WO2008098056A2 - Chélate à haute relaxation high relaxivity chelates - Google Patents

Chélate à haute relaxation high relaxivity chelates Download PDF

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WO2008098056A2
WO2008098056A2 PCT/US2008/053186 US2008053186W WO2008098056A2 WO 2008098056 A2 WO2008098056 A2 WO 2008098056A2 US 2008053186 W US2008053186 W US 2008053186W WO 2008098056 A2 WO2008098056 A2 WO 2008098056A2
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compound
formula
alkyl
nhso
iii
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PCT/US2008/053186
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WO2008098056A3 (fr
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Peter D. Caravan
Vincent Jacques
Stephane Dumas
Wei-Chuan Sun
Kevin L. Zhou
Heribert Schmitt-Willich
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Epix Pharmaceuticals, Inc.
Bayer Schering Pharma Ag
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Publication of WO2008098056A2 publication Critical patent/WO2008098056A2/fr
Publication of WO2008098056A3 publication Critical patent/WO2008098056A3/fr

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    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • 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
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2404—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/242—Esteramides the ester moiety containing a substituent or a structure which is considered as characteristic of hydroxyaryl compounds
    • 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
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • This disclosure relates to metal chelating ligands, and more particularly to metal chelating ligands having high relaxivity when in a metal chelate form.
  • metal chelating ligands currently used in MR are polyaminopolycarboxylate metal binding chelating ligands derived from two basic structures, DOTA and DTPA. These ligands are used typically because of their known affinity for metal ions, including gadolinium(III), although these ligands' ability to exploit high relaxivity mechanisms may be limited.
  • Relaxivity is the ability of the metal chelate to relax water protons, and is defined as the change in the relaxation rate of water divided by the concentration of the chelate in millimolar. Compounds with high relaxivity can provide the same contrast in an MRI exam at a lower concentration than compounds with low relaxivity.
  • Identifying compounds with high relaxivity would be valuable, because it would allow these compounds to be administered at a lower dose and would limit the exposure of the subject to the contrast agent.
  • High relaxivity compounds may also enable the imaging of low concentration targets and receptors that may not be able to be imaged with current technology.
  • the disclosure is based on one or more modifications of a chelating ligand to enhance the relaxivity of a resultant metal chelate upon metal binding.
  • modifications include changing the donor groups (functional groups that directly coordinate to the metal ion), introducing groups that organize water in the second coordination sphere (e.g., by hydrogen bonding), and introducing groups that slow down molecular tumbling either by increased molecular weight or by targeting the metal chelate to a macromolecule (e.g., a protein).
  • the donor groups can include a number of functionalities to exploit high relaxivity mechanisms, including, by way of example, enhancing the water exchange rate, or decreasing the electronic relaxation rate of the metal.
  • These modifications may also be effective in preventing unwanted anion (e.g. bicarbonate) coordination to the metal ion (e.g., by electrostatic repulsion).
  • Metal chelates prepared with the chelating ligands can be examined with techniques including relaxivity measurements at different magnetic fields and temperatures, variable temperature 17 O NMR measurements, and luminescence lifetime measurements.
  • Chelating ligands and metal chelates can also be useful as luminescent probes, e.g., fluorescent (or phosphorescent) probes having long fluorescence lifetimes.
  • chelating ligands may be useful for preparing diagnostic and/or therapeutic compositions of radioactive metal ions.
  • a chelate can have the following structure:
  • R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula: 17330-011WO1 / MET-24 and ES-32
  • R , R , and R can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 together can form a compound having the formula:
  • R 7 and R 8 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] m -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula: 17330-011WO1 / MET-24 and ES-32
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)CL 6 CO 2 H; CL 6 CF 3 ; CL 6 CCI 3 ; C 1-6 CBr 3 ; CL 6 CI 3 ; or CL 6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can be CR 4 R 5 R 6 or [L] m -[TBM] n .
  • R 1 is CR 4 R 5 R 6 , R 4 is H, R 5 is CO 2 H, and R 6 is selected from H, Ci-C 6 alkyl, aryl, C(O)N(OH)R 7 , C(O)NHSR 7 , and PO 3 R 7 R 8 .
  • R 2 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n .
  • R 5 is CO 2 H, and R 6 is selected from H and C L6 alkyl.
  • R 7 can be selected from H, CO 2 H; Ci-C 6 alkyl, and C L6 CO 2 H; in specific cases, R 7 is H.
  • R 8 is selected from Ci-C 6 alkyl, C L6 CO 2 H, C L6 CF 3 , CH(CO 2 H)C L6 CO 2 H, and C L6 PO 3 R 9 R 10 .
  • at least one of R 1 , R 2 , and R 3 is different from the others of R 1 , R 2 , or R 3 .
  • R 2 and R 3 are the same or R 1 and R 3 are the same.
  • a chelate can have the following structure:
  • R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C L 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 17330-011WO1 / MET-24 and ES-32
  • R 7 and R 8 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] m -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula:
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)C L6 CO 2 H; C L6 CF 3 ; C L6 CCI 3 ; Ci -6 CBr 3 ; C L6 CI 3 ; or C L6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl. 17330-011WO1 / MET-24 and ES-32
  • R 1 can be CR 4 R 5 R 6 or [L] m -[TBM] n .
  • R 1 is CR 4 R 5 R 6 , R 4 is H, R 5 is CO 2 H, and R 6 is selected from H, C 1 -C 6 alkyl, aryl, C(O)N(OH)R 7 , C(O)NHSR 7 , and PO 3 R 7 R 8 .
  • R 2 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n .
  • R 5 is CO 2 H
  • R 6 is selected from H and Ci_6 alkyl.
  • R 7 can be selected from H, CO 2 H; Ci-C 6 alkyl, and C L6 CO 2 H; in specific cases, R 7 is H.
  • R 8 is selected from Ci-C 6 alkyl, C L6 CO 2 H, C L6 CF 3 , CH(CO 2 H)C L6 CO 2 H, and C L6 PO 3 R 9 R 10 .
  • at least one of R 1 , R 2 , and R 3 is different from the others of R 1 , R 2 , or R 3 .
  • R 2 and R 3 are the same or R 1 and R 3 are the same.
  • a chelate can have the following structure:
  • R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C 1- 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 together can form a compound having the formula:
  • R 7 and R 8 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] m -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ;
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)C L6 CO 2 H; C L6 CF 3 ; C L6 CCI 3 ; Ci -6 CBr 3 ; C L6 CI 3 ; or C L6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can be CR 4 R 5 R 6 or [L] m -[TBM] n .
  • R 4 is H
  • R 5 is CO 2 H
  • R 6 is selected from H, Ci-C 6 alkyl, aryl,
  • R 2 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n .
  • R 4 is H
  • R 5 is CO 2 H
  • R 6 is selected from H and C L6 alkyl.
  • R 7 can be selected from H, CO 2 H;
  • R 8 is selected from Ci-C 6 alkyl, C L6 CO 2 H, C L6 CF 3 , CH(CO 2 H)C L6 CO 2 H, and C L6 PO 3 R 9 R 10 . 17330-011WO1 / MET-24 and ES-32
  • R 1 , R 2 , and R 3 is different from the others of R 1 , R 2 , or R 3 .
  • R 2 and R 3 are the same or R 1 and R 3 are the same.
  • a chelate can have the following structure:
  • R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 together can form a compound having the formula:
  • R 7 and R 8 are independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or
  • R 1 , R 2 , and R 3 be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 be a compound of the formula: 17330-011WO1 / MET-24 and ES-32
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C 1- 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula:
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)C L6 CO 2 H; C I-6 CF 3 ; C L6 CCI 3 ; Ci -6 CBr 3 ; C L6 CI 3 ; or C L6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can be CR 4 R 5 R 6 or [L] m -[SAM] n .
  • R 1 is CR 4 R 5 R 6 , R 4 is H, R 5 is CO 2 H, and R 6 is selected from H, Ci-C 6 alkyl, aryl, C(O)N(OH)R 7 , C(O)NHSR 7 , and PO 3 R 7 R 8 .
  • R 2 can be CR 4 R 5 R 6 or [L] 1n -[SAM] n .
  • R 2 is CR 4 R 5 R 6 , R 4 is H, R 5 is CO 2 H, and R 6 is selected from H and C L6 alkyl.
  • R 7 can be selected from H, CO 2 H; Ci-C 6 alkyl, and C L6 CO 2 H; in specific cases, R 7 is H.
  • R 8 is selected from Ci-C 6 alkyl, C L6 CO 2 H, C L6 CF 3 , CH(CO 2 H)C L6 CO 2 H, and C L6 PO 3 R 9 R 10 .
  • at least one of R 1 , R 2 , and R 3 is different from the others of R 1 , R 2 , or R 3 .
  • R 2 and R 3 are the same or R 1 and R 3 are the same.
