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Claims for Patent: 6,143,274

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Claims for Patent: 6,143,274

Title: Method for imaging and radiopharmaceutical therapy using 1-substituted-4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs
Abstract:A method for imaging mammalian tissue utilizing a non-ionic complex of a paramagnetic ion of lanthanide element and a macrocyclic chelating agent.
Inventor(s): Tweedle; Michael F. (Princeton, NJ), Gaughan; Glen T. (Oxford, OX2 7QB, GB), Hagan; James J. (Holmdel, NJ)
Assignee:
Application Number:08/469,544
Patent Claims: 1. A method for imaging brain tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the brain tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

2. The method of claim 1 wherein the effective amount of the complex is administered in a bolus dose.

3. The method of claim 1 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

4. The method of claim 1 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

5. The method of claim 1 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

6. The method of claim 1 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

7. The method of claim 1 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

8. The method of claim 1 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

9. The method of claim 1 wherein the complex is bonded to a biologically active entity.

10. The method of claim 9 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

11. The method of claim 1 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

12. The method of claim 1 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

13. The method of claim 1 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

14. The method of claim 1 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

15. The method of claim 1 wherein the tetraazacyclo compound is a tetraazacyclodecane.

16. The method of claim 1 wherein the tetraazacyclo compound has the formula represented below: ##STR25## or a pharmaceutically acceptable salt thereof, wherein Y is oxygen or ##STR26## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR27## wherein G is NH.sub.2, ##STR28## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR29## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

17. The method of claim 16 wherein Y is hydroxyalkyl.

18. The method of claim 16 wherein Y is 2-hydroxypropyl.

19. The method of claim 1 wherein the metal atom is gadolinium and the tetraazacyclo compound is 10-(2-hydroxypropyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

20. The method of claim 1 wherein the contrast agent is administered intravenously in a dose of 0.05 to 1.0 millimoles of complex per kilogram of host.

21. A method for imaging heart tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the heart tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

22. The method of claim 21 wherein the effective amount of the complex is administered in a bolus dose.

23. The method of claim 21 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

24. The method of claim 21 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

25. The method of claim 21 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

26. The method of claim 21 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

27. The method of claim 21 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

28. The method of claim 21 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

29. The method of claim 21 wherein the complex is bonded to a biologically active entity.

30. The method of claim 29 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

31. The method of claim 21 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

32. The method of claim 21 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

33. The method of claim 21 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

34. The method of claim 21 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

35. The method of claim 21 wherein the tetraazacyclo compound is a tetraazacyclodecane.

36. The method of claim 21 wherein the tetraazacyclo compound has the formula represented below: ##STR30## or a pharmaceutically acceptable salt thereof, wherein Y is oxygen or ##STR31## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR32## wherein G is NH.sub.2, ##STR33## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR34## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

37. The method of claim 36 wherein Y is hydroxyalkyl.

38. The method of claim 36 wherein Y is 2-hydroxypropyl.

39. The method of claim 21 wherein the metal atom is gadolinium and the tetraazacyclo compound is 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

40. The method of claim 21 wherein the contrast agent is administered intravenously in a dose of 0.25 to 1.0 millimoles of complex per kilogram of host.

41. A method for imaging kidney tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the kidney tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

42. The method of claim 41 wherein the effective amount of the complex is administered in a bolus dose.

43. The method of claim 41 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

44. The method of claim 41 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

45. The method of claim 41 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

46. The method of claim 41 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

47. The method of claim 41 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

48. The method of claim 41 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

49. The method of claim 41 wherein the complex is bonded to a biologically active entity.

50. The method of claim 49 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

51. The method of claim 41 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

52. The method of claim 41 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

53. The method of claim 41 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

54. The method of claim 41 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

55. The method of claim 41 wherein the tetraazacyclo compound is tetraazacyclodecane.

56. The method of claim 41 wherein the tetraazacyclo compound has the formula represented below: ##STR35## or a pharmaceutically acceptable salt thereof, wherein Y is

oxygen or ##STR36## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR37## wherein G is NH.sub.2, ##STR38## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR39## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

57. The method of claim 56 wherein Y is hydroxyalkyl.

58. The method of claim 56 wherein Y is 2-hydroxypropyl.

59. The method of claim 41 wherein the metal atom is gadolinium and the tetraazacyclo compound is 10-(2-hydroxypropyl)-1,4,7, 10-tetraazacyclododecane-1,4,7-triacetic acid.

