • A-(B) n -C (1) wherein: A is a chelator complexed to a metal or metal nuclide B is a spacer group n is selected from the integers 0 and 1 C is one of a plurality of potential targeting molecules; and
  • a method of obtaining a labeled compound for the purposes of diagnostic imaging having a desired targeting property comprising the steps of: (1) providing one or more sets of mixtures which comprise a mixture of candidate compounds of formula (1):
  • A-(B) n -C (1) wherein: A is a chelator complexed to a metal or metal nuclide B is a spacer group n is selected from the integers 0 and 1 C is one of a plurality of potential targeting molecules; and (11 ) selecting from among the set of candidate compounds a compound having the desired property by exposing the mixture of candidate compounds to a substance to which the compound having the desired targeting property will preferentially bind.
  • a method of obtaining a labeled compound for the purposes of therapy or radiotherapy having a desired targeting property comprising the steps of;
  • A is a chelator complexed to a metal or metal nuclide B is a spacer group n is selected from the integers 0 and 1 ;
  • C is one of a plurality of potential targeting molecules
  • a method of obtaining a compound having a desired targeting property comprising the steps of;
  • X is a multiple chelator binding moiety capable of coupling to at least one metal binding moiety
  • Y is a spacer group is selected from the integers 0 and 1 ;
  • Z comprises a mixture of potential targeting moieties m is greater than or equal to 1 ; and n is selected from the integers 0 and 1 ; and (11) selecting from among the set of compounds a compound having the desired targeting property by exposing the mixture of compounds to a substance to which the compound having a desired targeting property will preferentially bind.
  • a method of obtaining a molecule having a desired targeting property comprising the steps of:
  • A is a chelator complexed to a non-radioactive metal which is isostructural with an analogous complex of a radioactive metal
  • B is a spacer group n is selected from the integers 0 and 1 ; and C is one of a plurality of potential targeting molecules;
  • A is a chelator complexed to a non-radioactive metal which is isostructural with an analogous complex of a radioactive metal
  • B is a spacer group
  • n is selected from the integers 0 and 1 ;
  • C is one of a plurality of potential targeting molecules; comprising the steps of:
  • a method for the synthesis of a library comprising one or more sets of compounds comprising the steps of:
  • the invention provides an iterative approach of library synthesis followed by biological testing and subsequent deconvolution to provide final compounds.
  • a moderately sized focused library of non-radioactive rhenium compounds is prepared as mixtures of up to 25 compounds.
  • a large library of rhenium targeting moiety conjugates is delivered as equimolar mixtures of 9-25 compounds in 96 well microtiter plates (1mg/well) for in vitro testing. These are then tested in the relevant assays and the most promising mixtures are segregated for deconvolution.
  • a second round of testing may then be undertaken using a smaller subset of the rhenium containing molecules together with a second set of biological tests to further reduce the number of molecules.
  • the final iteration will provide a series of discrete compounds as both the rhenium complex and a free chelate ready for labeling with radioactive 99m technetium which is isostructural to the non-radioactive rhenium isotope used.
  • the potential imaging lead candidates (preferably about 10 compounds) are delivered as pure chelator targeting moiety conjugates for radiolabe ng development in in vivo studies. This process provides labeled compounds that are effective for binding a biological target in a rapid and cost effective manner.
  • the targeting moiety of the present invention is a molecule that can selectively deliver a chelated metal or radionuclide or MRI contrasting agent to a desired location in a mammal.
  • Preferred targeting molecules selectively target cellular receptors, transport systems, enzymes, glycoproteins and processes such as fluid pooling.
  • Examples of targeting molecules suitable for coupling to the chelator include, but are not limited to: steroids, proteins, peptides, antibodies, nucleotides and saccharides.
  • Preferred targeting molecules include proteins and peptides, particularly those capable of binding with specificity to cell surface receptors characteristic of a particular pathology. For instance, disease states associated with over-expression of particular protein receptors can be imaged by labeling that protein or a receptor binding fragment thereof coupled to a suitable chelator.
  • targeting molecules are peptides capable of specifically binding to target sites and have three or more amino acid residues.
  • the targeting moiety can be synthesized either on a solid support or in solution and is coupled to the next portion of the chelator-targeting moiety conjugates using known chemistry.