  • a chelate can have the following structure:
  • R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C 1- 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 together can form a compound having the formula:
  • R 7 and R 8 are independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or
  • R 1 , R 2 , and R 3 be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula: 17330-011WO1 / MET-24 and ES-32
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)CL 6 CO 2 H; CL 6 CF 3 ; CL 6 CCI 3 ; C 1-6 CBr 3 ; CL 6 CI 3 ; or CL 6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can be CR 4 R 5 R 6 or [L] m -[SAM] n .
  • R 1 is CR 4 R 5 R 6 , R 4 is H, R 5 is CO 2 H, and R 6 is selected from H, Ci-C 6 alkyl, aryl, C(O)N(OH)R 7 , C(O)NHSR 7 , and PO 3 R 7 R 8 .
  • R 2 can be CR 4 R 5 R 6 or [L] 1n -[SAM] n .
  • R 5 is CO 2 H, and R 6 is selected from H and C L6 alkyl.
  • R 7 can be selected from H, CO 2 H; Ci-C 6 alkyl, and C L6 CO 2 H; in specific cases, R 7 is H.
  • R 8 is selected from Ci-C 6 alkyl, C L6 CO 2 H, C L6 CF 3 , CH(CO 2 H)C L6 CO 2 H, and C L6 PO 3 R 9 R 10 .
  • at least one of R 1 , R 2 , and R 3 is different from the others of R 1 , R 2 , or R 3 .
  • R 2 and R 3 are the same or R 1 and R 3 are the same.
  • a chelate can have the following structure:
  • R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C 1- 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 17330-011WO1 / MET-24 and ES-32
  • R 7 and R 8 are independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or
  • R 1 , R 2 , and R 3 be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula:
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)C L6 CO 2 H; C L6 CF 3 ; C L6 CCI 3 ; Ci -6 CBr 3 ; C L6 CI 3 ; or C L6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl. 17330-011WO1 / MET-24 and ES-32
  • R 1 can be CR 4 R 5 R 6 or [L] m -[SAM] n .
  • R 1 is CR 4 R 5 R 6 , R 4 is H, R 5 is CO 2 H, and R 6 is selected from H, C 1 -C 6 alkyl, aryl, C(O)N(OH)R 7 , C(O)NHSR 7 , and PO 3 R 7 R 8 .
  • R 2 can be CR 4 R 5 R 6 or [L] 1n -[SAM] n .
  • R 5 is CO 2 H
  • R 6 is selected from H and Ci_6 alkyl.
  • R 7 can be selected from H, CO 2 H; Ci-C 6 alkyl, and C L6 CO 2 H; in specific cases, R 7 is H.
  • R 8 is selected from Ci-C 6 alkyl, C L6 CO 2 H, C L6 CF 3 , CH(CO 2 H)C L6 CO 2 H, and C L6 PO 3 R 9 R 10 .
  • at least one of R 1 , R 2 , and R 3 is different from the others of R 1 , R 2 , or R 3 .
  • R 2 and R 3 are the same or R 1 and R 3 are the same.
  • multiple chelates can be bound to either a TBM or SAM.
  • the compound can have the general structure:
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[W] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C L 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula: 17330-011WO1 / MET-24 and ES-32
  • R 7 and R 8 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl; [W] can be selected from TBM or SAM.
  • the variable m is 0 or 1; n is an integer from 1 to 5; q is an integer from 1 to 6; r is an integer from 0 to 5; and s is an integer from 1 to 6.
  • R 1 is not -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; and
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] m -[W] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula:
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)C L6 CO 2 H; C L6 CF 3 ; C L6 CCI 3 ; Ci -6 CBr 3 ; C L6 CI 3 ; or C L6 PO 3
  • R 9 R 10 ; R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • [W] can be TBM or SAM.
  • the variable m is O or 1; n is an integer from 1 to 5; q is an integer from 1 17330-011WO1 / MET-24 and ES-32
  • R 1 , R 2 , and R 3 are different from the others of R 1 , R 2 , or R 3 . In certain embodiments, R 2 and R 3 are the same or R 1 and R 3 are the same.
  • the chelate can be coordinated to a metal.
  • chelates can include:
  • M can have an atomic number of 21-31, 39-50, or 57-83.
  • M can be a stable or unstable isotope selected from Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Cu(III), Dy(III), Ho(III), Er(III), Pr(III), Eu(II), Eu(III), Nd(III), La(III), Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc(V), Re(III), Re(IV), Re(V), Bi(III), and Yb(III).
  • M is Gd(III).
  • any of the above embodiments can be in the form of a pharmaceutically acceptable salt.
  • FIG. 1 is a synthesis of a TBM intermediate useful for incorporating a TBM into a chelating ligand. See Examples 1-2.
  • FIG. 2 demonstrates the preparation of a chelating ligand having a TBM. See Examples 3, 4, and 14.
  • chelating ligand may be used to refer to any polydentate ligand that is capable of coordinating a metal ion, either directly or after removal of protecting groups, or is a reagent, with or without suitable protecting groups, that is used in the synthesis of a contrast agent and comprises substantially all of the atoms that ultimately will coordinate the metal ion of the final metal complex.
  • chelate or “metal chelate” refer to the actual metal-ligand complex, and it is understood that the polydentate ligand can eventually be coordinated to a medically useful or diagnostic metal ion. 17330-011WO1 / MET-24 and ES-32
  • binding affinity refers to the capacity of a contrast agent to be taken up by, retained by, or bound to a particular biological component to a greater degree than other components. Contrast agents that have this property are said to be “targeted” to the "target” component. Contrast agents that lack this property are said to be “non-specific” or “non-targeted” agents.
  • the binding affinity of a binding group for a target is expressed in terms of the equilibrium dissociation constant "IQ.”
  • target binding and “binding” for purposes herein refer to non- covalent interactions of a contrast agent with a target.
  • Non-covalent interactions are independent from one another and may be, inter alia, hydrophobic, hydrophilic, dipole-dipole, pi-stacking, hydrogen bonding, electrostatic associations, or Lewis acid- base interactions.
  • Coordination of metal ions by water and other ligands is often regarded in terms of coordination spheres (see e.g., D. T. Richens, The Chemistry of Aqua Ions, John Wiley and Sons, New York, 1997, Chapter 1).
  • the first or primary coordination sphere represents all the ligands directly bonded to the metal ion and is defined by the ligands.
  • There is a second coordination sphere where water molecules and counterions bond to the groups in the first coordination sphere via hydrogen bonding and electrostatic interactions.
  • the first coordination sphere is typically well-defined and the time that a water or other ligand spends in the first coordination sphere is longer than in other coordination spheres.
  • the second sphere is less well-defined, but the waters here have a longer 17330-011WO1 / MET-24 and ES-32
  • Gd Gd(III) paramagnetic metal ion.
  • alkyl alkenyl and alkynyl carbon chains, if not specified, contain from 1 to 20 carbons, or 1 or 2 to 16 carbons, and are straight or branched, substituted or unsubstituted. Alkenyl carbon chains of from 2 to 20 carbons, in certain embodiments, contain 1 to 8 double bonds, and alkenyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds.
  • alkyl, alkenyl, and alkynyl groups include, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, allyl (propenyl), and propargyl (propynyl).
  • cycloalkyl refers to a substituted or unsubstituted, saturated mono- or multi- cyclic ring system, in certain embodiments having 3 to 10 carbon atoms, in other embodiments having 3 to 6 carbon atoms.
  • aryl refers to a substituted or unsubstituted, aromatic monocyclic or multicyclic group containing from 6 to 19 carbon atoms.
  • Aryl groups include, but are not limited to groups such as unsubstituted or substituted fluorenyl, unsubstituted or substituted phenyl, and unsubstituted or substituted naphthyl.
  • heteroaryl refers to a substituted or unsubstituted, monocyclic or multicyclic aromatic ring system, in certain embodiments, of about 5 to about 15 members where one or more, in one embodiment 1 to 3, of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen, or sulfur.
  • the heteroaryl group may be optionally fused to a benzene ring.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolinyl, and isoquinolinyl.
  • heterocycle refers to a substituted or unsubstituted, monocyclic or multicyclic non-aromatic ring system, in one embodiment of 3 to 10 members, in 17330-011WO1 / MET-24 and ES-32
  • the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternized to form an ammonium group where the substituents are selected as above.
  • substituted refers to substitution by one or more substituents, in certain embodiments one, two, three or four substituents, where non- limiting examples of the substituents include halo, pseudohalo, hydroxy, carboxy, amino, nitro, thio, thionyl, sulfinyl, sulfonyl, sulfo, alkyl, haloalkyl, aminoalkyl, diaminoalkyl, alkylamine, phosphinate, phosphinate ester, phosphonate, phosphonate ester, phosphodiester, alkylphosphodiester, haloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, and alkoxy.
  • halo refers to F, Cl, Br or I.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, andl-chloro-2-fluoroethyl.