60. The method of claim 41 wherein the contrast agent is administered intravenously in a dose of 0.05 to 0.25 millimoles of complex per kilogram of host.

61. A method for imaging prostate tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the prostate tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

62. The method of claim 61 wherein the effective amount of the complex is administered in a bolus dose.

63. The method of claim 61 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

64. The method of claim 61 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

65. The method of claim 61 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

66. The method of claim 61 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

67. The method of claim 61 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

68. The method of claim 61 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

69. The method of claim 61 wherein the complex is bonded to a biologically active entity.

70. The method of claim 69 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

71. The method of claim 61 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

72. The method of claim 61 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

73. The method of claim 61 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

74. The method of claim 61 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

75. The method of claim 61 wherein the tetraazacyclo compound is tetraazacyclodecane.

76. The method of claim 61 wherein the tetraazacyclo compound has the formula represented below: ##STR40## or a pharmaceutically acceptable salt thereof, wherein Y is

oxygen or ##STR41## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR42## wherein G is NH.sub.2, ##STR43## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR44## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

77. The method of claim 76 wherein Y is hydroxyalkyl.

78. The method of claim 76 wherein Y is 2-hydroxyalkyl.

79. The method of claim 61 wherein the metal atom is gadolinium and the tetraazacyclo compound us 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

80. The method of claim 61 wherein the contrast agent is administered intravenously in a dose of 0.25 to 1.0 millimoles of complex per kilogram of host.

81. A method for imaging breast tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the breast tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

82. The method of claim 81 wherein the effective amount of the complex is administered in a bolus dose.

83. The method of claim 81 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

84. The method of claim 81 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

85. The method of claim 81 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

86. The method of claim 81 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

87. The method of claim 81 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

88. The method of claim 81 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

89. The method of claim 81 wherein the complex is bonded to a biologically active entity.

90. The method of claim 89 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

91. The method of claim 81 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

92. The method of claim 81 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

93. The method of claim 81 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

94. The method of claim 81 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

95. The method of claim 81 wherein the tetraazacyclo compound is tetraazacyclodecane.

96. The method of claim 81 wherein the tetraazacyclo compound has the formula represented below: ##STR45## or a pharmaceutically acceptable salt thereof, wherein Y is

oxygen or ##STR46## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR47## wherein G is NH.sub.2, ##STR48## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR49## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylakyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

97. The method of claim 96 wherein Y is hydroxyalkyl.

98. The method of claim 96 wherein Y is 2-hydroxypropyl.

99. The method of claim 81 wherein the metal atom is gadolinium and the tetraazacyclo compound is 10-(2-hydroxylpropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

100. The method of claim 81 wherein the contrast agent is administered intravenously in a dose of 0.05 to 1.0 millimoles of complex per kilogram of host.

101. A method for imaging bladder tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the bladder tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

102. The method of claim 101 wherein the effective amount of the complex is administered in a bolus dose.

103. The method of claim 101 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

104. The method of claim 101 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

105. The method of claim 101 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

106. The method of claim 101 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

107. The method of claim 101 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

108. The method of claim 101 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

109. The method of claim 101 wherein the complex is bonded to a biologically active entity.

110. The method of claim 109 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

111. The method of claim 101 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

112. The method of claim 101 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

113. The method of claim 101 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

114. The method of claim 101 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

115. The method of claim 101 wherein the tetraazacyclo compound is tetraazacyclodecane.

116. The method of claim 108 wherein the tetraazacyclo compound has the formula represented below: ##STR50## or a pharmaceutically acceptable salt thereof, wherein Y is

oxygen or ##STR51## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR52## wherein G is NH.sub.2, ##STR53## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR54## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

117. The method of claim 116 wherein Y is hydroxyalkyl.

118. The method of claim 116 wherein Y is 2-hydroxypropyl.

119. The method of claim 101 wherein the metal atom is gadolinium and the tetraazacylo compound is 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

120. The method of claim 101 wherein the contrast agent is administered intravenously in a dose of 0.05 to 1.0 millimoles of complex per kilogram of host.

