Radioimaging methods using teboroxime and thallium
A method for imaging is providing, including administering a teboroxime species to an adult human subject, administering TI-201-thallous chloride to the subject, performing a teboroxime species SPECT imaging procedure of the teboroxime species on a region of interest (ROI) of the subject, and, after administering the teboroxime species, performing a TI-201-thallous chloride SPECT imaging procedure of the TI-201-thallous chloride on the ROI. Administering the teboroxime species and the TI-201-thallous chloride and performing the teboroxime species and the TI-201-thallous chloride SPECT imaging procedures comprise administering the teboroxime species and the TI-201-thallous chloride and performing the teboroxime species and the TI-201-thallous chloride SPECT imaging procedures during a time period having a duration of no more than 30 minutes. Other embodiments are also described.
1. A method for imaging, comprising:
administering a 99m Tc-containing species to an adult human subject;
administering TI-201-thallous chloride to the subject;
performing a 99m Tc-containing species SPECT imaging procedure of the 99m Tc-containing species on a region of interest (ROI) of the subject; and
after administering the 99m Tc-containing species, performing a TI-201-thallous chloride SPECT imaging procedure of the TI-201-thallous chloride on the ROI,
wherein administering the 99m Tc-containing species and the TI-201-thallous chloride and performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprise administering the 99m Tc-containing species and the TI-201-thallous chloride and performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures during a time period having a duration of no more than 30 minutes, and
where said 99m Tc-containing species has the formula 99m TcX(Y) 3 Z, wherein:
X is an anion;
each Y, which is independently chosen, is a vicinal dioxime having the formula HON═C(R 1 )C(R 2 )═NOH or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R 1 and R 2 are —(CR 8 CR 9 ) n — wherein n is 3, 4, 5 or 6 and R 8 and R 9 are each independently hydrogen or alkyl; and
Z is a boron derivative of the formula B—R 3
wherein R 3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R 4 R 5 N)-alkyl and R 4 and R 5 are each independently hydrogen, alkyl, or arylalkyl, or R 4 and R 5 when taken together with the nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle.
2. The method according to claim 1 , wherein the duration is no more than 20 minutes.
3. The method according to claim 2 , wherein the duration is no more than 15 minutes.
4. The method according to claim 1 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises simultaneously performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures.
5. The method according to claim 1 , wherein performing the TI-201-thallous chloride SPECT imaging procedure comprises performing the TI-201-thallous chloride SPECT imaging procedure before performing the 99m Tc-containing species SPECT imaging procedure.
6. The method according to claim 1 , wherein performing the 99m Tc-containing species SPECT imaging procedure comprises performing the 99m Tc-containing species SPECT imaging procedure before performing the TI-201-thallous chloride SPECT imaging procedure.
7. The method according to claim 1 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedure after administering both the 99m Tc-containing species and the TI-201-thallous chloride.
8. The method according to claim 1 , wherein administering the 99m Tc-containing species comprises administering the 99m Tc-containing species before administering the TI-201-thallous chloride.
9. The method according to claim 1 , wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride before administering the 99m Tc-containing species.
10. The method according to claim 1 , wherein administering the 99m Tc-containing species and administering the TI-201-thallous chloride comprise (a) administering one of the 99m Tc-containing species and the TI-201-thallous chloride while the subject is at rest, and (b) administering the other of the 99m Tc-containing species and the TI-201-thallous chloride while subjecting the subject to stress.
11. The method according to claim 10 , wherein administering the 99m Tc-containing species comprises administering the 99m Tc-containing species while the subject is at rest, and wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride while subjecting the subject to the stress.
12. The method according to claim 11 , wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride after completion of the 99m Tc-containing species SPECT imaging procedure.
13. The method according to claim 11 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises simultaneously performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures.
14. The method according to claim 11 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing the 99m Tc-containing species SPECT imaging procedure before performing the TI-201-thallous chloride SPECT imaging procedure.