  • pseudohalides or pseudohalo groups are groups that behave substantially similar to halides. Such compounds can be used in the same manner and treated in the same manner as halides. Pseudohalides include, but are not limited to, cyanide, cyanate, thiocyanate, selenocyanate, trifluoromethoxy, and azide.
  • sulfinyl or thionyl refers to -S(O)-.
  • sulfonyl or “sulfuryl” refers to -S(O) 2 -.
  • sulfo refers to -S(O) 2 O-.
  • phosphinate refers to -P(R)O 2 H
  • phosphinate ester refers to -P(R)O 2 R'
  • phosphonate refers to -POsH 2
  • phosphonate ester refers to -PO3RR'
  • phosphodiester refers to -OPO3R-
  • alkylphosphodiester refers to -OPO3RR'.
  • R is H or alkyl
  • R' is alkyl. 17330-011WO1 / MET-24 and ES-32
  • chelating ligands useful for preparing metal chelates having high relaxivity.
  • Chelating ligands can be used to prepare non-specific metal chelates having high relaxivity, or may be modified to incorporate target binding moieties
  • TBMs Chelating ligands having target binding moieties allow the chelating ligands (and metal chelates) to be targeted to various sites in vivo.
  • Chelating ligands and metal chelates may be modified to incorporate self-assembling moieties (SAMs), which are groups that promote the self assembly of the chelates into micelles, liposomes, emulsions, etc.
  • SAMs self-assembling moieties
  • Chelating ligands and metal chelates are also useful as luminescent probes for use in high-throughput, multiplex, and/or real-time detection and analysis of biological molecules (e.g., immunoassays or real-time PCR applications).
  • Chelating ligands described herein are based on derivatives of a 1,4,7,10- tetraazacyclodecane scaffold.
  • Derivatives are prepared by modifying the amine moieties of the scaffold with from one to four donor groups (DG).
  • DGs are able to coordinate a metal ion and are chosen for their ability to enhance the relaxivity of the chelating ligand when in a metal chelate form. Relaxivity may be enhanced, for example, by a DG 's effect on the water exchange rate of a metal chelate; its ability to decrease the electronic relaxation rate of the metal ion; or its ability to prevent anion coordination (e.g., by electrostatic repulsion).
  • a DG may also incorporate a second sphere moiety (SSM), a group that increases relaxivity by its ability to coordinate a second sphere of water (e.g., by hydrogen bonding).
  • SSM second sphere moiety
  • a DG may also incorporate a TBM, optionally through a linker (L) as discussed below. Relaxivity can be further enhanced by binding to the target of the TBM or by forming self-assembled systems such as liposomes.
  • a variety of chelating ligands can be prepared. Chelating ligands can have a general formula as follows:
  • each DGi_4 is not H.
  • Stereochemistries of each DG can be independent of one another.
  • each reference to -[L] m -[TBM] n includes the limitation that m can be 0 or 1 and n can range from 1 to 5.
  • Appropriate DGi, DG 2 , DG3, and DG 4 groups can be independently selected from the groups set forth in Table 1 and Table 2 below. In some embodiments, at least one of the DG groups is chosen from Table 2. Table 2 sets forth donor groups capable of coordinating a second (or higher) sphere of water molecules.
  • a chelating ligand incorporating a TBM can have the following general structure: Formula II: 17330-011WO1 / MET-24 and ES-32 where R can be any of the DG set forth above, and where R' is as set forth previously.
  • R can be any of the DG set forth above, and where R' is as set forth previously.
  • R' is as set forth previously.
  • a chelating ligand according to Formula II is:
  • R can be any of the DG set forth above, and where R' is as set forth previously.
  • a chelating ligand according to Formula III is:
  • R can be any of the DG set forth above, and where R' is as set forth previously.
  • R can be any of the DG set forth above, and where R' is as set forth previously.
  • a fifth general structure of a chelating ligand incorporating a TBM is as follows:
  • R can be any of the DG set forth above, and where R' is as set forth previously.
  • R can be any of the DG set forth above, and where R' is as set forth previously.
  • a chelating ligand according to Formula V is: 17330-011WO1 / MET-24 and ES-32
  • a further example of a chelating ligand incorporating an [L]-[TBM] group can have the following general structure: Formula VI:
  • DGi_ 3 is selected from Table 2 above.
  • a chelating ligand according to Formula VI is:
  • Chelating ligands and metal chelates can also be represented by Formula's VII-
  • R 1 , R 2 and R 3 represent DGs.
  • One such chelate and metal-bound chelate incorporating an [L]-[TBM] group can have the following structures: Formula VII 17330-011WO1 / MET-24 and ES-32
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C L6 CO 2 H; C I -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 - C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 together can form a compound having the formula:
  • R 7 and R 8 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or 17330-011WO1 / MET-24 and ES-32
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] m -[TBM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; C 1- 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula:
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; Ci_ 6 CO 2 H; CH(CO 2 H)C L6 CO 2 H; C L6 CF 3 ; C L6 CCI 3 ; Ci -6 CBr 3 ; C L6 CI 3 ; or C L6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n .
  • CR 4 R 5 R 6 can have the formula:
  • X is CZ or a heteroatom and Y is CH, CZ, or a heteroatom, and at least one of X or Y is CZ or a heteroatom.
  • Each V can be independently CH, CR 12 , CZ, or a heteroatom.
  • Z can be selected from -OH, -OR 12 , -NR 12 R 13 , -NO 2 , -CO 2 H, - C(O)NR 12 R 13 , -SH, -SR 12 , -P(R 12 )O 2 R 13 , and -PO 3 R 12 R 13 .
  • R 12 and R 13 can be independently selected from H and Ci-C 6 alkyl. With the proviso, if X is N, then Y is not CZ when Z is CO 2 H.
  • R 2 can be CR 4 R 5 R 6 or [L] 1n -[TBM] n .
  • a chelate or metal-containing chelate having an [L]-[SAM] moiety can have the general structure of Formula IX or X:
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 together can form a compound having the formula:
  • R 7 and R 8 are independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • R 1 can not be -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; or
  • a compound having Formula IX or X can have one of R 1 , R 2 , and R 3 be CR 4 R 5 R 6 or [L] 1n -[SAM] n , and the remaining two of R 1 , R 2 , and R 3 be a compound of the formula :
  • R , R , and R can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula: 17330-011WO1 / MET-24 and ES-32
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)CL 6 CO 2 H; CL 6 CF 3 ; CL 6 CCI 3 ; C 1-6 CBr 3 ; CL 6 CI 3 ; or CL 6 PO 3 R 9 R 10 .
  • R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • a chelating ligand or metal chelate having either an [L]- [TBM] or [L]-[SAM] group is a compound having the general structure of Formula XI or XII.
  • R 1 , R 2 , and R 3 are as described above, and each R 14 can be independently selected from H, CR 4 R 5 R 6 , [L] 1n -[TBM] n , or [L] 1n -[SAM] n .
  • multiple chelates can be bound to either a TBM or SAM.
  • the compound can have the general structure of Formula XIII or XIV.
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[W] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ; C(O)NHSO 2 R 7 ; CH 2 NHSO 2 R 7 ; N(OH)C(O)R 7 ; P(R 7 )O 2 R 8 ; PO 3 R 7 R 8 ; or R 4 , R 5 , and R 6 can together form a compound having the formula:
  • R 7 and R 8 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl; [W] can be selected from TBM or SAM.
  • the variable m is O or 1; n is an integer from 1 to 5; q is 17330-011WO1 / MET-24 and ES-32
  • R 1 is not -CH 2 CO 2 H; -CH 2 CONHCH 3 ; -(CH 2 ) 3 SO 3 H; and
  • one of R 1 , R 2 , and R 3 can be CR 4 R 5 R 6 or [L] 1n -[W] n , and the remaining two of R 1 , R 2 , and R 3 can be a compound of the formula:
  • R 4 , R 5 , and R 6 can be independently selected from the group consisting of H; CO 2 H; Ci_ 6 CO 2 H; Ci-C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 4 -C 6 cycloalkyl; aryl; C 5 -C 6 heterocycle; C 5 -C 6 heteroaryl; C(O)NR 7 R 8 ; CH 2 NHCOR 7 ; C(O)N(OH)R 7 ;
  • R 7 and R 8 can be independently selected from the group consisting of H; Ci-C 6 alkyl; C L 6 CO 2 H; CH(CO 2 H)C L6 CO 2 H; C L6 CF 3 ; C L6 CCI 3 ; Ci -6 CBr 3 ; C L6 CI 3 ; or C L6 PO 3
  • R 9 R 10 ; R 9 and R 10 can be independently H or a substituted or unsubstituted Ci-C 6 alkyl.
  • [W] can be TBM or SAM.
  • the variable m is O or 1; n is an integer from 1 to 5; q is an integer from 1 to 6; r is an integer from O to 5; and s is an integer from 1 to 6.
