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Claims for Patent: 8,394,356

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Claims for Patent: 8,394,356

Title:Diagnostic imaging contrast agents with extended blood retention
Abstract: The present invention relates to contrast agents for diagnostic imaging with prolonged blood retention. In particular, this invention relates to novel compounds that are characterized by an image enhancing moiety (IEM); a protein plasma binding moiety (PPBM); and a blood half-life extending moiety (BHEM). This invention also relates to pharmaceutical compositions comprising these compounds and to methods of using the compounds and compositions for blood half-life extension and contrast enhancement of diagnostic imaging.
Inventor(s): McMurry; Thomas J. (Winchester, MA), Sijiki; Hironao (Gifu, JP), Scott; Daniel M. (Weston, MA), Lauffer; Randall B. (Brookline, MA)
Assignee: Lantheus Medical Imaging, Inc. (North Billerica, MA)
Application Number:13/220,103
Patent Claims: 1. A method for examining vasculature of a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the following formula: IEM-L-BHEM-PPBM or a pharmaceutically acceptable salt thereof, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00028## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said tissue.

2. The method of claim 1, wherein the IEM moiety is: ##STR00029##

3. The method of claim 1, wherein the IEM is a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

4. The method of claim 1, wherein the pharmaceutically acceptable salt is a trisodium salt.

5. The method of claim 1, wherein said L is a --CH.sub.2-- group.

6. The method of claim 1, wherein the PPBM binding moiety is selected from the group consisting of: ##STR00030## where the wavy line signifies attachment to the BHEM moiety.

7. The method of claim 1, wherein said tissue is selected from the group consisting of a tumor, a heart, a brain, a leg, a lung, and a kidney.

8. The method of claim 1, wherein a portion of said imaging occurs 10 minutes or later after administration of said diagnostic imaging contrast agent.

9. The method of claim 1, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.001 to about 1 mmol/kg body weight.

10. The method of claim 9, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.005 to about 0.05 mmnol/kg body weight.

11. The method of claim 1, wherein said diagnostic imaging contrast agent is selected from the group consisting of: ##STR00031## ##STR00032## or a pharmaceutically acceptable salt thereof.

12. The method of claim 1, wherein said imaging of said mammal comprises imaging a tumor of said mammal.

13. The method of claim 1, wherein said imaging of said mammal comprises imaging the brain of said mammal.

14. The method of claim 12, wherein said imaging of said brain comprises imaging the blood-brain barrier of said brain.

15. The method of claim 12, wherein said imaging of said brain occurs when said mammal is undergoing cognitive events.

16. A method for examining perfusion in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the following formula: IEM-L-BHEM-PPBM or a pharmaceutically acceptable salt thereof, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00033## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said tissue of said human.

17. The method of claim 16, wherein the IEM moiety is: ##STR00034##

18. The method of claim 16, wherein the IEM is a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

19. The method of claim 18, wherein the salt is a trisodium salt.

20. The method of claim 16, wherein said L is a --CH.sub.2-- group.

21. The method of claim 16, wherein the PPBM binding moiety is selected from the group consisting of: ##STR00035## where the wavy line signifies attachment to the BHEM moiety.

22. The method of claim 16, wherein said tissue is selected from the group consisting of a tumor, a heart, a brain, a leg, a lung, and a kidney.

23. The method of claim 16, wherein a portion of said imaging occurs 10 minutes or later after administration of said diagnostic imaging contrast agent.

24. The method of claim 16, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.001 to about 1 mmol/kg body weight.

25. The method of claim 24, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.005 to about 0.05 mmnol/kg body weight.

26. The method of claim 16, wherein said diagnostic imaging contrast agent is selected from the group consisting of: ##STR00036## ##STR00037## or a pharmaceutically acceptable salt form thereof.

27. The method of claim 16, wherein said imaging of said mammal comprises imaging a tumor of said mammal.

28. The method of claim 16, wherein said imaging of said mammal comprises imaging the brain of said mammal.

29. The method of claim 28, wherein said imaging of said brain comprises imaging the blood-brain barrier of said brain.

30. The method of claim 28, wherein said imaging of said brain occurs when said mammal is undergoing cognitive events.

31. A method of monitoring a human's brain during cognitive events, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the following formula: IEM-L-BHEM-PPBM or a pharmaceutically acceptable salt thereof, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00038## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said brain of said human.

32. The method of claim 31, wherein the IEM moiety is: ##STR00039##

33. The method of claim 31, wherein the IEM is a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

34. The method of claim 33, wherein the pharmaceutically acceptable salt is a trisodium salt.

35. The method of claim 31, wherein said L is a --CH.sub.2-- group.

36. The method of claim 31, wherein the PPBM binding moiety is selected from the group consisting of: ##STR00040## where the wavy line signifies attachment to the BHEM moiety.

