WO2012150302A1 - Ligands à base de tétraaza-cycloalcanes et leur utilisation en médecine nucléaire et en imagerie moléculaire - Google Patents

Ligands à base de tétraaza-cycloalcanes et leur utilisation en médecine nucléaire et en imagerie moléculaire Download PDF

Info

Publication number
WO2012150302A1
WO2012150302A1 PCT/EP2012/058130 EP2012058130W WO2012150302A1 WO 2012150302 A1 WO2012150302 A1 WO 2012150302A1 EP 2012058130 W EP2012058130 W EP 2012058130W WO 2012150302 A1 WO2012150302 A1 WO 2012150302A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
group
general formula
imaging
compounds according
Prior art date
Application number
PCT/EP2012/058130
Other languages
English (en)
Inventor
Johannes NOTNI
Hans-Jürgen Wester
Original Assignee
Technische Universität München
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 Technische Universität München filed Critical Technische Universität München
Publication of WO2012150302A1 publication Critical patent/WO2012150302A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom

Definitions

  • the present invention relates to the field of nuclear medicine and molecular imaging, i.e. radiopharmaceuticals for imaging and targeted radiotherapy using metal ion radionuclides or paramagnetic metal ions in combination with chelators that are highly functional i zed with peptidic or nonpeptidic ligands.
  • Metal radionuclides are currently used in nuclear imaging and therapy.
  • Related tracers are usually formed from a metal binding group (chelate ligand), which is bound, with or without linkers, to one or more targeting vectors.
  • chelate ligand metal binding group
  • DOTA (l ,4,7, 10-tetraazacyclododecane-l ,4,7,10-tetraacetic acid) is the most used compound for this purpose. It forms stable complexes with many transition metal ions as well as lanthanide ions. Very frequently, one of the acetic acid side arms of this molecule is transferred into a secondary or tertiary amide, bearing the linker or the targeting vector. For imaging purposes, the metal ion is added as the last step, thereby forming the complex which serves as the tracer.
  • DOTA DOTA
  • D03A 10-tetraazacyclododecane- 1 ,4,7-triacetic acid
  • the coordination of the metal ion occurs on the nitrogen atoms of the azamacrocycle backbone and on the deprotonated carboxyl groups of the acetic acid substituents. These carboxylic acid moieties thus have to be deprotonated in order to act as coordination sites. Therefore, a pH value exceeding their ⁇ ⁇ of approx. 3.5—4.5 must be maintained during the labelling procedure. Labelling at a lower pH is substantially hampered. In addition, labelling of DOTA-like structures requires either heating, usually up to 80-95 °C, or comparably high ligand concentrations (in the range of 1 mM).
  • bioconjugates of chelators that is, molecules consisting of a targeting vector covalently bound to a chelating unit
  • the use of protecting groups on either side is mandatory in most cases.
  • the carboxylate moieties intended for metal complexation have to be protected during amide coupling.
  • the tris-tert- butyl esters of these compounds are thus employed for conjugation, requiring an additional subsequent deprotection step in order to obtain the desired conjugate.
  • the term multimer refers to molecules which comprise more than one targeting vector of the same kind.
  • Multimers are desirable because in comparison to monomers, they can exhibit increased affinity to the respective target, thus resulting in higher accumulation at the target side, better image contrast and/or better therapeutic results.
  • DOTA-like chelators are usually bound to a linker which allows more than one targeting vector to be bound.
  • the assembly of such molecules usually involves multistep syntheses with low overall yield.
  • the invention aims at chelate ligands that can form complexes with non-radioactive as well as radioactive metal ions.
  • a further aim of the invention is the possibility of simple preparation of conjugates of said chelate ligands to other functional molecules such as linkers or biomolecules.