  • Chelating ligands can be synthesized by methods known in the art. See, Examples 1-4 and 14 below and U.S. Pat. Nos. 6,406,297 and 6,515,113. 17330-011WO1 / MET-24 and ES-32
  • TBMs can include peptides, nucleic acids, or small organic molecules. TBMs allow chelating ligands and metal chelates to be bound to targets in vivo.
  • a TBM has an affinity for a target.
  • the TBM can bind its target with a dissociation constant of less than 10 ⁇ M, or less than 5 ⁇ M, or less than 1 ⁇ M, or less than 100 nM.
  • the TBM has a specific binding affinity for a specific target relative to other physiologic targets.
  • the TBM may exhibit a smaller dissociation constant for collagen relative to its dissociation constant for fibrin.
  • TBMs can be synthesized and conjugated to the chelating ligands by methods well known in the art, including standard peptide and nucleic acid synthesis methods; see, e.g., WO 01/09188, WO 01/08712, and U.S. Pat. Nos. 6,406,297 and 6,515,113.
  • a TBM is covalently bound to the chelating ligand, and can be covalently bound to the chelating ligand through an optional Linker (L).
  • L optional Linker
  • a TBM may be anywhere on a chelating ligand.
  • the TBM may be bound, optionally via an L, to an ethylene group on the tetraazacyclododecane backbone, or to the ethylene C atoms of any acetate groups on the chelating ligand, or to any DGs on the backbone, as shown below:
  • Chelating ligands having a TBM can be assayed for relaxivity values (as the metal chelate) in the presence or absence of the target, e.g., when bound or unbound to the target, respectively.
  • a metal chelate having a TBM will exhibit a higher relaxivity when bound to a target because of the RIME effect (see, e.g., U.S. Pat. Nos.
  • Typical targets include human serum albumin (HSA), fibrin, an extracellular component of myocardium (e.g., collagen, elastin, and decorin), or an extracellular component of a lesion (e.g., hyaluronic acid, heparin, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, versican, and biglycan).
  • HSA human serum albumin
  • fibrin an extracellular component of myocardium
  • an extracellular component of myocardium e.g., collagen, elastin, and decorin
  • an extracellular component of a lesion e.g., hyaluronic acid, heparin, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, versican, and biglycan.
  • TBMs for binding to HSA
  • Ph sPh where n is 2 to 20 and Ph is phenyl. See, for example, WO 96/23526.
  • TBMs for binding fibrin are described in U.S. Pat. Application Ser. No. 10/209,183, entitled PEPTIDE-B ASED MULTIMERIC TARGETED CONTRAST AGENTS, filed July 30, 2002.
  • TBMs for binding an extracellular component of a lesion include peptides having affinity for Hyaluranic Acid (HA). Peptides that have affinity for HA are known. For example, peptides that bind to HA from a random 12-mer phage peptide library have 17330-011WO1 / MET-24 and ES-32
  • GAHWQFNALTVR SEQ ID. NO: 1
  • HA binding peptides include TSYGRP ALLP AA (SEQ ID NO:2), MDHLAPTRFRPAI (SEQ ID NO:3), TLRAIWPMWMSS (SEQ ID NO:4), and IPLTANYQGDFT (SEQ ID NO:5).
  • peptides having affinity for HA can include a consensus binding motif found in many HA-binding peptides, including RHAMM, CD44, and the link protein.
  • the consensus motif can be B(X) 7 , where B is a basic residue (e.g., Lys, His or Arg) and X is a non acidic residue.
  • a lesion-targeting peptide can have affinity for heparin, and can include a heparin-binding motif found in heparin-binding proteins.
  • Heparin- binding motifs for inclusion in the peptides include XBBXBX or XBBBXXBX, where B is a basic residue (e.g., Lys, His, or Arg) and X is a non-acidic residue.
  • B is a basic residue (e.g., Lys, His, or Arg) and X is a non-acidic residue.
  • the heparin-binding peptide ACQWHRVSVRWG conforms to the
  • XBBXXXBX sequence see e.g., Nielsen, P.K., Gho, Y.S., Hoffman, M.P., Watanabe, H., Makino, M., Nomizu, M., and Yamada, Y. J. Biol. Chem. (2000) 275, 14517-14523).
  • HIP heparin sulfate / heparin interacting protein sequence
  • HIP heparin sulfate / heparin interacting protein sequence
  • Useful TBMs for targeting an extracellular component of myocardium include peptides derived from the propolypeptide of von Willebrand factor, which is known to bind collagen. As used herein, all peptides are written from the N to C terminus. Additionally, peptides containing two or more cysteine residues can form disulfide bonds under non-reducing conditions.
  • a peptide for targeting collagen can include the following general formula: XI-X 2 -X 3 -X 4 -X 5 -X 6 -XV-XS-X 9 -XIO (SEQ ID NO:8) where Xi can be W, C, or A; X 2 can be R, C, or A; X 3 can be E, C, A, K, or T; X 4 can be P, C, or A; X 5 can be D, G, S, C, or A; X 6 can be F, R, C, or A; X 7 can be C, M, or A; X 8 can be A, E, or C; X9 can be L, M, R, C, or A; and X 10 can be S, N, G, L, C, or A; where no more than 3 OfX 1 -X 10 are C or A, independently, and where the total number of C and A residues in X 1 -X 10 is a maximum of 4.
  • a peptide can have the following
  • WREPSFCALS SEQ ID NO:9
  • WREPSFMALS SEQ ID NO: 10
  • WREPGFCALS SEQ ID NO: 11
  • a peptide that binds collagen has the following general formula: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13 (SEQ ID NO:12) where Xi can be W, C, or A; X 2 can be R, C, or A; X 3 can be E, C, A, K, or T; X 4 can be P, C, or A; X 5 can be D, G, S, C, or A; X 6 can be F, R, C, or A; X 7 can be C, M, or A; X 8 can be A, E, or C; X 9 can be L, M, R, C, or A; X 10 can be S, N, G, L, C, or A; Xn can be C, M, or A; X 12 can be P, A, or C; and where X 13 can be K, Q, P, H, G, C, or A; where no more
  • a peptide for binding collagen can also have the following general formula: X 1 - X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 13) where Xi can be V, I, C, or A; X 2 can be A, G, R, D, or C; X 3 can be W, C, or A; X 4 can be R, C, or A; X 5 can be E, C, A, K, or T; X 6 can be P, C, or A; X 7 can be D, G, S, C, or A; X 8 can be F, R, C, or A; X 9 can be C, M, or A; Xi 0 can be E, A, or C; Xn can be L, C, A, M, or R; Xi 2 can be S, C, A, N, G., or L; Xi 3 can be C, M,
  • peptides for targeting collagen can be found in U.S. Patent Application Serial No. 11/618,564, entitled “Collagen Binding Peptides", filed December 29, 2006.
  • Other peptides for targeting collagen can be identified by modifying (e.g., mutating, truncating, lengthening) the peptides described above.
  • TBMs for binding folate receptors, vitronectins, alpha-v-beta-3 and alpha- v-beta-5 integrins, RGD peptides for MMP targets, porphyrins, and phosphonates are described in WO 2004/112839, filed June 17, 2004, and references therein.
  • SAMs Self-Assembly Moieties
  • Magnetic resonance imaging of low concentration targets can be limited by the relaxivity of the contrast agent.
  • Different strategies have been employed to assemble many chelates together to improve the sensitivity of the contrast agent including covalent and non-covalent assembly of chelating ligands and metal chelates.
  • Chelating ligands may be modified to incorporate one or more Self-Assembly Moieties (SAM), as indicated above.
  • SAMs can include lipids, long chain alkyl or substituted alkyl groups, perfluorocarbons, peptides, nucleic acids, or small organic molecules. SAMs allow chelating ligands and metal chelates to associate with themselves to form larger aggregates, particles, or assemblies.
  • SAMs can be synthesized and conjugated to chelating ligands by methods well known in the art, including standard peptide and nucleic acid synthesis methods; see, e.g., WO 01/09188, WO 01/08712, and U.S. Pat. Nos. 6,406,297 and 6,515,113.
  • a SAM is covalently bound to a chelating ligand, and can be covalently bound to a chelating ligand through an optional Linker (L).
  • L optional Linker
  • a SAM may be anywhere on a chelating ligand.
  • the SAM may be bound, optionally via an L, to an ethylene group on the tetraazacyclododecane backbone, or to the ethylene C atoms of any acetate groups on the chelating ligand, or to any DGs on the backbone, as shown below:
  • Chelating ligands having a SAM can be assayed for relaxivity values (as the metal chelate) at or above a critical self-assembly concentration. At very low concentrations the chelate may exist in predominantly monomeric, unassembled form; above a critical self-assembly concentration the chelate may exist predominantly in the self-assembled form. Typically, a metal chelate having a SAM will exhibit a higher relaxivity when in the self-assembled form because of the RIME effect (see, e.g., U.S. Pat. Nos. 4,899,755 and 4,880,008).