  • the second portion of the molecule serves the purpose of separating the targeting portion from the imaging portion of the conjugate.
  • a multiple chelator coupling unit is attached to the targeting moiety (optionally via a linker subunit).
  • This is of oligomeric or dendrimeric construction and is capable of coupling multiple chelator units to the conjugate.
  • this multiple chelator coupling unit is a dendrimer containing a functionality to which suitable chelators can be attached.
  • the multiple chelator coupling unit is a branched lysine dendrimer.
  • the metal chelators used for the purposes of the present invention have the following general formula:
  • X is a linear or branched, saturated or unsaturated C ⁇ alkyl chain that is optionally interrupted by one or two heteroatoms selected from N,
  • O.and S is optionally substituted by at least one group selected from hydroxyl, amino, carboxyl, C 1 6 alkyl, aryl and C(O)Z;
  • Y is H or a substituent defined by X
  • Z is the position of attachment for the targeting portion of the library
  • R 1 through R 4 are selected independently from H; carboxyl; C, ⁇ alkyl;
  • R 5 is selected from H and a sulphur protecting group
  • T is carbonyl or CH 2
  • the complex has the following general formula:
  • X is a linear or branched, saturated or unsaturated C.,. 6 alkyl chain that is optionally interrupted by one or two heteroatoms selected from N, O, and S; and is optionally substituted by at least one group selected from hydroxyl, amino, carboxyl, C 1 6 alkyl, aryl and C(O)Z;
  • Y is H or a substituent defined by X
  • Z is the position of attachment for the targeting portion of the library
  • R 1 through R 4 are selected independently from H; carboxyl; C, ⁇ alkyl;
  • T is carbonyl or CH 2 ;
  • RP414 and RP455 The preferred chelators for 99m technetium radiopharmaceuticals are RP414 and RP455.
  • the structures of RP414 and RP455 are as follows:
  • R C(CH 3 ) 3 RP455
  • Re and Tc complexes of these chelators are isostructural. Also, these chelators are advantageous because the chemistry of these compounds is well understood and they form neutral Re and 99 Tc complexes. It is possible to label these chelators with Re or 99m Tc in one easy step. In addition these chelators have the advantage of being applicable for conjugation to a variety of targeting molecules, being compatible with solid phase synthesis.
  • Labeling of RP414 with 99m Tc can be carried out either at ambient or elevated temperature, rapidly, and with quantities of chelator approaching stoichiometric amounts.
  • the complex is stable to both acidic and basic conditions and remains unchanged in-vivo.
  • chelators may be used to carry out the invention.
  • the invention is not limited to the preferred chelators listed above.
  • the chelator comprises a functionality chosen from the known Gd chelators and is attached to the remainder of the conjugate by either solid phase or solution chemistry.
  • N-methylpyrrolidone, dimethylformamide, 2-(1 H- benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyl-uronium hexafluorophosphate, 1- hydroxybenzotriazole, diisopropylethyl-amine, dichloromethane and trifluoroacetic acid were purchased from Applied Biosystems Inc.
  • Triethylamine and terf-butyl methyl ether were purchased from Aldrich Chemical Inc.
  • Fmoc amino acids and Sasrin resin were purchased from Bachem Bioscience Inc. All chemicals were used as received.
  • the mobile phase was changed from 100% 0.1 % aqueous trifluoroacetic acid to 100% acetonitrile containing 0.1 % trifluoroacetic acid over 20 minutes at a flow rate of 2 mL/min.
  • the HPLC analyses of the RP487 peptide mixture and the Re complexes of the peptide mixture were performed by changing the mobile phase from 100% 0.1% aqueous trifluoroacetic acid to 60% acetonitrile containing 0.1% trifluoroacetic acid over 20 minutes at a flow rate of 2 mL/min. All HPLC analyses were monitored with a UV detector set at 215 and 254 nm.
  • Solid phase peptide syntheses were performed on an ABI Peptide Synthesizer model 433A using FastMoc chemistry and sasrin resin (User" Manual of Peptide Synthesizer Model 433A, Applied BioSystems, Philadelphia, 1993).
  • a set of potentially receptor specific structurally distinct molecules are placed on a solid support.