  • the invention aims at the preparation of ligands that allow for the conjugation of multiple other units without the necessity of usage of additional branched linker groups.
  • the invention aims at the preparation of ligands that consist of multiple but different signalling units, e.g. a radionuclide within the chelate and a fluorescent dye at the chelate's side arms, and an addressing unit, i.e. a peptide, protein, small molecule or other molecules that bind with high affinity to a given molecular target overexpressed in a pathological state or disease.
  • signalling units e.g. a radionuclide within the chelate and a fluorescent dye at the chelate's side arms
  • an addressing unit i.e. a peptide, protein, small molecule or other molecules that bind with high affinity to a given molecular target overexpressed in a pathological state or disease.
  • the invention furthermore aims at coordination compounds (metal ion chelates) of said ligands with radioactive metal ions that can be applied in nuclear imaging techniques such as gamma szintigraphy, single photon emission computed tomography (SPECT), or positron emission tomography (PET), as well as in targeted radiotherapy.
  • coordination compounds metal ion chelates
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • Figure 1 ESI-MS (positive mode) of compound 2, showing the isotope pattern of natural Gadolinium.
  • Figure 2 ESI-MS (positive mode) of compound 5.
  • Figure 3 Radioactivity incorporation (%) for the labeling of compound 5 and DOTA with 177 Lu (100 MBq)
  • Figure 6 Szintigraphic images of M21 tumor xenografted CD-I nude mice.
  • FIG. 7 PET image (maximum intensity projection, 75 min after injection of 35 MBq of 64 Cu-5/compound 5) of a M21 tumor xenografted CD-I nude mouse. M21 Tumor position is indicated with an arrow.
  • the invention relates to chelators based on monocyclic and polycyclic tetraaza-cycloalkanes with methyl(2-carboxyethyl)phosphinic acid groups at all four nitrogen atoms (see general formula (I)).
  • the present invention therefore relates to compound according to general formula (I)
  • n, o and p are independently of another selected from integers 0, 1 and/or 2, preferably m, n, o and p are independently of another selected from integers 1 and/or 2.
  • m, n, o and p have the following meanings: m is 1 , n is 1 , o is 1 and p is 1 , or
  • n 1
  • o 1
  • p 1
  • n 1
  • o 1
  • p 2
  • cyclen-derivative that is, the chelator according to general formula (I), with all four variables m, n, o, and p equalling 1.
  • the present invention preferably relates to compounds according to general formula (I) as mentioned above, wherein m is 1 , n is 1 , o is 1 and p is 1.
  • methyl(2-carboxyethyl)phosphinic acid) substituents can be reacted with primary or secondary amines to form the corresponding amides.
  • Useful reagents for this procedure are uronium-like coupling reagents, such as HBTU (0-Benzotriazole-N,N,N',N'-tetramethyl- uronium-hexafluoro-phosphate), TBTU (0-(Benzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate), and particularly HATU (2-(lH-7-Azabenzotriazol-l- yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate Methanaminium).
  • the phosphinic acid moieties are in general not affected by this coupling protocol. Particularly, it was found that no formation of any phosphinamide is observed. It must be noted that, according to the invention, the use of the coupling reagents TBTU and HBTU on methyl(2- carboxyethylphosphinic acid) N substituents is identical to a method described in prior art. (Notni, J.; Hermann, P.; Havlickova, J.; Kotek, J.; Kubicek, V.; Plutnar, J.; Lokomova, N.; Riss, P. J.; Rosch, F.; Lukes, I. A triazacyclononane-based bifunctional phosphinate ligand for the preparation of multimeric 68 Ga tracers for positron emission tomography. Chem. Eur. J. 2010, 16, 7174-7185.)
  • the present invention further relates to compounds according to general formula ( ⁇ )