  • SAMs can include lipids and lipid- like groups capable of forming micelles (see e.g., Nicolle, G. M., Toth, E., Eisenwiener, K.P., Macke, H.R., and Merbach, A.E. J Biol 17330-011WO1 / MET-24 and ES-32
  • SAMs can also facilitate incorporation into mixed liposomes or emulsions (see e.g., U.S. Patent No. 6,869,591)
  • SAMs can also be perfluoroalkyl groups that promote self-assembly (see e.g.,
  • peptides can also form self-assemblies (see e.g., WO 2004/0204561 and peptide sequences disclosed therein).
  • the TBM is covalently bound to the chelating ligand through a linker (L).
  • L can include, for example, a linear, branched or cyclic peptide sequence.
  • an L can include the linear dipeptide sequence G-G (glycine-glycine).
  • the L can cap the N-terminus of the TBM peptide, the C-terminus, or both N- and C- termini, as an amide moiety.
  • Other exemplary capping moieties include sulfonamides, ureas, thioureas and carbamates.
  • Ls can also include linear, branched, or cyclic alkanes, alkenes, or alkynes, and phosphodiester moieties. L may be substituted with one or more functional groups, including ketone, ester, amide, ether, carbonate, sulfonamide, or carbamate functionalities.
  • L is linked to the chelate via a DG, as defined in Tables I and II.
  • a chelate may have the general formula: 17330-011WO1 / MET-24 and ES-32
  • Chelating ligands are capable of binding one or more metal ions to result in a metal chelate.
  • Metal chelates can be prepared by methods well known in the art; see e.g., WO 96/23526, U.S. Pat. Nos. 6,406,297 and 6,515,113, and Examples, below.
  • Metal chelates can include a metal ion with an atomic number of 21 -31 , 39-50, or 57-83.
  • Metal chelates can include a stable or unstable isotope selected from Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Cu(III), Dy(III), Ho(III), Er(III), Pr(III), Eu(II), Eu(III), Nd(III), La(III), Lu(III), Sm(III), Tb(III), Tb(IV), Tm(III), Y(III), In(III), Ga(III), Tc(III), Tc(IV), Tc(V), Re(III), Re(IV), Re(V), Bi(III), or Yb(III).
  • the metal ion can be paramagnetic.
  • K f The formation constant, K f , of a chelating ligand for a metal ion is an indicator of binding affinity, and is typically discussed with reference to a log K f scale.
  • Physiologically compatible metal chelates can have a log K f ranging from 15 to about 25 M "1 . Methods for measuring K f are well known in the art; see, e.g., Martell, A.E. and Motekaitis, R.J., Determination and Use of Stability Constants. 2d Ed., VCH Publishers, New York (1992).
  • the relaxivity values of metal chelates can also be assessed. If the metal chelate incorporates a TBM, the relaxivity can be measured in the presence and absence of the target molecule. Methods for measuring relaxivity are well known in the art; see e.g., WO 96/23526 and Example 5A, below.
  • TBM TBM
  • SAM SAM group
  • chelates that have a common TBM in the presence of the target protein e.g., albumin
  • the high relaxivity chelates identified in this way can be further modified to incorporate a different TBM. While many of the examples listed here employ a common TBM for serum albumin, this is incorporated as a screening tool.
  • Other TBMs can be used with the high relaxivity chelates identified in the albumin binding/re laxivity screen, for instance a fibrin TBM described in compound 105 and Example 21 below. Alternately, high relaxivity chelates can be conjugated to a SAM group as described in Example 20 below.
  • Metal chelates can also be evaluated for the mean residence time of water molecule(s) in the first (or higher) coordination sphere(s).
  • the mean residence time of water molecules is the inverse of the water exchange rate and is dependent on temperature.
  • the mean residence time of water in the coordination sphere of the metal chelates at 37 0 C is preferably between 1 and 100 ns, or between 3 and 30 ns. 17 O NMR can be used to evaluate the mean residence time of water molecules. See, e.g., Example 5B, below.
  • Luminescence lifetime measurements can be used to evaluate the number of water molecules bound to a metal chelate. Methods for measuring luminescence lifetimes are known in the art, and typically include monitoring emissive transitions of the chelate at particular wavelengths for lifetime determination, followed by fitting of luminescence decay data; see Example 5C, below. Luminescence lifetime measurements are also useful for evaluating the suitability of the metal chelates as luminescent probes.
  • Chelating ligands can be used to prepare metal chelates, as described above, for diagnostic purposes.
  • metal chelates prepared with Gd(III) can be useful as contrast agents in MR imaging.
  • Contrast agents incorporating a TBM can bind a target 17330-011WO1 / MET-24 and ES-32
  • the contrast agent can be bound to the desired target at physiologically relevant concentrations of contrast agent and target.
  • concentrations of contrast agent and target can be assessed by a variety of equilibrium binding methods, e.g., ultrafiltration methods; equilibrium dialysis; affinity chromatography; or competitive binding inhibition or displacement of probe compounds.
  • Contrast agents can exhibit high relaxivity as a result of target binding, which can lead to better MR image resolution.
  • the increase in relaxivity upon binding is typically 1.5-fold or more (e.g., at least a 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold increase in relaxivity).
  • Targeted contrast agents having 7 to 8-fold, 9 to 10-fold, or even greater than 10-fold increases in relaxivity are particularly useful.
  • the preferred relaxivity of an MRI contrast agent at 20 MHz and 37 0 C is at least 10 mM " 's " ' per paramagnetic metal ion (e.g., at least 15, 20, 25, 30, 35, 40, or 60 mM 4 s " ' per paramagnetic metal ion). Contrast agents having a relaxivity greater than 60 mM " 's " ' at 20 MHz and 37° C are particularly useful.
  • Luminescent metal chelate probes can be useful in a variety of assays, e.g., to detect, separate, and/or quantify chemical and biological analytes in research and diagnostic applications, including high-throughput, real-time, and multiplex applications.
  • probes incorporating a TBM can bind to a target analyte of interest, and can have long luminescent lifetimes (e.g., greater than 0.1 ⁇ s, or 100 ⁇ s, or 1 ms), thereby improving sensitivity and applicability of various assay formats. See, generally, U.S. Pat. Nos. 6,406,297 and 6,515,113, for a description of assays suitable for inclusion of luminescent metal chelate probes.
  • Luminescent metal chelate probes are particularly useful in immunoassays and real-time PCR detection assays.
  • MRI contrast agents may be used in the same manner as conventional MRI contrast agents.
  • the contrast agent is administered to a patient (e.g., an animal, such as a human) and an MR image of the patient is acquired.
  • a patient e.g., an animal, such as a human
  • an MR image of the patient is acquired.
  • TBM a contrast-enhancing imaging sequence that preferentially increases a contrast ratio 17330-011WO1 / MET-24 and ES-32
  • a magnetic resonance signal of the target having a contrast agent bound thereto relative to the magnetic resonance signal of background blood or tissue can be used.
  • These techniques include, but are not limited to, black blood angiography sequences that seek to make blood dark, such as fast spin echo sequences; flow-spoiled gradient echo sequences; and out-of-volume suppression techniques to suppress in-flowing blood.
  • These methods also include flow independent techniques that enhance the difference in contrast due to the Ti difference between contrast-enhanced target and blood and tissue, such as inversion-recovery prepared or saturation-recovery prepared sequences that will increase the contrast between the target and background tissues. Methods of preparation for T 2 techniques may also prove useful.
  • preparations for magnetization transfer techniques may also improve contrast with contrast agents.
  • Contrast agents can be formulated as a pharmaceutical composition in accordance with routine procedures.
  • the contrast agents can include pharmaceutically acceptable derivatives thereof.
  • “Pharmaceutically acceptable” means that the agent can be administered to an animal without unacceptable adverse effects.
  • a “pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a contrast agent or compositions that, upon administration to a recipient, is capable of providing (directly or indirectly) a contrast agent or an active metabolite or residue thereof.
  • Other derivatives are those that increase the bioavailability when administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or that enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) thereby increasing the exposure relative to the parent species.
  • acceptable salts of the contrast agents include counter ions derived from pharmaceutically acceptable inorganic and organic acids and bases known in the art, including, without limitation, sodium, calcium, and N-methyl-glucamine.
  • compositions can be administered by any route, including both oral and parenteral administration.
  • Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intraarterial, interstitial, intrathecal, and intracavity administration.
  • pharmaceutical compositions When administration is intravenous, pharmaceutical compositions may be given as a bolus, as two or more doses separated in time, or as a constant or non-linear flow infusion.
  • contrast agents can be formulated for any route of administration.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent, a stabilizing agent, and a local anesthetic such as lidocaine to ease pain at the site of the injection.
  • the ingredients will be supplied either separately, e.g., in a kit, or mixed together in a unit dosage form, for example, as a dry lyophilized powder or water free concentrate.
  • the composition may be stored in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent in activity units.
  • the composition is administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade "water for injection,” saline, or other suitable intravenous fluids.
  • an ampule of sterile water for injection or saline may be provided so that the ingredients may be mixed prior to administration.