121. A method for imaging spleen tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the spleen tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

122. The method of claim 121 wherein the effective amount of the complex is administered in a bolus dose.

123. The method of claim 121 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

124. The method of claim 121 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

125. The method of claim 121 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

126. The method of claim 121 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

127. The method of claim 121 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

128. The method of claim 121 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

129. The method of claim 121 wherein the complex is bonded to a biologically active entity.

130. The method of claim 129 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

131. The method of claims 121 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

132. The method of claim 121 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

133. The method of claim 121 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

134. The method of claim 121 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

135. The method of claim 121 wherein the tetraazacyclo compound is tetraazacyclodecane.

136. The method of claim 121 wherein the tetraazacyclo compound has the formula represented below: ##STR55## or a pharmaceutically acceptable salt thereof, wherein Y is

oxygen or ##STR56## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR57## wherein G is NH.sub.2, ##STR58## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR59## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

137. The method of claim 136 wherein Y is hydroxyalkyl.

138. The method of claim 136 wherein Y is 2-hydroxypropyl.

139. The method of claim 121 wherein the metal atom is gadolinium and the tetraazacyclo compound is 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

140. The method of claim 121 wherein the contrast agent is administered intravenously in a dose of 0.05 to 1.0 millimoles of complex per kilogram of host.

141. A method for imaging tumor tissue of a mammalian host comprising the steps of:

administering an effective amount of a contrast agent to the host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image of the tumor tissue in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

142. The method of claim 141 wherein the effective amount of the complex is administered in a bolus dose.

143. The method of claim 141 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

144. The method of claim 141 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

145. The method of claim 141 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

146. The method of claim 141 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

147. The method of claim 141 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

148. The method of claim 141 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

149. The method of claim 141 wherein the complex is bonded to a biologically active entity.

150. The method of claim 149 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

151. The method of claim 141 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

152. The method of claim 141 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

153. The method of claim 141 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

154. The method of claim 141 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

155. The method of claim 141 wherein the tetraazacyclo compound is tetraazacyclodecane.

156. The method of claim 141 wherein the tetraazacyclo compound has the formula represented below: ##STR60## or a pharmaceutically acceptable salt thereof, wherein Y is

oxygen or ##STR61## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR62## wherein G is NH.sub.2, ##STR63## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR64## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

157. The method of claim 156 wherein Y is hydroxyalkyl.

158. The method of claim 156 wherein Y is 2-hydrodroxypropyl.

159. The method of claim 141 wherein the metal atom is gadolinium and the tetraazacyclo compound is 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.

160. The method of claim 141 wherein the contrast agent is administered intravenously in a dose of 0.05 to 1.0 millimoles of complex per kilogram host.

161. A method for arthrography comprising the steps of:

administering an effective amount of a contrast agent to a host, the contrast agent comprising a complex of a metal atom and a tetraazacyclo compound, the complex being charge neutral in aqueous solution; and

obtaining an image in vivo with an x-ray, radionuclide, ultrasound, or magnetic resonance imaging apparatus.

162. The method of claim 161 wherein the effective amount of the complex is administered at a dose of .gtoreq.0.5 mmol/Kg by intraarticular injection.

163. The method of claim 161 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 19.

164. The method of claim 161 wherein the Keq (M.sup.-1) (25.degree. C.; aqueous solution) for the complex is over 23.

165. The method of claim 161 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 10.

166. The method of claim 161 wherein the aqueous conductivity for the complex (mho.cm.sup.2.mmol.sup.-1, 25.degree. C.) is less than 2.

167. The method of claim 161 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 1.

168. The method of claim 161 wherein the osmolality of the complex (Osmol/kg water, 37.degree. C.) in a 0.5M aqueous solution is less than 0.65.

169. The method of claim 161 wherein the complex is bonded to a biologically active entity.

170. The method of claim 161 wherein the biologically active entity is selected from the group consisting of bile acids, fatty acids, lipids, sugars and other alcohols, amino acids, peptides, and monoclonal antibodies and other proteins.

171. The method of claim 161 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.25M at 20-37.degree. C.

172. The method of claim 161 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.5M at 20-37.degree. C.

173. The method of claim 161 wherein the complex in aqueous solution is stable, dissolved and the complex remains in solution when in a concentration of .gtoreq.0.75M at 20-37.degree. C.