  • m, n, o and p are independently of another selected from the integers 1 and/or 2 and R', R", R'" and R"" are independently of another selected from OH or an amide residue - NR R 2, wherein R and R are independently of another selected from hydrogen or residues obtained from compounds selected from the group consisting of residues with high affinity to a molecule or molecular structure pathologically or normally expressed in tissues small, such as antigens, receptors, transporters, enzymes organic molecules. Examples for these residues are small molecules, amino acids, peptides, proteins, amino sugars, nucleobases, biomolecules, fluorophores and mixtures thereof.
  • R 1 and R 2 are independently of another selected from hydrogen or the group consisting of signalling units, such as fluorophors, metal chelators, or chemical groups comprising radioisotopes, or residues with high affinity to a molecule or molecular structure pathologically or normally expressed in tissues, such as antigens, receptors, transporters, enzymes, or organic molecules, e.g. amino acids, peptides, proteins, carbohydrates, nucleobases, antibodies, antibody fragments, and mixtures thereof.
  • signalling units such as fluorophors, metal chelators, or chemical groups comprising radioisotopes, or residues with high affinity to a molecule or molecular structure pathologically or normally expressed in tissues, such as antigens, receptors, transporters, enzymes, or organic molecules, e.g. amino acids, peptides, proteins, carbohydrates, nucleobases, antibodies, antibody fragments, and mixtures thereof.
  • R 1 and R 2 are independently of another biomolecules selected from the group consisting of c(RGDfK)(Pbf,tBu), c(DGRKf)(Pbf,tBu), cyclo(d-Tyrl- d-Orn2-Arg3-Nal4-Gly5) linked via D-Orn2 (CPCR4), H-D-Phe-Cys-Phe-D-Trp-Lys-Thr- Cys- Thr-ol (Disulfide bridge: 2-7), linked via D-Phel ,H-D-Phe-Cys-Phe-D-Trp-Lys-Thr- Cys-Thr-OH (Disulfide bridge: 2-7), linked via D-Phel, H-D-Phe-Cys-BzThi3-D-Trp-Lys- Thr-Cys-Thr-OH (Disulfide bridge: 2-7, linked via D-P
  • R 1 and R 2 are independently of another selected from fluorophores selected from the group consisting of derivates of acridine, derivates of anthraquinone, arylmethane dyes, diarylmethane dyes, triarylmethane dyes, azo dyes, diazonium dyes, nitro dyes, nitroso dyes, derivates of phthalocyanine, derivates of quinone, azin dyes, eurhodin dyes, safranin dyes, indamins, indophenol dyes, oxazin dyes, oxazone dyes, thiazin dyes, thiazole dyes, derivates of thiazole, xanthene dyes, fluorene dyes, pyronin dyes, fluorone dyes, Rhodamine dyes, Porphyrine dyes, Cyanine dyes (Merocyanine, Indocyanine), coumarine dyes
  • R 1 and R 2 are independently of another selected from CEST or PARACEST agents selected from the group of lanthanoid metal ion chelates, particularly those based on azamacrocyclic chelating units, such as DOTA complexes.
  • R is hydrogen and R is selected from the above mentioned residues.
  • R', R", R'" and/or R"" being OH or -NR'R 2
  • one, two, three or four carboxylic acid groups are transferred to amide groups.
  • one, two, three or four of R', R", R'" and/or R" " are -NR ! R 2 , wherein R 1 and R 2 have the meanings as mentioned above.
  • R 1 and/or R 2 contain at least one additional functional group allowing for further functionalisation (so-called linkers).
  • Such functional groups can be carboxylic acid, carboxylic acid ester, amine, carbamoyl ester, terminal alkyne, terminal alkene, azide, cyanide, thiol, isothiocyanate, aldehyde, succinimide.
  • chelators according to general formula (II)
  • R and/or R are small, Afunctional molecules which contain at least one additional functional group allowing for further functionalisation (so-called linkers).
  • Such functional groups can be carboxylic acid, carboxylic acid ester, amine, carbamoyl ester, terminal alkyne, terminal alkene, azide, cyanide, thiol, isothiocyanate, aldehyde, succinimide, maleimide.
  • the invention therefore preferably relates to compounds according to general formula (II) wherein R 1 and/or R belong to this group of substituents.