  • a bifunctional chelator such as dimethylglycine-serine-cysteine-glycine is attached to the library of molecules using tetrafluorophenol and 1-[3-(dimethylamino)-propyl]3-ethylcarbodiimide chloride.
  • the resulting solid phase library is then heated in a solution of ReOCI 3 (PPh 3 ) 2 or [ReO 2 (en) 2 ]CI to produce a library of Re complexes.
  • the library of 99m Tc complexes can be prepared by reacting the library with pertechnetate in the presence of tin (II) chloride and sodium gluconate.
  • the library of Re and 99m Tc complexes can be prepared by reacting the set of potentially receptor specific molecules with the tetrafluorophenol esters of Re and Tc dimethglycine-serine-cysteine-glycine complexes.
  • the libraries of Re and 99m Tc complexes are then cleaved off the solid support and evaluated in biological assay or in imaging studies.
  • Example 2 Synthesis of Gd complex as a receptor specific MRI contrasting agent.
  • a series of potentially receptor specific structurally distinct molecules are attached to solid phase support.
  • the chelator diethylenetriaminetetraacetic acid (DTPA) is attached to the set of potentially receptor specific molecules.
  • the resulting solid phase library is then placed in a solution of Gd acetate to produce a solid phase library of potentially receptor specific Gd complexes.
  • the Gd is coordinated to the DTPA chelator.
  • the library of Gd complexes is then cleaved off the solid support and evaluated in a biological assay.
  • Example 3 Development of a magnetic resonance imaging agent.
  • Some current attempts to produce efficient relaxation have resulted in the preparation of molecules having a number of gadolinium chelator molecules attached to one targeting molecule, often by way of a linker moiety to allow space between the target and the chelation parts of the molecule 37 39 .
  • the molecule can be divided into four parts; the targeting moiety, an optional suitable linker, a multiple chelator coupling unit capable of coupling multiple chelator moieties, and the chelator moieties coupled to the multiple chelator coupling unit.
  • the targeting moiety is a molecule that can selectively deliver a chelated radionuclide or MRI contrasting agent to a desired location in a mammal.
  • the second portion of the molecule, the optional linker, serves the purpose of separating the targeting portion from the imaging portion of the conjugate.
  • a multiple chelator coupling unit is attached to the targeting moiety (optionally via a linker subunit).
  • This is of oligomeric or dendrimeric construction and is capable of coupling multiple chelator units to the conjugate.
  • this multiple chelator coupling unit is a dendrimer containing a functionality to which suitable chelators can be attached.
  • the multiple chelator coupling unit is a branched lysine dendrimer.
  • the final portion of the conjugate will consist of the chelator units. This comprises a functionailty chosen from the known Gd chelators and is attached to the remainder of the conjugate by either solid phase or solution chemistry.
  • mixtures of compounds in any or all of the above subsections of the agent are prepared.
  • preparation of a combination of libraries having a mixture in one of the sections, together with a series of related libraries produced by the alteration of the previous or subsequent parts of the agent is carried out in a parallel fashion.
  • a library of targeting molecules would be split and each part attached to a single linker- dendrimer-chelator subunit.
  • Such a route provides a parallel series of libraries each having a single linker-dendrimer-chelator unit in order to optimize the targeting of the molecules.
  • Producing a mixture of compounds based on the dendrimer and single targeting-linker and chelator units allows for variation of the relaxivity of the system.
  • Peptides of various amino acid sequences and with varying side chain protection groups were prepared via a solid phase peptide synthesis method on an automated peptide synthesizer using FastMoc 1.0 mmole chemistry.
  • 3 Preloaded Fmoc amino acid sasrin resin and Fmoc amino acid derivatives were used.
  • the FMOC group Prior to the addition of each amino acid residue to the N-terminus of the peptide chain, the FMOC group was removed with 20% piperidine in NMP.
  • Each Fmoc amino acid residue was activated with 0.50 M HBTU/ HOBt/ DMF, in the presence of 2.0M DIEA/ NMP.
  • the C-terminus of the completed peptide was attached to the resin via the sasrin linker.