  • compositions comprise the contrast agents and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable ingredient, excipient, carrier, adjuvant or vehicle.
  • a contrast agent is preferably administered to the patient in the form of an injectable composition.
  • the method of administering a contrast agent is preferably parenterally, meaning intravenously, intra-arterially, intrathecally, interstitially or intracavitarilly.
  • Pharmaceutical compositions can be administered to mammals including humans in a manner similar to other diagnostic or therapeutic agents.
  • the dosage to be administered, and the mode of administration will depend on a variety of factors including age, weight, sex, condition of the patient and genetic factors, and will ultimately be decided by medical personnel subsequent to experimental determinations of 17330-011WO1 / MET-24 and ES-32
  • dosage required for diagnostic sensitivity or therapeutic efficacy will range from about 0.001 to 50,000 ⁇ g/kg, preferably between 0.01 to 25.0 ⁇ g/kg of host body mass.
  • the optimal dose will be determined empirically following the disclosure herein.
  • the MOM protected biphenol from example Ib (19.39 g, 68.2 mmol, 1.0 eq.) was dissolved in isopropanol (20 mL) and the solution and flask charged with argon for five minutes. The contents were stirred at 0 0 C and shielded from light. Concentrated HCl (3 mL) was added, and the solution was stirred between 0 0 C and room temperature shielded from light for 4 days. The acid was neutralized by careful addition of saturated NaHCO 3 (500 mL) and the aqueous layer was extracted with a 9:1 hexanes/EtOAc mixture (3 x 500 mL).
  • Butylhydroperoxide (1.15 mL, 8.3 mmol, 2eq.) was added and the oxidation was complete (-12.8 ppm) in 40 minutes.
  • the molecular sieves and the white solid formed were filtered off and the filtrate was diluted with EtOAc (100 mL) and then washed successively with 10% Na 2 S 2 O 3 twice, with saturated NaHCO 3 and with brine. The organic layer was dried over Na 2 SO 4 .
  • the alcohol from B (2.16g, 3.9 mmol) was dissolved in methylene chloride (50 mL) and triethylamine (1.0 mL, 7.2 mmol, 1.8 eq.) was added at once.
  • 4-Nosyl chloride (2.50 g, 11.3 mmol, 2.9 eq.) was added at once at 0 0 C and the solution was stirred for Ih at 0 0 C and was warmed to RT in 2 h.
  • the reaction mixture was washed with saturated NaHCO 3 and the organic layer was dried over Na 2 SO 4 .
  • 1,7-DO 2 A bis-(tert-butyl ester) (2.29 g, 5.7 mmol, 2 eq.) was dissolved in anhydrous acetonitrile (10 mL) and K 2 CO 3 ( 0.79 g, 5.72 mmol, 2 eq.) was added under argon.
  • the nosylate from example 2C (2.10 g, 2.9 mmol, 1 eq.) dissolved in acetonitrile (6 mL) was added dropwise over 50 minutes at room temperature. The mixture was stirred for 25 h and the acetonitrile was evaporated. The residue was triturated in ether (50 mL) and the solid was filtered off. The ether layer was washed successively with 0.5% citric acid (2 x 17330-011WO1 / MET-24 and ES-32
  • 1,4-DO 2 A bis-(tert-butyl ester) (see, e.g., Li, C. and W.-T. Wong (2003). J. Org. Chem. 68: 2956) (0.202 g, 0.5 mmol, 1 eq.) was dissolved in anhydrous acetonitrile (5 mL) and K 2 CO 3 ( 0.345 g, 2.5 mmol, 5 eq.) was added under argon. The nosylate from example 2C (0.183 g, 0.25 mmol, 0.5 eq.) dissolved in acetonitrile (5 mL) was added dropwise over 14 minutes at room temperature.
  • Relaxivities can be determined in the presence and absence of target molecules. Relaxivity can be measured at varying magnetic fields (e.g., from 0.5 T to 3 T, using spectrometers of the appropriate field strength) and varying temperatures (e.g., from about 10 to about 90 0 C). For example, relaxivity at about 37 0 C can be measured with a Bruker NMS-120
  • Minispec NMR spectrometer operating at 0.47 Tesla (20 MHz H-I Larmor frequency) and 37°C or a Konig-Brown relaxometer (20 MHz, H-I Larmor frequency) operating at 35 0 C.
  • the Ti of water protons is determined by an inversion recovery pulse sequence using the instrument's software.
  • Relaxivity is determined by measuring the Ti of multiple solutions of the target (for example, solutions of 4.5% HSA) containing zero, 20, 30, and 40 ⁇ M Gd(III), respectively. The samples are incubated at 37 0 C for at least 15 minutes to ensure temperature equilibration before the Ti measurement is performed.
  • the Gd(III) content of the samples is determined by inductively coupled plasma - mass spectrometry (ICP-MS).
  • the relaxivity (per Gd(III) ion) is determined by plotting the relaxation rate (1/Ti) in s "1 versus the Gd(III) concentration in mM. The slope of a linear fit to the data gives the relaxivity.
  • the relaxivity of the compounds in the absence of target is also determined in an analogous manner.
  • the mean residency time at 37° C (310 K) is obtained by fitting a plot of the reduced relaxation rates (1/T 2r ) as a function of temperature (T) (Eqs 1 - 5).
  • gL is the Lande g factor for Gd
  • ⁇ is the Bohr magneton
  • S is the spin quantum number of Gd
  • AITi is the hyperf ⁇ ne coupling constant (-3.8 x 10 6 rad/s)
  • R is the gas constant
  • h is Planck's constant
  • k B is Boltzmann's constant.
  • Ti e 310 the electronic relaxation time at 310 K
  • E ⁇ i e the activation energy for electronic relaxation
  • ⁇ S ⁇ the entropy of activation for water exchange
  • ⁇ H ⁇ the enthalpy of activation for water exchange
  • the number of coordinated water molecules can be extracted from luminescence lifetime measurements.
  • europium(III) or terbium(III) chelates are used.
  • two 50 ⁇ M solutions of a test Eu(III) complex are prepared in PBS: one in H 2 O and the other in D 2 O.
  • Eu(III) excitation spectra of the 7 Fo -> 5 Do transition (578-581 nm) and excited 5 Do state lifetimes are obtained using a tunable Continuum TDL-50 dye laser pumped by a YG-581C Q-switched Nd:YAG laser (10 Hz, 40-70 mJ/pulse).
  • the 5 Do -> 7 F 2 emissive transition at 614 nm is monitored for lifetime determination.
  • the determination of Eu(III) excited state lifetime is achieved by fitting Eu(III) luminescence decay data to a monoexponential decay function.
  • the number of bound waters, q is determined using the following equation:
  • ⁇ H2 ° and ⁇ D2 ° are the excited state lifetimes in water and deuterium oxide solution, respectively.
  • t-Butyl glycinate hydrochloride salt (3.00 g, 10.6 mmol, 1 eq.) and DMAP (15 mg, 0.12 mmol, 0.01 eq.) were dissolved in 10 mL CH 2 Cl 2 .
  • Triethylamine (2.8 niL, 20.0 mmol, 2 eq.) was added and the suspension was cooled to -70 0 C.
  • a solution of bromoacetyl bromide (0.9 mL, 10.0 mmol, 1 eq.) in 40 mL CH 2 Cl 2 was added over 15 minutes between -70 0 C and -60 0 C.
  • 1,7-Bis-Cbz cyclen (2.1 g, 4.8 mmol, 1 eq.) and 2-chloro-N-methyl-acetamide Ia (2.0 g, 18.6 mmol, 3.9 eq.) were dissolved in 2 mL acetonitrile and K 2 CO 3 (3.3g, 23.9 mmol, 5 eq.) was added and the reaction mixture was stirred overnight.
  • An additional 2- chloro-iV-methyl-acetamide (0.82 g, ⁇ .Ommol, 1.25 eq.) was added and the reaction mixture was stirred for 4 additional hours. The solvent was evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO 3 and then with brine.
  • 1,7-Bis-Cbz cyclen (1.0 g, 2.3 mmol, 1 eq.) and (S)-2-(2-bromo-acetylamino)- succinic acid di-tert-butyl ester Ic (1.92 g, 5.2 mmol, 2.3 eq.) were dissolved in 15 mL acetonitrile and Na 2 CO 3 (2.8 g, 26.4 mmol, 11.7 eq.) was added.
  • the reaction mixture was microwaved for 5 minutes at 120 0 C. The solvent was evaporated. The residue was dissolved in ether (150 mL) and washed with 0.2N KHSO 4 and then with brine. The organic layer was dried over Na 2 SO 4 .