  • the present invention further relates to a process for the preparation of compounds according to general formula (II) as defined above by reaction of compounds of general formula (I) as defined above and compounds H-NR ! R 2 2 , wherein R 1 and R 2 have the same meanings as defined above.
  • This process according to the present invention can in general be conducted under conditions that are known to the skilled artisan.
  • this process according to the present invention is conducted in the presence of at least one coupling agent, for example selected from uronium-like coupling reagents, such as HBTU (0-Benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluoro-phosphate), TBTU (0-(Benzotriazol- 1 -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate), and HATU (2-(lH-7-Azabenzotriazol-l-yl)-l ,l ,3,3- tetramethyl uronium hexafluorophosphate Methanaminium).
  • uronium-like coupling reagents such as HBTU (0-Benzotriazole-N,N,N',N'- tetramethyl-uron
  • the present invention further relates to compounds (chelates) according to general formula (III)
  • R 1 and R 2 are independently of another selected from hydrogen or residues obtained from compounds selected from the group consisting of amino acids, peptides, proteins, amino sugars, nucleobases, biomolecules, fluorophores and mixtures thereof, M is at least one metal cation, wherein k is the oxidation state of M, for example 2, 3 or 4.
  • R 1 is hydrogen and R is selected from the above mentioned residues.
  • a preferred embodiment relates to coordination compounds (chelates) according to general formula (III), consisting of chelators according to formulae (I) and (II) and at least one metal ion, wherein m, n, o and p are independently of another selected from the integers 1 and/or 2, R', R", R" ' and R" " are independently of another selected from OH or an amide residue -NR'R 2 2 , wherein R 1 and R 2 are independently of another selected from hydrogen or residues obtained from compounds selected from the group consisting of amino acids, peptides, proteins, amino sugars, nucleobases, biomolecules, fluorophores, and mixtures thereof.
  • M k+ is at least one metal cation, wherein k is the oxidation state of M, for example 2, 3 or 4.
  • R is OH and R is selected from the above mentioned residues.
  • M k+ is usually coordinated by the oxygen atoms of the phosphinate groups, and preferably also by the tertiary nitrogen atoms of the macrocycle.
  • M is preferably selected from the group consisting of La 3+ , Ce 3+ , Pr 3+ , Nd 3+ , Sm 3+ , Eu 2+ , Gd 3+ , Tb 3+ , Dy 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+ , Lu 3+ , Sc 3+ , Y 3+ , Ga 3+ , Ge 4+ , In 3+ , Sn 2+ , Sn 4+ , Bi 3+ , Rh 3+ , Ru 3+ , Ru 4+ , Ag + , Au 3+ , Pd 2+ , Pd 4+ , Pm 3+ , Ac 3+ , Ti 4+ , Zr 4+ Al 3+ , Cr 3+ , Cu 2+ , Zn 2+ and mixtures thereof.
  • M + is selected from the group consisting of Gd , Cu , Sc , Y , and Lu .
  • the present invention therefore preferably relates to a compounds according to general formula (III) wherein M* + is selected from the group consisting of La 3+ , Ce 3+ , Pr 3+ , Nd 3+ , Sm 3+ , Eu 2+ , Gd 3+ , Tb 3+ , Dy 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+ , Lu 3+ , Sc 3+ , Y 3+ , Ga 3+ , Ge 4+ , In 3+ , Sn 2+ , Sn 4+ , Bi 3+ , Rh 3+ , Ru 3+ , Ru 4+ , Ag + , Au 3+ , Pd 2+ , Pd 4+ , Pm 3+ , Ac 3+ , Ti 4+ , Zr 4+ Al + , Cr 3+ , Cu 2+ , Zn + and mixtures thereof, and particularly preferably relates to compounds according to general formula (III), wherein M k+ is selected from
  • M is selected from radioisotopes, for example selected from the group consisting of 44 Sc, 46 Sc, 47 Sc, 55 Co, 99m Tc, 203 Pb, 66 Ga, 67 Ga, 68 Ga, 72 As, H 1 In, n3m In, 1 14m In, 97 Ru, 62 Zn, 62 Cu, 64 Cu, 52 Fe, 52m Mn, 51 Cr, 186 Re, 188 Re, 77 As, 90 Y, 67 Cu, l69 Er, 1 , 7m Sn, 121 Sn, 127 Te, l42 Pr, 143 Pr, 198 Au, 199 Au, 149 Tb, l61 Tb, ,09 Pd, 165 Dy, 1 49 Pm, 151 Pm, 153 Sm, , 57 Gd, 166 Ho, 172 Tm, 169 Yb, 175 Yb, 177 Lu, 105 Rh, m Ag, 88 Zr, 89 Zr, 2
  • k is selected from 2, 3 or 4.
  • M is selected from the group consisting of 44 Sc, 47 Sc, 99m Tc, 67 Ga, 68 Ga, 1 11 In, 64 Cu, 89 Zr, , 88 Re, 90 Y, 177 Lu and mixtures thereof.