  • the peptidyi resin was washed with dichloromethane and dried under vacuum for 20-24 hours. This method was used to prepare the following peptidyi resin of varying amino acid sequences containing side chain protection groups:
  • Example 5 Synthesis of RP487 peptide mixture-resin, Dimethylgly-Ser(O e -Trt)- Cys(S e -Mott)-Gly-X-Tyr(O e -f-bu)-Gly-Z-Gly-[resin] (where X are Leu, Arg(N e - Pmc) or Phe and Z are Lys(N e -Boc), Ser(O e -Trt) or Tyr(O e -f-bu)).
  • the synthesis of the RP487 peptide mixture resin was performed using FastMoc 0.25 mmol chemistry on an automated synthesizer.
  • 35 Fmoc-Gly sasrin- resin (0.7 mmol/ g, 0.25 mmol, 357 mg) was placed in the reaction vessel.
  • Amino acid cartridges 2, 3, 5, 6, and 7 counted from the C-terminus contained 1 mmol of each Fmoc amino acid derivatives, Gly, Tyr(O -Bu), Gly, Cys(S e -Mott), and Ser(O e -Trt), respectively.
  • Cartridge 1 had Fmoc amino acid derivatives of Lys(N e - Boc), Ser(O e -Trt), and Tyr(O -Bu) (0.33 mmol / amino acid). Meanwhile, cartridge 4 carried Fmoc amino acids of Arg(N e -Pmc), Leu, and Phe (0.33 mmol/ amino acid).
  • N,N-Dimethylglycine (1mmol) in cartridge 8 was pre-treated with 0.50 M HBTU/ HOBt/ DMF (0.8 mL) before it was inserted on the synthesizer. After completion of the automatic synthesis, the resulting product was removed from the synthesizer, and dried under vacuum for 2 hours to afford the titled RP487 peptide mixture-resin (610 mg).
  • Example 6 Synthesis of RP487 peptide mixture, Dimethylgly-Ser-Cys-Gly- - Tyr-Gly-Z-Gly (where X is Leu, Arg or Phe and Z is Lys, Ser or Tyr).
  • the RP487 peptide mixture-resin 120 mg, 0.05 mmol was added to a cleavage composition of 82.5% TFA/ 5% phenol/ 5% thioanisole/ 2.5% 1 ,2-ethane dithiol/ 5% mili-Q water (1 mL) at 0 °C. 36
  • the reaction suspension was then stirred at room temperature for 5 hours.
  • the cleavage suspension was filtered by vacuum after 5 hours, and the filtrate was allowed to add in cold .erf-butyl methyl ether (20 mL) at 5°C.
  • the precipitated residue was subsequently washed with tetf-butyl methyl ether (2 x 30 mL).
  • ReOCI 3 (PPh 3 ) 2 (0.3793 g, 0.000456 moles) and 1 mL of triethylamine were added to the NMP resin mixture.
  • the ReOCI 3 (PPh 3 ) 2 dissolved to give a purple mixture.
  • the mixture was heated at 40-50 °C for 4 hours.
  • the resin was then collected by vacuum filtration.
  • the resin was washed with 3 x 10 mL NMP, followed by 3 x 10 mL CH 2 CI 2 .
  • the resin was dried under vacuum overnight.
  • the resin was placed in 90 % aqueous trifluoroacetic acid and stirred for 4 hours. The resin was removed by vacuum filtration and the supernatant was added dropwise to tetf-butyl methyl ether at 0 °C. Red-brown precipitate formed. The precipitate was collected by centrifugation and analyzed by HPLC and electrospray mass spectrometry. The syn and anti isomers of the Re complex were observed in the HPLC chromatogram. This is consistent with other known Re complexes with N 4.X S X chelators.
  • Example 8 Synthesis of Re oxo complex of Dimethylgly-Ser-Cys-Gly using RP443-resin.
  • RP443-resin (0.1621 g) was swollen in 3 mL of NMP.
  • ReOCI 3 (PPh 3 ) 2 (0.4023 g, 0.000483 moles) and 1 mL of triethylamine were added to the NMP resin mixture.
  • the ReOCI 3 (PPh 3 ) 2 dissolved to give a purple mixture.
  • the mixture was heated at 40-50 °C for 4 hours.
  • the resin was then collected by vacuum filtration.
  • the resin was washed with 3 x 10 mL NMP, followed by 3 x 10 mL CH 2 CI 2 .