37. The method of claim 31, wherein said obtaining occurs during a cognitive event.

38. The method of claim 31, wherein a portion of said imaging occurs 10 minutes or later after administration of said diagnostic imaging contrast agent.

39. The method of claim 31, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.001 to about 1 mmol/kg body weight.

40. The method of claim 39, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.005 to about 0.05 mmnol/kg body weight.

41. The method of claim 31, wherein said diagnostic imaging contrast agent is selected from the group consisting of: ##STR00041## ##STR00042## or a pharmaceutically acceptable salt form thereof.

42. A method for determining blood volume in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the following formula: IEM-L-BHEM-PPBM or a pharmaceutically acceptable salt thereof, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00043## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said brain of said human.

43. The method of claim 42, wherein the IEM moiety is: ##STR00044##

44. The method of claim 42, wherein the IEM is a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

45. The method of claim 44, wherein the pharmaceutically acceptable salt is a trisodium salt.

46. The method of claim 42, wherein said L is a --CH.sub.2-- group.

47. The method of claim 42, wherein the PPBM binding moiety is selected from the group consisting of: ##STR00045## where the wavy line signifies attachment to the BHEM moiety.

48. The method of claim 42, wherein said tissue is selected from the group consisting of a tumor, a heart, a brain, a leg, a lung, and a kidney.

49. The method of claim 42, wherein a portion of said imaging occurs 10 minutes or later after administration of said diagnostic imaging contrast agent.

50. The method of claim 42, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.001 to about 1 mmol/kg body weight.

51. The method of claim 50, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.005 to about 0.05 mmnol/kg body weight.

52. The method of claim 42, wherein said diagnostic imaging contrast agent is selected from the group consisting of: ##STR00046## ##STR00047## or a pharmaceutically acceptable salt form thereof.

53. The method of claim 42, wherein said imaging of said mammal comprises imaging a tumor of said mammal.

54. The method of claim 42, wherein said imaging of said mammal comprises imaging the brain of said mammal.

55. The method of claim 54, wherein said imaging of said brain comprises imaging the blood-brain barrier of said brain.

56. The method of claim 54, wherein said imaging of said brain occurs when said mammal is undergoing cognitive events.

57. A method of MR imaging of a mammal, said method comprising the steps of: a) administering to said mammal a diagnostic imaging contrast agent or a pharmaceutically acceptable salt thereof, said diagnostic imaging contrast agent having the formula: IEM-L-BHEM-PPBM or a pharmaceutically acceptable salt thereof, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00048## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) subjecting said mammal to MR imaging.

58. The method of claim 57, wherein the IEM moiety is: ##STR00049##

59. The method of claim 57, wherein the IEM is a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

60. The method of claim 57, wherein the pharmaceutically acceptable salt is a trisodium salt.

61. The method of claim 57, wherein said L is a --CH.sub.2-- group.

62. The method of claim 57, wherein the PPBM binding moiety is selected from the group consisting of: ##STR00050## where the wavy line signifies attachment to the BHEM moiety.

63. The method according to claim 57, wherein said mammal is a human.

64. The method according to claim 57, wherein said MR imaging comprises imaging at least a portion of the vasculature of said mammal.

65. The method according to claim 57, wherein a portion of said imaging occurs 10 minutes or later after administration of said diagnostic imaging contrast agent.

66. The method according to claim 57, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.001 to about 1 mmol/kg body weight.

67. The method according to claim 66, wherein said diagnostic imaging contrast agent is administered to said mammal at a concentration between about 0.005 to about 0.05 mmnol/kg body weight.

68. The method according to claim 57, wherein said diagnostic imaging contrast agent is selected from the group consisting of: ##STR00051## ##STR00052## or a pharmaceutically acceptable salt form thereof.

69. The method according to claim 57, wherein said imaging of said mammal comprises imaging a tumor of said mammal.

70. The method according to claim 57, wherein said imaging of said mammal comprises imaging the brain of said mammal.

71. The method according to claim 70, wherein said imaging of said brain comprises imaging the blood-brain barrier of said brain.

72. The method according to claim 70, wherein said imaging of said brain occurs when said mammal is undergoing cognitive events.

73. A method for examining vasculature of a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the structure: ##STR00053## or a pharmaceutically acceptable salt thereof; and b) obtaining an MR image of said tissue.

74. The method of claim 73, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

75. The method of claim 74, wherein the pharmaceutically acceptable salt is a trisodium salt.

76. A method for examining perfusion in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the structure: ##STR00054## or a pharmaceutically acceptable salt thereof; and b) obtaining an MR image of said tissue of said human.

77. The method of claim 76, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

78. The method of claim 77, wherein the pharmaceutically acceptable salt is a trisodium salt.

79. A method of monitoring a human's brain during cognitive events, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the structure: ##STR00055## or a pharmaceutically acceptable salt thereof; and b) obtaining an MR image of said brain of said human.