  • M is selected from the afore-mentioned radioisotopes.
  • M is selected from the group consisting of 44 Sc, 47 Sc, 99m Tc, 11 'in, 6 Cu, 89 Zr, , 88 Re,
  • the present invention therefore preferably relates to a compound according to general formula (III) wherein M k+ is selected from the group consisting of La 3+ , Ce 3+ , Pr 3+ , Nd 3+ , Sm 3+ , Eu 2+ , Gd 3+ , Tb 3+ , Dy 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+ , Lu 3+ , Sc 3+ , Y 3+ , Ga 3+ , Ge 4+ , In 3+ , Sn 2+ , Sn 4+ , Bi 3+ , Rh 3+ , Ru 3+ , Ru 4+ , Ag + , Au 3+ , Pd 2+ , Pd 4+ , Pm 3+ , Ac 3+ , Ti 4+ , Zr 4+ Al 3+ , Cr 3+ , Cu 2+ , Zn and mixtures thereof.
  • M k+ is selected from the group consisting of La 3+ , Ce 3+
  • the present invention therefore preferably further relates to a compound according to general formula (III) wherein M is selected from the group consisting of 44 Sc, 46 Sc, 47 Sc, 55 Co, 99m Tc, 203 Pb, 66 Ga, 67 Ga, 68 Ga, 72 As, i n In, 1 I3m In, 114m In, 97 Ru, 62 Zn, 62 Cu, 64 Cu, 52 Fe, 52m Mn, 5, Cr, 186 Re, 188 Re, 77 As, 90 Y, 67 Cu, 169 Er, U 7m Sn, 1 1 Sn, ,27 Te, 1 2 Pr, ,43 Pr, 198 Au, ,99 Au, 149 Tb, 16, Tb, 109 Pd, 165 Dy, 149 Pm, 151 Pm, 153 Sm, 157 Gd, 166 Ho, 172 Tm, 169 Yb, 175 Yb, 177 Lu, 105 Rh, , u Ag, 88 Zr,
  • the present invention therefore preferably further relates to compounds according to general formula (III), wherein M is selected from the group consisting of 44 Sc, 46 Sc, 7 Sc, 55 Co, 99m Tc, 203 Pb, 66 Ga, 67 Ga, 68 Ga, 72 As, m In, U3m In, 114m In, 97 Ru, 62 Zn, 62 Cu, 64 Cu, 5 Fe, 52m Mn, 51 Cr, , 86 Re, 188 Re, 77 As, 90 Y, 67 Cu, 169 Er, 117m Sn, ,21 Sn, 127 Te, 142 Pr, I43 Pr, 198 Au, 199 Au, 149 Tb, 161 Tb, 109 Pd, 165 Dy, 149 Pm, !
  • k is selected from 2, 3 or 4, and particularly preferably relates to compounds according to general formula (III), wherein M is selected from the group consisting of 44 Sc, 47 Sc, 99m Tc, n , In, 64 Cu, 89 Zr, 188 Re, 90 Y, 177 Lu, and mixtures thereof.
  • compounds of general formula (III) are labelled with radioisotopes, where in this context, the term labelling is referring to binding of the radioactive metal ions by the chelator by means of complex formation.
  • the present invention further relates to a process for the preparation of compounds according to general formula (III) by reacting compounds of general formula (II) with compounds comprising the metal cation M k+ .
  • Compounds comprising the metal cation M k+ are for example selected from the group consisting of sulfates, fluorides, clorides, bromides, nitrates, phosphates, carbonates, hydro gencarbonates, sulfonates and acetates.
  • compounds comprising the metal cation M k+ are preferably solutions of metal salts comprising M** and various anions, selected from the group of sulfates, fluorides, clorides, bromides, nitrates, phosphates, carbonates, hydrogencarbonates, sulfonates, acetates, acetylacetonates, and mixtures thereof.
  • This process according to the present invention is in general conducted under usual conditions for reactions of this kind which are known to the skilled artisan.
  • the process is conducted at ambient temperature (room temperature).
  • the process is conducted at temperatures ranging from ambient temperature (room temperature) to 37 °C.
  • a further central aim of the invention is the use of the described metal complexes for molecular imaging.
  • a further central aim of the invention is the use of the described metal complexes for molecular imaging and radiotherapy.
  • the present invention therefore further relates to the method of using compounds according to general formula (III) in molecular or nuclear imaging as well as in radiotherapy.
  • the present invention therefore further relates to the method of using compounds according to general formula (II) or (III) as defined above, preferably according to general formula (III), in molecular or nuclear imaging as well as in radiotherapy.