  • the resin was dried under vacuum overnight.
  • the resin was placed in 90 % aqueous trifluoroacetic acid and stirred for 4 hours. The resin was removed by vacuum filtration and the supernatant was added dropwise to terf-butyl methyl ether at 0 °C. Red-brown precipitate formed. The precipitate was collected by centrifugation and analyzed by HPLC and electrospray mass spectrometry. The syn and anti isomers of the Re complex was observed in the HPLC chromatogram. The coordination of the peptide to the Re metal caused the displacement of the cysteine sulfur trityl protection group but did not cause the peptide to be cleaved off the resin.
  • Example 9 Synthesis of Re oxo complex of Dimethylgly-Ser-Cys-Gly-Thr-Lys- Pro-Pro-Arg using RP441 -resin.
  • RP441-resin (0.0799 g) was swollen in 3 mL of NMP.
  • ReOCI 3 (PPh 3 ) 2 (0.3983 g, 0.000478 moles) and 1 mL of triethylamine were added to the NMP resin mixture.
  • the ReOCI 3 (PPh 3 ) 2 dissolved to give a purple mixture.
  • the mixture was heated at 40-50 °C for 8 hours.
  • the resin was then collected by vacuum filtration.
  • the resin was washed with 3 x 10 mL NMP, followed by 3 x 10 mL CH 2 CI 2 .
  • the resin was dried under vacuum overnight.
  • the resin was placed in 90 % aqueous trifluoroacetic acid and stirred for 4 hours. The resin was removed by vacuum filtration and the supernatant was added dropwise to ter-butyl methyl ether at 0 °C. Red-brown precipitate formed. The precipitate was collected by centrifugation and analyzed by HPLC and electrospray mass spectrometry. The syn and anti isomers of the Re complex were observed in the HPLC chromatogram. The coordination of the peptide to the Re metal caused the displacement of the cysteine sulfur trityl protection group but did not cause the peptide to be cleaved off the resin.
  • Example 11 Synthesis of Re oxo complex of Dimethylgly-Ser-Cys-Gly-Gly-Lys- Lys-Leu-Leu-Lys-Lys-Leu-Lys-Lys-Leu-Leu-Lys-Lys-Leu-NH 2 using RP478- resin.
  • the resin was placed in 90 % aqueous trifluoroacetic acid and stirred for 8 hours. The resin was removed by vacuum filtration and the supernatant was added dropwise to tetf-butyl methyl ether at 0 °C. Red-brown precipitate formed. The precipitate was collected by centrifugation and analyzed by HPLC and electrospray mass spectrometry. The syn and anti isomers of the Re complex was observed in the HPLC chromatogram. The coordination of the peptide to the Re metal caused the displacement of the cysteine sulfur trityl protection group but did not cause the peptide to be cleaved off the resin.
  • Example 12 Synthesis of Re oxo complex of Dimethyigly-Ser-Cys-Gly- -Tyr- Gly-Z-Gly (where X is Leu, Arg or Phe and Z is Lys, Ser or Tyr) using RP487- resin.
  • ReOCI 3 (PPh 3 ) 2 (0.9210 g, 0.00111 moles) and 1 mL of triethylamine were added to the NMP resin mixture.
  • the ReOCI 3 (PPh 3 ) 2 dissolved to give a purple mixture.
  • the mixture was heated at 40-50 °C for 12 hours.
  • the resin was then collected by vacuum filtration.
  • the resin was washed with 3 x 10 mL NMP, followed by 3 x 10 mL CH 2 CI 2 .
  • the resin was dried under vacuum overnight.
  • the resin was placed in 90 % aqueous trifluoroacetic acid and stirred for 4 hours. The resin was removed by. vacuum filtration and the supernatant was added dropwise to tetf-butyl methyl ether at 0 °C. Red-brown precipitate formed. The precipitate was collected by centrifugation and analyzed by HPLC and electrospray mass spectrometry. Since the Re complex of each peptide sequence exists as the syn and anti isomers, the total number of compounds prepared was 18.
  • Example 13 Synthesis of Re oxo complex of Dimethylgly-Ser-Cys-Gly-X-Tyr- Gly-Z-Gly (where X are Leu, Arg or Phe and Z are Lys, Ser or Tyr) in aqueous solution.