80. The method of claim 79, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

81. The method of claim 80, wherein the pharmaceutically acceptable salt is a trisodium salt.

82. A method for determining blood volume in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent, or a pharmaceutically acceptable salt thereof, to said human, said diagnostic imaging contrast agent having the structure: ##STR00056## or a pharmaceutically acceptable salt thereof; and b) obtaining an MR image of said brain of said human.

83. The method of claim 82, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

84. The method of claim 83, wherein the pharmaceutically acceptable salt is a trisodium salt.

85. A method of MR imaging of a mammal, said method comprising the steps of: a) administering to said mammal a diagnostic imaging contrast agent or a pharmaceutically acceptable salt thereof, said contrast agent having the structure: ##STR00057## or a pharmaceutically acceptable salt thereof; and b) subjecting said mammal to MR imaging.

86. The method of claim 85, wherein the pharmaceutically acceptable salt is selected from the group consisting of: N-methyl-D-glucamine, calcium, and sodium.

87. The method of claim 86, wherein the pharmaceutically acceptable salt is a trisodium salt.

88. A method for examining vasculature of a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00058## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said tissue.

89. A method for examining perfusion in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00059## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said tissue of said human.

90. A method of monitoring a human's brain during cognitive events, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the following formula: IEM-L-BHEM-PPBM, b) wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00060## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and c) obtaining an MR image of said brain of said human.

91. A method for determining blood volume in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00061## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said brain of said human.

92. A method of MR imaging of a mammal, said method comprising the steps of: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00062## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) subjecting said mammal to MR imaging.

93. A method for examining vasculature of a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the structure: ##STR00063## and b) obtaining an MR image of said tissue.

94. A method for examining perfusion in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the structure: ##STR00064## and b) obtaining an MR image of said tissue of said human.

95. A method of monitoring a human's brain during cognitive events, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the structure: ##STR00065## and b) obtaining an MR image of said brain of said human.

96. A method for determining blood volume in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the structure: ##STR00066## and b) obtaining an MR image of said brain of said human.

97. A method of MR imaging of a mammal, said method comprising the steps of: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a sodium salt having the structure: ##STR00067## and b) subjecting said mammal to MR imaging.

98. A method for examining vasculature of a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00068## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said tissue.

99. A method for examining perfusion in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00069## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said tissue of said human.

100. A method of monitoring a human's brain during cognitive events, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the following formula: IEM-L-BHEM-PPBM, b) wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00070## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and c) obtaining an MR image of said brain of said human.

101. A method for determining blood volume in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00071## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) obtaining an MR image of said brain of said human.

102. A method of MR imaging of a mammal, said method comprising the steps of: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the following formula: IEM-L-BHEM-PPBM, wherein PPBM is a plasma protein binding moiety, wherein the plasma protein is human serum albumin (HSA); wherein the PPBM has 7-18 carbon atoms and comprises at least 1 aryl ring selected from phenyl, naphthyl, biphenyl, and benzyl; wherein IEM is an image enhancing moiety and is selected from the following group: ##STR00072## wherein one of R.sub.1-R.sub.11 is L-BHEM-PPBM and the R.sub.1-R.sub.11 groups that are not L-BHEM-PPBM are hydrogen; wherein R.sub.12, R.sub.13, and R.sub.14 can be the same or different and are selected from the group consisting of O.sup.- and NH.sub.2; wherein R.sub.15 is H, CH.sub.2CH(OH)CH.sub.3, hydroxyl alkyl, or CH.sub.2COR.sub.12; wherein said M is a paramagnetic metal ion chelated by the IEM and selected from the group consisting of Gd(III), Fe(III), Mn(II), Mn(III), Cr(III), Cu(II), Dy(III), Tb(III), Ho(III), Er(III), and Eu(III); wherein L is a linker connecting the IEM to the BHEM consisting of 1 to 4 --CH.sub.2-- groups; and wherein the BHEM moiety is a blood half-life extending moiety and is a phosphodiester; and b) subjecting said mammal to MR imaging.

103. A method for examining vasculature of a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the structure: ##STR00073## and b) obtaining an MR image of said tissue.

104. A method for examining perfusion in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the structure: ##STR00074## and b) obtaining an MR image of said tissue of said human.

105. A method of monitoring a human's brain during cognitive events, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the structure: ##STR00075## and b) obtaining an MR image of said brain of said human.

106. A method for determining blood volume in a tissue comprising HSA in a human, said method comprising: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the structure: ##STR00076## and b) obtaining an MR image of said brain of said human.

107. A method of MR imaging of a mammal, said method comprising the steps of: a) administering a diagnostic imaging contrast agent to said human, said diagnostic imaging contrast agent being a trisodium salt having the structure: ##STR00077## and b) subjecting said mammal to MR imaging.
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