  • a preferred method of using compounds (chelates) according to general formula (III) in molecular and nuclear imaging is the use in magnetic resonance imaging (MRI), gamma scintigraphy, single photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, Cherenkov imaging, and combinations thereof.
  • MRI magnetic resonance imaging
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • fluorescence imaging Cherenkov imaging, and combinations thereof.
  • the complexes of said radioisotopes can be used in nuclear imaging, such as gamma scintigraphy, single photon emission computed tomography (SPECT) and particularly in positron emission tomography (PET).
  • nuclear imaging such as gamma scintigraphy, single photon emission computed tomography (SPECT) and particularly in positron emission tomography (PET).
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • the present invention therefore preferably relates to the method of using as mentioned above, preferably compounds according to formula (III), wherein the molecular or nuclear imaging is magnet resonance tomography (MRT), magnetic resonance imaging (MRI), gamma scintigraphy, single photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, Cherenkov imaging, and combinations thereof.
  • MRT magnet resonance tomography
  • MRI magnetic resonance imaging
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • fluorescence imaging preferably relates to the method of using as mentioned above, preferably compounds according to formula (III), wherein the molecular or nuclear imaging is magnet resonance tomography (MRT), magnetic resonance imaging (MRI), gamma scintigraphy, single photon emission computed tomography (SPECT), positron emission tomography (PET), fluorescence imaging, Cherenkov imaging, and combinations thereof.
  • the invention therefore relates to the method of using compounds according to general formula (III) in targeted radiotherapy, or in targeted radiotherapy in combination with magnetic resonance imaging (MRI) and/or gamma scintigraphy and/or single photon emission computed tomography (SPECT) and/or positron emission tomography (PET) and/or fluorescence imaging and/or Cherenkov imaging.
  • MRI magnetic resonance imaging
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • fluorescence imaging and/or Cherenkov imaging fluorescence imaging and/or Cherenkov imaging.
  • Analytical HPLC was performed using a Sykam HPLC system with low-pressure gradient mixer, equipped with a Nucleosil C18-RP column (100 x 4.6 mm, 5 ⁇ particle size), at a flow rate of 1 mL/min. Eluents were water and acetonitrile, both containing 0.1% trifluoroacetic acid (TFA). Two gradients were used: Gradient A, 20-80% MeCN in 24 min, and Gradient B, 40-100% MeCN in 24 min.
  • TFA trifluoroacetic acid
  • Preparative HPLC was done using a Sykam system with two separate solvent pumps, equipped with a YMC CI Sec column (250x30 mm, 5 ⁇ particle size), at a flow rate of 20 mL/min. Solvents were similar to analytical HPLC. ESI-MS analysis was done using a Varian Ion-trap 500 system (Varian Deutschland GmbH, Darmstadt, Germany).
  • the cyclic RGD pentapeptide cyclo(RGDfK(tBu,Pbf) suitable for bioconjugation were prepared according to literature protocols, using standard methods for solid phase peptide synthesis (Fmoc strategy).
  • the retentate was concentrated and subjected to preparative HPLC (column: YMC ODS-A, 250x30 mm, flow rate 20 ml/min, gradient: 20-60% MeCN in water (both eluents containing 0.1% TFA), in 40 min, UV detection at wavelength of 220 nm).
  • the product was eluted at a retention time of 30 min.
  • the eluate fraction containing the product was evaporated, 20 mL of water added, and neutralized by addition of sodium bicarbonate. Then ultrafiltration was performed as described above. After 50 mL of eluate had passed, the retentate was lyophilized to afford the pure product as sodium salt. Yield: 20 mg.
  • TFA trifluoroacetic acid
  • n.c.a. Lu was obtained from ITG (Isotope Technologies Garching GmbH, Germany) as 177 LuCl 3 solution (total activity of 2.00 GBq) in 0.04 M HC1. 100 MBq of l 77 Lu and 100 ⁇ of 1M NH 4 OAc buffer were placed in an eppendorf cup and 10 ⁇ , of a solution of the precursor (varying concentrations, corresponding to final content of 0.5, 0.3, 0.2, 0.15 and 0.1 nmol in labeling solution) was added.