  • Example 14 Use of multiple discrete loaded resins in one reactor vessel to provide a combinatorial library
  • the various peptide sequences containing varying side chain protecting groups in these examples were synthesized via a solid phase synthesis method on an automated synthesizer using FastMoc chemistry on scales varying from 0.1 to I .Ommol.
  • the FMOC group Prior to the addition of each amino acid residue to the N-terminus of the peptide chain the FMOC group was removed with 20% piperidine in NMP. Each FMOC amino acid was activated with 0.5M HOBT/HBTU/DMF in the presence of 2.0M DIEA/NMP. The C-terminus was attached to the solid phase via the sasrin linker. After completion of the synthesis the resin was washed with NMP followed by dichloromethane and dried under vacuum for up to 24 hours.
  • Example 15 Synthesis of a library of peptides on solid phase having the sequence Dimethylglycine-Ser(O-Trt)-Cys(S-Acm)-Gly-X-Tyr(O-t-Bu)-Gly-Z-Y (Where X is Leu, Arg(N-Pmc), or Phe, Z is Lys(N-Boc), Ser(O-Trt), or Tyr(o_t- Bu), and Y is Gly, Phe, Leu, Arg(N-Pmc), or Lys(N-Boc))
  • the reactor vessels employed in the peptide synthesizer were loaded with a mixture of 5 MicroKans (supplied by IRORI ) each containing 30mg of Tenta gel TGA resin having the following amino acids preloaded; glycine, Phenylalanine, Leucine, Arginine, Lysine. This mixture was then subjected to the conditions described above to synthesize the following amino acid sequence onto each of the resins;
  • RPLIB6G-resin Dimethylgly-ser(O-t-bu)-Cys(S-Acm)-Gly-X-Tyr(O-t-Bu)-Gly-Z- Gly-Resin
  • RPLIB6F-resin Dimethylgly-ser(O-t-bu)-Cys(S-Acm)-Gly-X-Tyr(O-t-Bu)-Gly-Z- Phe-Resin
  • RPLIB6K-resin Dimethylgly-ser(O-t-bu)-Cys(S-Acm)-Gly-X-Tyr(O-t-Bu)-Gly-Z- Lys-Resin
  • X consists of a mixture of FMOC amino acid derivatives of Leu, Arg (N-Pmc), or Phe
  • Z consists of a mixture of FMOC amino acid derivatives of Lys(N-boc), Ser(O-trt) or Tyr(O-t-Bu).
  • Example 16 Synthesis of a series of peptides having the sequence Dimethylglycine-Ser-Cys-Gly-X-Tyr-Gly-Z-Y (Where X is Leu, Arg, or Phe, Z is Lys, Ser, or Tyr, and Y is Gly, Phe, Leu, Arg, or Lys)
  • N-terminal amine of the above peptide attached to sasrin resin (100mg) is deprotected of its Fmoc group under standard Fmoc deprotection conditions.
  • the amine is then capped with a suitably reactive reagent (see list below).
  • the resin is placed in a solution of NMP (500uL) for the resin to swell.
  • DIEA 25uL, 2M
  • one of the capping agents O. ⁇ mmol
  • the capped peptide is removed from the resin by shaking in the presence of 95% Trifluoroacetic acid (0.5-1 mL) at room temperature for 4 hours. After the cleavage is complete the resin is filtered off and then washed with further trifluoroacetic acid (0.5mL). The combined trifluoroacetic acid solutions are then combined and concentrated under reduced pressure.
  • the capped peptide is then purified by reverse phase HPLC on C18 silica gel using a gradient of 0-100% acetonitrile in water over a period of 20 mins The cuts containing the relevant compound are then lyophilized and the peptide analyzed by electrospray mass spectroseopy. The peptides display the properties shown in the table below.
  • a list of the amine capping agents includes but is not limited to:
  • Example 18 Synthesis of a library of 324 potential chemotactic peptides using a combination of parallel synthesis and split and mix technologies
  • the various peptide sequences (that is the sequence Gly-Lys(DDE)-(mixture A,B,C)-(mixture D,E,F)-Phe-Leu-Nle-NH 2 and numbered RP552 through RP557) containing varying side chain protecting groups in these examples were synthesised via a solid phase synthesis method on an automated synthesizer using FastMoc chemistry on 1.0 mmol scale.