174. The method of claim 161 wherein the complex in aqueous solution at a concentration of 0.5M has a falling ball viscosity of less than 1.5 centipoise at 25.degree. C.

175. The method of claim 161 wherein the tetraazacyclo compound is a tetraazacyclodecane.

176. The method of claim 161 wherein the tetraazacyclo compound has the formula represented below: ##STR65## or a pharmaceutically acceptable salt thereof, wherein Y is

oxygen or ##STR66## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR67## wherein G is NH.sub.2, ##STR68## N(R.sub.4).sub.2, CN, wherein R.sub.4 is alkyl or hydroxyalkyl, ##STR69## wherein n and m are zero or an integer from one to five, R.sub.2 is hydrogen or alkyl,

R.sub.3 is hydrogen, hydroxyalkyl having from one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

177. The method of claim 176 wherein Y is hydroxyalkyl.

178. The method of claim 176 wherein Y is 2-hydroxypropyl.

179. The method of claim 161 wherein the metal atom is gadolinium and the tetraazacyclo compound is 10-(2-hydroxypropyl)-1,4,7, 10-tetraazacyclododecane-1,4,7-triacetic acid.

180. The method of claim 161 wherein the contrast agent is administered intravenously in a dose of 0.1 to 0.25 millimoles of complex per kilogram of host.

181. A method for radiopharmaceutical therapy comprising:

administering an effective amount of a complex comprising a radioactive metal ion and a tetraazacyclo compound, said complex bound to a disease specific entity and said complex being charge neutral in aqueous solution.

182. The method of claim 181 wherein the disease specific entity is a monoclonal antibody or a fragment thereof.

183. The method of claim 181 wherein the complex is administered into a specific body cavity.

184. A method for radiopharmaceutical therapy comprising:

administering an effective amount of a complex comprising a radioactive metal ion and a tetraazacyclo compound, said complex bound to a disease specific entity, wherein the tetraazacyclo compound has the formula represented below: ##STR70## or a pharmaceutically acceptable salt thereof, wherein Y is oxygen or ##STR71## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR72## wherein G is NH.sub.2, ##STR73## N(R.sub.4).sub.2, CN, wherein R.sub.4 is an alkyl or hydroxyalkyl, ##STR74## wherein n and m are zero or an integer from one to five, R.sub.2 is a hydrogen or alkyl,

R.sub.3 is a hydrogen, hydroxyalkyl having form one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.

185. A method for radiopharmaceutical therapy comprising:

administering an effective amount of a complex comprising a radioactive metal ion and an unsymmetrically substituted tetraazacyclo compound, said complex bound to a disease specific entity.

186. A method for radiopharmaceutical therapy comprising:

administering an effective amount of a complex comprising a radioactive metal ion and an unsymmetrically substituted tetraazacyclo compound, said complex bound to a disease specific entity, wherein the tetraazacyclo compound has the formula represented below: ##STR75## or a pharmaceutically acceptable salt thereof, wherein Y is oxygen or ##STR76## R.sub.1 is hydrogen, alkyl having from one to five carbon atoms, arylalkyl wherein the aryl portion is phenyl or substituted phenyl, alkoxy having from one to five carbon atoms, hydroxyalkyl wherein the alkyl portion has from one to five carbon atoms and having one or more hydroxy groups, ##STR77## wherein G is NH.sub.2, ##STR78## N(R.sub.4).sub.2, CN, wherein R.sub.4 is an alkyl or hydroxyalkyl, ##STR79## wherein n and m are zero or an integer from one to five, R.sub.2 is a hydrogen or alkyl,

R.sub.3 is a hydrogen, hydroxyalkyl having form one to five carbon atoms and having one or more hydroxy groups, alkoxy having from one to five carbon atoms, phenyl or substituted phenyl or phenylalkyl or substituted phenylalkyl and

X is chloro, bromo or iodo,

with the proviso that if R.sub.1 is --(CH.sub.2).sub.n G, n is one and R.sub.2 is hydrogen, then G is not CO.sub.2 H, and

wherein the term substituted phenyl refers to phenyl groups substituted with one, two or three halogen, hydroxyl, alkyl, alkoxy carbamoyl or carboxyl groups.
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