  • the cartridge was purged with water (2 mL) and air and the labeled product was quantitatively eluted with 0.5 mL of a 1 : 1 mixture (by volume) of ethanol and PBS. After addition of water (1 mL) and PBS (1 mL), the mixture was concentrated in vacuo to a final volume of 1.5 mL in order to remove ethanol. TLC (silica gel, 0.1 M sodium citrate) showed a radiochemical purity > 99 %.
  • integrin receptor affinity was carried out using M21 human melanoma cells, possessing high ⁇ ⁇ ⁇ 3 expression. Experiments were carried out in 24-well plates. Ca. 2 l0 5 cells were seeded into wells containing RPMI 1640 media and incubated for 24 h at 37 °C and 5% C0 2 .
  • the medium was exchanged with 0.5 mL binding buffer (20 mmol/L tris(hydroxymethyl)aminomethane (TRIS), pH 7.4, 150 mmol/L NaCl, 2 mmol/L CaCl 2 *2H 2 0, 1 mmol/L MgCl 2 *6H 2 0, 1 mmol/L MnCl 2 *4H 2 0, 0.1% (m m) BSA), containing 30.000-50.000 cpm I-echistatin and the respective RGD peptide conjugate in increasing concentrations from 10 ⁇ u -10 ⁇ M.
  • TMS tris(hydroxymethyl)aminomethane
  • mice were injected 10-12 MBq of 177 Lu-5 formulation which was prepared as described. After 120 min, the mice were sacrificed, the organs/tissues taken out and counted in a gamma counter. For blockade, the mice were administered 100 ⁇ g (approx. 5 mg/kg) of unlabeled compound 5 10 min before tracer injection. Results are shown in Table 3 and Figure 5.
  • mice were anaesthesized with isoflurane and and injected ca. 20 MBq of 177 Lu-5 via the tail vein 2, 4 and 24 h prior to gamma szintigraphic imaging.
  • Blockade was done as described for biodistribution and imaged 2 h p.i.. Imaging was performed on a Forte gamma camera system (Philips) using a MEGP collimator, recording time was 1 h. Results are depicted in Figure 6.
  • radio-TLC 0.2 mm silica gel 60, Merck, eluent: 0.1 M EDTA
  • Radioactivity incorporation was > 98 %.
  • the reaction solution was passed over a SPE cartridge (SepPak C8 light, pre-conditioned according to manufacturer's instructions), which was then purged with water and air.
  • the labeled product was eluted with 0.5 mL of ethanol and diluted with 1 mL of PBS.
  • the ethanol was removed in vacuo, water was replenished to reach again a total volume of 1 mL, and the solution passed through a sterile filter.
  • This solution was used for administration to M21 tumor xenografted nude mouse, which was subjected to PET imaging 75 min after injection (Figure 14).
  • the invention also refers to the following embodiments:
  • M k+ is selected from the group consisting of La 3+ , Ce 3+ , Pr 3+ , Nd 3+ , Sm 3+ , Eu 2+ , Gd 3+ , Tb 3+ , Dy 3+ , Ho 3+ , Er 3+ , Tm 3+ , Yb 3+ , Lu 3+ , Sc 3+ , Y 3+ , Ga 3+ , Ge 4+ , In 3+ , Sn 2+ , Sn 4+ , Bi 3+ , Rh 3+ , Ru 3+ , Ru 4+ , Ag + , Au 3+ , Pd 2+ , Pd 4+ , Pm 3+ , Ac 3+ , Ti 4+ , Zr 4+ Al 3+ , Cr 3+ , Cu 2+ , Zn 2+ and mixtures thereof.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne le domaine de la médecine nucléaire et de l'imagerie moléculaire, à savoir des produits radiopharmaceutiques pour l'imagerie et la radiothérapie ciblée, à l'aide de radionucléides ioniques métalliques ou des ions métalliques paramagnétiques en combinaison avec des chélateurs qui sont hautement fonctionnalisés par des ligands peptidiques ou non peptidiques ou des unités de signalisation radioactives ou non radioactives. L'invention concerne des produits de formule (II) où m, n, o et p sont indépendamment les uns des autres choisis parmi les entiers 1 et 2 ; et R', R", R'" et R'" sont indépendamment les uns des autres choisis parmi OH ou un résidu amide -NR1R2 2.
PCT/EP2012/058130 2011-05-04 2012-05-03 Ligands à base de tétraaza-cycloalcanes et leur utilisation en médecine nucléaire et en imagerie moléculaire WO2012150302A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161482258P 2011-05-04 2011-05-04
US61/482,258 2011-05-04