  • the FMOC group Prior to the addition of each amino acid residue (or mixture of acids as described above) to the N-terminus of the peptide chain the FMOC group was removed with 20% piperidine in NMP. Each FMOC amino acid was activated with 0.5M HOBT/HBTU/DMF in the presence of 2.0M DIEA/NMP.
  • the C-terminus was attached to the solid phase via the sasrin linker. After completion of the synthesis the resin was washed with NMP followed by dichloromethane and dried under vacuum for up to 24 hours. Where mixture of amino acids were employed the three amino acids were added as equimolar mixtures of suitably side chain protected FMOC acid residues in a single coupling step and otherwise treated as a single amino acid residue.
  • each mixture of 9 compounds is deprotected of its Fmoc group under standard fmoc deprotection conditions.
  • the amine is then capped with a suitably reactive reagent (see list).
  • Each microkan is placed in a solution of NMP (500uL) for the resin to swell.
  • DIEA 25uL, 2M
  • one of the capping agents O. ⁇ mmol.
  • the reaction is shaken for 2 to 18 hours at room temperature. Completion of the capping was confirmed by treatment of a small portion of the resin with 3% ninhydrin-EtOH. Lack of blue/purple colour indicated a complete reaction.
  • the reaction is filtered and the resin is washed with NMP (3x5mL) then dichloromethane (3x ⁇ mL) and the resin is dried in vacuo.
  • Each of the peptides was liberated from the support in 9 ⁇ % TFA: 5% water (1mL) after 4 hours shaking at room temperature, followed by filtration. The products were concentrated in vacuo. The residue was redissolved in trifluoroacetic acid (150uL) and dripped into t-butyl-methyl ether ( ⁇ mL) to precipitate. Each was centrifuged to a pellet, the solvent decanted and the pellets dried in vacuo. The products were dissolved in water and acetontrile ( ⁇ mL) and lyophilized to pale beige powders.
  • Example 20 Routes for the introduction of the rhenium complexes to each mixture (RP552-557)
  • lysine side chain first be deprotected and one of the chelators (RP414 or RP4 ⁇ ) be attached to the sequence as a single residue or stepwise.
  • chelators RP414 or RP4 ⁇
  • the cysteine residue must be sulphur protected with a labile group which is lost 3 ⁇
  • the column was first washed with a 5% acetonitrile: 9 ⁇ % water solution acidified to pH2 with 3N HCI.
  • the product was eluted in a 60% acetonitrile: 60% water solution acidified to pH2 with 3N HCI.
  • the appropriate pure fractions were identified by silica TLC (t-butanol:water:methanol, 10:3:2, rf: 0.8 ⁇ ) followed by KMnO 4 staining.
  • the correct fractions were pooled and 0 concentrated in vacuo to a red-brown glass (58mg, % yield).
  • ReO- 0 Dimethylglycine-t-butyl-glycine-S-Acetamidomethyl-Cysteine-Glycine(ReO-RP4 ⁇ ) tetrafluorophenyi ester (10mg) in ethyl acetate (1 mL).
  • the reactions were capped and shaken 20 hours at room temperature, followed by filtration, washing with copious ethyl acetate, N-methylpyrrolidone, dichloromethane. The red-brown resins were dried in vacuo. ⁇
  • Example 2 ⁇ Deconvolution of Peptide Mixture ReORP552 with N-terminus capping goups attached.
  • Resin-gly-lys(DDE)-lys-tyr-phe-leu-Nle Each of the following resins containing the peptides was then capped with a cyclopropylcarbonyl group as follows: Each resin is placed in a solution of NMP (500uL) for the resin to swell. To this solution is added DIEA (2 ⁇ uL, 2M) and cyclopropane carbonyl chloride (O. ⁇ mmol). The reaction is shaken for 18 hours at room temperature. The reaction is filtered and the resin is washed with NMP (3x ⁇ mL) then dichloromethane (3x ⁇ mL) and the resin is dried in vacuo. Completion of the reaction is ensured by the use of a ninhydrin test to indicate complete reaction of amino groups.