  • Tri-substituted macrocycle 4b was prepared as described above using the corresponding bis-amide 3b (128 mg, 0.25 mmol, 1 eq.) , nosylate (183 mg, 0.25 mmol, 1 eq.) and K 2 CO 3 (173 mg, 1.25 mmol, 5 eq.). Excess nosylate was partially removed by treatment with a tris-amine resin overnight to give after filtration of the resin and 17330-011WO1 / MET-24 and ES-32
  • Paraformaldehyde (0.23 g, 7.5 mmol, 1.5 eq.), triethylamine (60 ⁇ L, 0.5 mmol, 0.1 eq.) and tert-butyl phosphite (0.97 g, 5 mmol, 1 eq.) were introduced in a 5 mL vial and the vial was sealed.
  • the reaction mixture was heated in a microwave instrument for 20 minutes at 90 0 C.
  • the reaction mixture was cooled to RT and purified by flash chromatography on silica gel (Hexanes/EtOAc/Et 3 N 100:10:0.5 to 80:20:0.5 to 50:50:0.5) to give 0.72 g of the desired product (64%).
  • Phosphonate 5b was prepared as described for 5a. Secondary amine 4b (65 mg. 0.062 mmol, 1 eq.), triflate ( 32.6 mg, 0.077 mmol, 1.25 eq.) and DIEA (24 ⁇ L, 0.14 mmol, 2 eq.) were dissolved in 0.7 mL acetonitrile. After 4 hours a second portion of triflate and DIEA was added and the mixture stirred for 22 hours. After work-up 158 mg of the crude desired product 5b was obtained.
  • Phosphonate 5c was prepared as described for 5a. Secondary amine 4c (0.16 g, 0.12 mmol, 1 eq.), triflate ( 0.10 g, 0.23 mmol, 2 eq.) and Et 3 N (0.05 g, 0.50 mmol, 4 eq.) were dissolved in 3 mL CH 2 Cl 2 . After stirring for 6 h a second portion (0.25 eq. of each) of triflate and Et 3 N was added and the mixture stirred for 24 hours.
  • the bis-(N-methylacetamide) cyclen 3a (0.30 g, 0.95 mmol, 1 eq.) was dissolved in 4 mL DMF and nosylate (0.23 g, 0.48 mmol, 0.5 eq.) was added.
  • K 2 CO 3 was added in small portions (3 x 7 mg, 3 x 0.05 mmol, 3 x 0.1 eq.) and the reaction was monitored by LC-MS. After 48 hours more nosylate (0.14 g, 0.29 mmol, 0.3 eq) was added and the reaction was stirred for 5 hours. The solvent was evaporated under high vacuum and the residue was partitioned between EtOAc and saturated NaHCO 3 .
  • Example 13 Synthesis ofmultimeric chelate with fibrin targeted TBM A. Synthesis of protected HgandlO4a.
  • Peptide 19 was prepared as described in U.S. Pat. Application Ser. No. 10/209,183, entitled PEPTIDE-B ASED MULTIMERIC TARGETED CONTRAST AGENTS, filed July 30, 2002.
  • Peptide 19 and activated ester 18a are dissolved in DMF.
  • the pH is adjusted to 6-6.5 with DIEA (wet pH paper test).
  • the reaction is monitored by LC-MS and additional portions of activated ester are added until most of the trimer is converted into tetramer with care taken to limit the formation of pentamer.
  • the reaction is quenched by addition of brine after 22.5 hours.
  • the white solid is filtered and dried in vacuo to give the desired product 104a in mixture with NaCl.
  • the gadolinium chelate 104 is purified by preparative HPLC on Akzo-Nobel C- 18 column using a gradient of 50 mM ammonium formate and acetonitrile.
  • the chelate is obtained as a white powder and as the ammonium salt.
  • Di-benzyl hydroxymethyl phosphonate was synthesized following a procedure in Bioorg. Med. Chem. Lett., 9 (1999), 3069-3074.
  • Di-benzyl phosphite 13.11 g, 50 mmol, 1 eq
  • paraformadehyde (1.80 g, 55 mmol, 1.1 eq.
  • Triethylamine 0.7 mL, 5 mmol, 0.1 eq.
  • the resulting oil was cooled in an ice bath and purified by flash chromatography on silica gel (EtOH/ CH 2 Cl 2 0/100 to 5/100).
  • Di-benzyl hydroxymethyl phosphonate (1.0Og, 3.6 mmol, 1 eq.) was dissolved in CH 2 Cl 2 (10 mL) and cooled to -50 0 C (acetone/dry ice). Lutidine (0.50 mL, 4.3 mmol, 1.2 eq) was added at once and triflic anhydride ( 0.73 mL, 4.3 mmol, 1.2 eq.) was added after 5 minutes. The reaction was stirred for Ih at -50 0 C and quenched with H 2 O. The aqueous layer was extracted with CH 2 Cl 2 and the combined organic layers were dried over Na 2 SO 4 .
  • Ligand (25b) was chelated according the general procedure to give, after purification by the same method, Compound 25 as a white solid.
  • MS [M 1 1 ] :::: ⁇ SK ⁇ with expected isotopic mass distribution.
  • the protected ligand (43a) was deprotected following the general procedure to give the crude ligand (43b).
  • MS: [M+l] 787.4.
  • the ligand (43b) was chelated following the general procedure to give, after purification by prep-HPLC, the desired chelate compound 43 (33 mg, 43% overall from 3 steps).
  • MS: [M+l] 942.5 with expected isotopic mass distribution.
  • the protected ligand (67a, 0.291 g) was deprotected following the general procedure for Ih using 5 ml of deprotection cocktail.
  • the ligand was purified by prep- HPLC (C-4 column, TFA method) to give a pure fraction (67b, 40.8 mg).
  • MS: [M+l] 865.1.
  • This ligand (67b, 20mg) was chelated following the general procedure to give, after purification by prep-HPLC, the desired chelate compound 67 (8.4 mg).
  • MS: [M+l] 1019.8 with expected isotopic mass distribution.
  • the protected ligand (55a, 133 mg, 122 ⁇ mol) was deprotected in TFA/MeSO 3 OH/PhOH (94:3:3, 10 mL) with stirring at 20 0 C for 2 hr.
  • the reaction was diluted with ether (100 mL), and the precipitate collected by filtration to yield 105 mg of deprotected crude ligand (55b) as a white solid.
  • MS [M+l] 866.3, 868.3 in expected mass ratio.
  • the crude ligand (55b, 33 mg) was chelated following the general procedure to give, after purification by prep-HPLC, the desired chelate compound 55 (24 mg).
  • MS: [M+l] 1024.2 with expected isotopic mass distribution.
  • the crude protected ligand (100a) was deprotected as described in the general procedure.
  • the crude solid (89 mg) was used as is for the final deprotection.
  • the compound was dissolved in 12 mL of methanol. It was placed in a hydrogenation flask and cooled down to about 0 0 C before addition of 30 mg of 10% Pd/C. The mixture was shaken overnight at room temperature under 3 bars of hydrogen.
  • the catalyst was filtered through a 0.45 ⁇ m filter and washed with methanol and water. The methanol was evaporated under reduced pressure and the residual liquid was removed by lyophilization to give 54 mg of fully deprotected ligand (100b).
  • the protected ligand (79a, 0.291 g) was deprotected following the general procedure for 1 hr using 5 ml of deprotection cocktail.
  • the ligand was purified by prep- HPLC (C-4 column, TFA method) to give a pure deprotected ligand (79b, 40.8 mg).
  • MS: [M+l] 807.3.
  • the ligand (79b, 35 mg, 33.8 ⁇ mol.) was chelated following the general procedure to give 30 mg of purified product (compound 79) with correct molecular weight.
  • MS: [M+l] 962.4 with expected isotopic mass distribution.
  • a concentrated ( ⁇ 10 mM) solution of the Gd chelate referred to as the stock solution, is prepared by dissolving the appropriate weight of chelate in water. The concentration is checked by ICP. A 200 ⁇ M solution is then obtained by dilution of the stock solution and the concentration is again checked by ICP. The 200 ⁇ M solution is used to prepare a series of four solutions, such that the concentrations of the solutions are 17330-011WO1 / MET-24 and ES-32
  • T 1 of each sample is measured at both 20 and 60 MHz on Bruker Minispecs set at a temperature of 37 0 C. Samples are placed in the magnet and left to equilibrate for 15 minutes before any measurement. T 1 is measured using an inversion recovery pulse sequence with 10 data points per T 1 measurement.
  • the x i (relaxivity) values are calculated using the measured T 1 values.
  • the 1/T 1 values are plotted against the Gd concentrations in mM, one graph for the samples containing HSA and another for those in buffer. Each plot should result in a linear graph, the slope of which is equal to x ⁇ .
  • the relaxivity was measured at 37° C, pH 7.4 in either HEPES buffer alone or HEPES buffer + 4.5% w/v human serum albumin. Data and structures are shown in Tables 3, 4, and 5 below.