Publications (1)

Publication Number Publication Date
WO2012150302A1 true WO2012150302A1 (fr) 2012-11-08

Family

ID=46046181

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/058130 WO2012150302A1 (fr) 2011-05-04 2012-05-03 Ligands à base de tétraaza-cycloalcanes et leur utilisation en médecine nucléaire et en imagerie moléculaire

Country Status (1)

Country Link
WO (1) WO2012150302A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017084645A1 (fr) * 2015-11-20 2017-05-26 Univerzita Karlova Composés à base de cyclame, leurs conjugués, composés de coordination, composition pharmaceutique les contenant, procédé de préparation et utilisation associés

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOHANNES NOTNI ET AL: "A triazacyclononane-based bifunctional phosphinate ligand for the preparation of multimeric<68>GA tracers for positron emission tomography", CHEMISTRY - A EUROPEAN JOURNAL, WILEY - V C H VERLAG GMBH & CO. KGAA, WEINHEIM, DE, vol. 16, no. 24, 25 June 2010 (2010-06-25), pages 7174 - 7185, XP002632285, ISSN: 0947-6539, [retrieved on 20100512], DOI: 10.1002/CHEM.200903281 *
JOHANNES NOTNI,JAKUB SIMECEK, PETR HERMANN, HANS-JÜRGEN WESTER: "TRAP, a Powerful and Versatile Framework for Gallium-68Radiopharmaceuticals", CHEMISTRY - A EUROPEAN JOURNAL, vol. 17, no. 52, 6 December 2011 (2011-12-06), pages 14718 - 14722, XP002679787, DOI: 10.1002/chem.201103503 *
NOTNI, J.; HERMANN, P.; HAVLÍCKOVÁ, J.; KOTEK, J.; KUBICEK, V.; PLUTNAR, J.; LOKTIONOVA, N.; RISS, P. J.; ROSCH, F.; LUKE§, 1.: "A triazacyclononane-based bifunctional phosphinate ligand for the preparation of multimeric 68Ga tracers for positron emission tomography", CHEM. EUR. J, vol. 16, 2010, pages 7174 - 7185, XP002632285, DOI: doi:10.1002/CHEM.200903281
PVEL REZANKA ET AL: "Synthesis of a Bifunctional Monophosphinate DOTA Derivative Having a Free Carboxylate Group in the Phosphorus Side Chain", SYNTHESIS, GEORG THIEME VERLAG, STUTTGART, DE, no. 9, 1 September 2008 (2008-09-01), pages 1431 - 1435, XP009126087, ISSN: 0039-7881, [retrieved on 20080327], DOI: 10.10555/S-2008-1072571 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017084645A1 (fr) * 2015-11-20 2017-05-26 Univerzita Karlova Composés à base de cyclame, leurs conjugués, composés de coordination, composition pharmaceutique les contenant, procédé de préparation et utilisation associés
GB2560269A (en) * 2015-11-20 2018-09-05 Univ Karlova Cyclam based compounds, their conjugates, co-ordination compounds, pharmaceutical composition containing thereof, method of preparation and use thereof

Similar Documents

Publication Publication Date Title
AU2018308699B2 (en) Dual mode radiotracer and -therapeutics
EP2663571B1 (fr) Ligand phosphinate à base de triazacyclononane et son utilisation en imagerie moléculaire
EP2790732B1 (fr) Analogues conjugués de somatostatine coupés pour des applications biologiques
EP1904460B1 (fr) Ligands aza multidentes complexants d&#39;ions metalliques et utilisation dans des methodes diagnostiques et therapeutiques
EP2921482B1 (fr) Inhibiteurs marqués de l&#39;antigène membranaire spécifique de la prostate (psma), évaluation biologique, et utilisation en tant qu&#39;agents d&#39;imagerie
Šimeček et al. A Cyclen‐Based Tetraphosphinate Chelator for the Preparation of Radiolabeled Tetrameric Bioconjugates
Hueting et al. Bis (thiosemicarbazones) as bifunctional chelators for the room temperature 64-copper labeling of peptides
David et al. Improved conjugation, 64-cu radiolabeling, in vivo stability, and imaging using nonprotected Bifunctional macrocyclic ligands: Bis (Phosphinate) Cyclam (BPC) Chelators
BR112020011727A2 (pt) ligantes de psma para imageamento e endorradioterapia
AU2022288744A9 (en) Trislinker-conjugated dimeric labelling precursors and radiotracers derived therefrom
Failla et al. Peptide-based positron emission tomography probes: Current strategies for synthesis and radiolabelling
JP3341001B2 (ja) テクネチウム放射性薬剤の新しいコア
WO2008144728A1 (fr) Conjugués qui se lient à une protéine sanguine telle que la sérum albumine humaine et des procédés les utilisant dans des applications diagnostiques et thérapeutiques
WO2013060793A1 (fr) Ligands bifonctionnels pour métaux radioactifs
US20080124270A1 (en) Compounds Useful as Metal Chelators
Abada et al. Phosphonated chelates for nuclear imaging
WO2012150302A1 (fr) Ligands à base de tétraaza-cycloalcanes et leur utilisation en médecine nucléaire et en imagerie moléculaire
JP2024517971A (ja) 放射性医薬品のソマトスタチン受容体リガンドおよびその前駆体
PT1590317E (pt) Áçido (4s, 8s) - e (4r, 8r) -4-p-nitrobenzil-8-metil-3, 6, 9, triaza-sp 3/sp n, sp 6/sp n, sp 9/sp n-tricarboximetil-1, 11-undecanóico enantiomericamente puro e seus derivados, processo para a sua preparação e utilização para a preparação de agentes
US9079867B2 (en) Polyazamacrocyclic compound, and a production method and a biomedical use therefor
Floresta et al. RSC Medicinal Chemistry
CA3179555A1 (fr) Formulations pharmaceutiques
WO2023227535A1 (fr) Dérivés fonctionnalisés du bisaminothiol, complexes avec ces dérivés de bisaminothiol et utilisation de ces complexes comme agents de diagnostic et therapeutiques
EA046402B1 (ru) Двухрежимная радиоактивная метка и радиотерапевтическое средство

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12719680

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12719680

Country of ref document: EP

Kind code of ref document: A1