  • the rhenium complex was introduced as follows: The Dde epsilon amino group protection on C-terminus Lysine was first removed with three, five minute washes of 2% hydrazine in N-methylpyrrolidone (3x1 mL). The resin was ⁇ then thoroughly washed with N-methylpyrrolidone then dichloromethane, and dried in vacuo.
  • the rhenium complex was liberated from the resin using 9 ⁇ % trifluoroacetic acid (600 L) for 1. ⁇ h at room temperature. Filtration of the solution and removal of the trifluoroacetic acid under reduced pressure gave glycyl-lysine( -Re ⁇ oxo Dimethylglycyl-t-Butylglycyl-cysteinyl-glycyl)-N-(4-phenylpiperazin-1 - ylacetamide):ESMS 963 (M+H + ), expected 963.
  • the resin was dried on the aspirator and then cleaved with 9 ⁇ % trifluoroacetic acid in water (3 hours).
  • the trifluoroacetic acid/peptide solution was filtered into tert-butyl methyl ether (10 mL) and centrifuged. The ether was decanted. This washing process was repeated 3 times. After the final wash the ether was decanted leaving behind the peptide which had precipitated.
  • the peptide was dissolved in water (1 mL), frozen with liquid nitrogen ⁇ and lyophilized.
  • Example 30 Construction of a solid phase library of 1,000 metallocarbohydrates for use as imaging agents
  • R represents diversity groups as outlined in the procedure
  • This solid phase library is then treated with 20% piperidine in NMP to remove the Fmoc group from the C-2 amino functionality and the resulting resin treated with a solution of ReO-N,N,-dimethylglycine-ser-cys-gly-tetrafluorophenyl ester to provide the solid phase library.
  • This library is then liberated from the solid support by treatment with 50% TFA in dichloromethane. Removal of the TFA and dichloromethane under vacuum followed by lyophilisation provides the metaliocarbohydrate library.
  • Sprague-Dawley rats weighing 300-350 g were purchased from Charles River-Bausch & Lomb Laboratories (St.Constant, Quebec).
  • BOC-MLP BOC-MLP
  • cytochalasin B oyster shell glycogen
  • polyethyienimine polyethyienimine
  • OPD o- ⁇ phenylenediamine
  • H 2 0 2 and H 2 SO 4 Sigma Chemical Corp., St. Louis, MO
  • 3 H-fMLP New England Nuclear, Boston, MA
  • Peptide fMLP derivatives, N- formyl-norleucyl — tyrosyl-lysine (For-Nle-LP-Nle-YK) and iso-boc-MLFK were synthesized in-house by Resolution Pharmaceuticals Inc. (Mississauga, ON).
  • HBSS- Hanks' buffered salt solution
  • EDTA ethylene-diaminetetra-acetic acid
  • Neutrophil fMLP receptor binding assays Neutrophil fMLP receptor binding assays. fMLP saturation binding experiments used to determine K D values were carried out with 2.6 X 10 5 PMNs per sample suspended in a final volume of 160 uL of fMLP, 3 H-fMLP and/or HBSS+. Samples were done in quadruplicate and non-specific binding was assessed in the presence of 10 uM fMLP and 3 H-fMLP in the range of 1 nM to 160 nM. Total binding was evaluated following the addition of 3 H-fMLP in the concentration range of 1 nM to 150 nM.
  • Competition assays were conducted with 6 nM 3 H-fMLP in addition to the nonradioactive competing ligand added at 10 uM and 1.0 uM. Total binding in the competition assays was assessed in the presence of 1.0 x 10 6 PMNs per sample while non-specific binding was determined in the absence of cells.
  • library RP ⁇ 3-capped-17 was selected for further deconvolution.

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AU4170100A (en) * 1999-03-01 2000-09-21 Combimatrix Corporation Combinatorial chelator array
CA2379647A1 (en) * 1999-08-12 2001-02-22 Palatin Technologies, Inc. Melanocortin metallopeptide constructs, combinatorial libraries and applications
AU1623801A (en) 1999-11-19 2001-05-30 Palatin Technologies, Inc. Opioid metallopeptide compositions and methods
US7385025B2 (en) 2000-12-19 2008-06-10 Palatin Technologies, Inc. Metallopeptide compounds
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