  • HSA human serum albumin
  • Binding for compounds 25, 28, 29, and 40 to HSA was 99.3, 99.5, 98.9, and 99.0% respectively. Relaxivity was determined as described in Example 15 for these same four compounds. Relaxivity was determined either in 4.5% HSA solution or in a pH 7.4 HEPES buffer solution containing no HSA. The relaxivities of compounds 25, 28, 29, and 40 at 20 MHz in the absence of HSA were 5.9, 6.23, 6.27, and 6.9 mM ' V 1 , respectively. In the presence of 4.5% HSA, the relaxivities of compounds 25, 28, 29, and 40 at 60 MHz were 25.1, 59.9, 31.8, and 24.3 mM ' V 1 , respectively.
  • binding to the target HSA confers an increase of 330%, 860%, 410%, and 250% in relaxivity at 60 MHz for compounds 25, 28, 29, and 40, respectively.
  • Example 16 also demonstrates the influence of the donor group on relaxivity.
  • the four compounds in this example differ only in the substitution at N7: methylphosphonate, 2-isopropylacetate, methylpyridyl, or a substituted amide functionality.
  • the relaxivities in the absence of target HSA are very similar and differ by, at most, 17%. In the presence of protein relaxivities differ by up to 150%.
  • Theory see R.B. Lauffer, Chem. Rev. 1987, 87: 901-27) teaches that for fast tumbling complexes such of similar size, the relaxivity should be influenced primarily by the tumbling rate (rate of rotational diffusion). When metal chelates tumble slowly, e.g.
  • relaxivity can be improved by appropriate introduction of second sphere moieties (SSMs) that serve to hydrogen bond to waters in the second coordination sphere and immobilize these second sphere waters long enough so that they can be relaxed by the paramagnetic ion.
  • SSMs second sphere moieties
  • compounds 81 and 73 contain the same donor groups (phosphonate donor, two amide donor groups, and an acetate donor group) and the same TBM. They only differ in that 81 has two N-methyl substituted amides while in 73 the methyl groups are replace by acetate (CH 2 COO " ) groups. Relaxivity was determined as described in Example 15 for 17330-011WO1 / MET-24 and ES-32
  • a second example of the effect of the SSM on relaxivity is given by compounds 93, 78, and 84.
  • the donor groups are different than those in Example 18.
  • Compounds 93 and 78 only differ in that 93 has two CF 3 CH 2 - substituted amides while in 78 the CF 3 CH 2 - groups are replace by acetate (CH 2 COO " ) groups.
  • Relaxivity was determined as described in Example 15 for the compounds in 4.5% HSA at 37 0 C and 20 MHz. Replacing the CF 3 CH 2 - groups with acetates increases relaxivity from 37.2
  • Relaxivity was determined as described in Example 15 for compound 103 in HEPES buffer, pH 7.4, 37 0 C.
  • the relaxivity of this compound in buffer at 20 MHz was 23.4 InM 1 S 1 .
  • This relaxivity in buffer is much higher than that of all the other compounds listed in Tables 3 - 5.
  • compounds of similar size and with the same number of waters bound to the gadolinium would be expected to show similar relaxivity.
  • Compound 91 has a similar molecular weight to 103 but its relaxivity is almost three times lower than that of 103 (8.7 vs. 23.4 mlVrV 1 ).
  • compound 28 has the same donor groups as 103 but also has much lower relaxivity in buffer (6.2 mM ' V 1 ).
  • Compound 103 has a phosphatidylethanolamine moiety conjugated to the metal chelate.
  • Phosphatidylethanolamine is a lipid. It is well established that PE and its nitrogen functionalized derivatives form membranes, liposomes, emulsions and other self-assembled structures. In this compound the PE group acts as a self-assembly moiety (SAM) that serves to assemble multiple copies of the chelate together in solution.
  • SAM self-assembly moiety
  • the relaxivity of the chelate with the SAM group is almost 3 times higher than a chelate of similar molecular weight but lacking the SAM property.
  • Example 21 Relaxivity of compound 105 in presence and absence of fibrin.
  • Compound 105 (5 - 20 ⁇ M) was mixed with human fibrinogen (30 ⁇ M) and the fibrinogen was converted to fibrin gel by addition of human thrombin and calcium chloride.
  • the relaxivity of 105 in, and bound to, human fibrin at 37 0 C was 27.4 rnM ' V 1 per Gd (129.6 per molecule) at 20 MHz and 23.3 mM ' V 1 per Gd (93.2 per molecule) at 60 MHz.
  • the relaxivity was 11.3 per Gd (45.2 per molecule).

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Abstract

La présente invention concerne des ligands chélateurs de métal, et plus particulièrement des ligands chélateurs de métal ayant une haute relaxation lorsqu'ils se trouvent sous une forme de chélate de métal.
PCT/US2008/053186 2007-02-06 2008-02-06 Chélate à haute relaxation high relaxivity chelates WO2008098056A2 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008134289A2 (fr) * 2007-04-26 2008-11-06 Mallinckrodt Inc. Complexes de lanthanide insaturés de manière coordonnée à relaxivité élevée
DE102008045937A1 (de) * 2008-04-11 2009-10-15 Johannes-Gutenberg-Universität Mainz Verbindung aus einem Metallion und einem Markierungsvorläufer und Verwendung der Verbindung
WO2011121002A1 (fr) * 2010-03-31 2011-10-06 General Electric Company Agents hydroxylés, phosphorylés d'amélioration du contraste
JP2013520495A (ja) * 2010-02-25 2013-06-06 コルゲート・パーモリブ・カンパニー マグノロールおよびその類似体化合物の合成
JP2014240394A (ja) * 2008-12-05 2014-12-25 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド テクネチウム及びレニウム−ビス（ヘテロアリール）錯体及びその使用方法
JP2015007054A (ja) * 2014-07-24 2015-01-15 コルゲート・パーモリブ・カンパニーＣｏｌｇａｔｅ−Ｐａｌｍｏｌｉｖｅ Ｃｏｍｐａｎｙ マグノロールおよびその類似体化合物の合成
CN106316745A (zh) * 2016-08-24 2017-01-11 苏州氟拓化工科技有限公司 一种联苯化合物的制备方法
US20210276971A1 (en) * 2018-06-20 2021-09-09 The Research Foundation For The State University Of New York Triazamacrocycle-derived chelator compositions for coordination of imaging and therapy metal ions and methods of using same
TWI794304B (zh) * 2017-10-31 2023-03-01 日商東洋合成工業股份有限公司 光酸產生劑、抗蝕劑組合物、以及使用該抗蝕劑組合物的設備的製造方法

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ZECH S G ET AL: "Probing the water coordination of protein-targeted MRI contrast agents by pulsed ENDOR spectroscopy." CHEMPHYSCHEM : A EUROPEAN JOURNAL OF CHEMICAL PHYSICS AND PHYSICAL CHEMISTRY, vol. 6, no. 12, 9 December 2005 (2005-12-09), pages 2570-2577, XP009105424 ISSN: 1439-4235 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008134289A2 (fr) * 2007-04-26 2008-11-06 Mallinckrodt Inc. Complexes de lanthanide insaturés de manière coordonnée à relaxivité élevée
WO2008134289A3 (fr) * 2007-04-26 2008-12-11 Mallinckrodt Inc Complexes de lanthanide insaturés de manière coordonnée à relaxivité élevée
DE102008045937A1 (de) * 2008-04-11 2009-10-15 Johannes-Gutenberg-Universität Mainz Verbindung aus einem Metallion und einem Markierungsvorläufer und Verwendung der Verbindung
DE102008045937B4 (de) * 2008-04-11 2017-01-26 Johannes-Gutenberg-Universität Mainz Radiopharmakon aus einem Metallion und einem Markierungsvorläufer und Verwendung des Radiopharmakons
JP2014240394A (ja) * 2008-12-05 2014-12-25 モレキュラ インサイト ファーマシューティカルズ インコーポレイテッド テクネチウム及びレニウム−ビス（ヘテロアリール）錯体及びその使用方法
JP2013520495A (ja) * 2010-02-25 2013-06-06 コルゲート・パーモリブ・カンパニー マグノロールおよびその類似体化合物の合成
WO2011121002A1 (fr) * 2010-03-31 2011-10-06 General Electric Company Agents hydroxylés, phosphorylés d'amélioration du contraste
JP2015007054A (ja) * 2014-07-24 2015-01-15 コルゲート・パーモリブ・カンパニーＣｏｌｇａｔｅ−Ｐａｌｍｏｌｉｖｅ Ｃｏｍｐａｎｙ マグノロールおよびその類似体化合物の合成
CN106316745A (zh) * 2016-08-24 2017-01-11 苏州氟拓化工科技有限公司 一种联苯化合物的制备方法
TWI794304B (zh) * 2017-10-31 2023-03-01 日商東洋合成工業股份有限公司 光酸產生劑、抗蝕劑組合物、以及使用該抗蝕劑組合物的設備的製造方法
US20210276971A1 (en) * 2018-06-20 2021-09-09 The Research Foundation For The State University Of New York Triazamacrocycle-derived chelator compositions for coordination of imaging and therapy metal ions and methods of using same

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