15. The method according to claim 11 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing TI-201-thallous chloride SPECT imaging procedure before performing the 99m Tc-containing species SPECT imaging procedure.
16. The method according to claim 11 , wherein performing the TI-201-thallous chloride SPECT imaging procedure comprises performing the TI-201-thallous chloride SPECT imaging procedure for a duration of between 3 and 5 minutes.
17. The method according to claim 10 , wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride while the subject is at rest, and wherein administering the 99m Tc-containing species comprises administering the 99m Tc-containing species while subjecting the subject to the stress.
18. The method according to claim 17 , wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride after completion of the 99m Tc-containing species SPECT imaging procedure.
19. The method according to claim 17 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises simultaneously performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures.
20. The method according to claim 17 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing the 99m Tc-containing species SPECT imaging procedure before performing the TI-201-thallous chloride SPECT imaging procedure.
21. The method according to claim 17 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing TI-201-thallous chloride SPECT imaging procedure before performing the 99m Tc-containing species SPECT imaging procedure.
22. The method according to claim 10 , wherein subjecting the subject to the stress comprises subjecting the subject to pharmacological stress.
23. The method according to claim 10 , wherein subjecting the subject to the stress comprises subjecting the subject to exercise stress.
24. The method according to claim 1 , wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride having a radioactivity of between 3 and 5 mCi at a time of the administering.
25. The method according to claim 1 , wherein administering the 99m Tc-containing species, administering the TI-201-thallous chloride, performing the 99m Tc-containing species SPECT imaging procedure, and performing the TI-201-thallous chloride imaging procedure comprise administering the 99m Tc-containing species, administering the TI-201-thallous chloride, performing the 99m Tc-containing species SPECT imaging procedure, and performing the TI-201-thallous chloride SPECT imaging procedure while the subject remains in place at a camera of an imaging system.
26. The method according to claim 1 , wherein administering the 99m Tc-containing species and administering the TI-201-thallous chloride comprise administering the 99m Tc-containing species and the TI-201-thallous chloride using an automated administration system that is configured to receive imaging protocol information for use with the 99m Tc-containing species and the TI-201-thallous chloride, and to administer the 99m Tc-containing species and the TI-201-thallous chloride into the subject at least in part responsively to the protocol information.
27. The method according to claim 1 , wherein the ROI is a cardiac ROI, and wherein performing the 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures comprises performing the 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures on the cardiac ROI.
28. The method according to claim 1 , wherein performing the 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures comprises performing dynamic 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures.
29. The method according to claim 1 , wherein said Tc-99m-containing species has the structure:
30. The method according to claim 1 , comprising mixing:
(i) a source of anion;
(ii) a boronic acid derivative, or compounds which can react in situ to form a boronic acid derivative, having the formula R 3 B(OR 7 )(OR 7 ) or a pharmaceutically acceptable salt thereof, wherein R 3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxy-alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl, or R 4 R 5 N-alkyl and R 4 and R 5 are each independently hydrogen, alkyl, or arylalkyl, or R 4 and R 5 when taken together with nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle, and each R 7 is independently selected from hydrogen, alkyl and aryl;
(iii) at least one dioxime having the formula HON═C(R 1 )C(R 2 )═NOH or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R 1 and R 2 are —(CR 8 R 9 ) n — wherein n is 3, 4, 5 or 6 and R 8 and R 9 are each independently hydrogen or alkyl;
(iv) a reducing agent; and
(v) a source of 99m Tc;
whereby to obtain the 99m Tc-containing species,
wherein administering comprises administering the 99m Tc-containing species thus obtained.
31. The method according to claim 30 , wherein said mixing further comprises mixing hydroxypropyl gamma cyclodextrin with said source of anion, said boronic acid derivate, said dioxime and said reducing agent.
32. A method for imaging, comprising:
administering TI-201-thallous chloride to an adult human subject;
after administering the TI-201-thallous chloride, administering a 99m Tc-containing species to the subject;
performing a 99m Tc-containing species SPECT imaging procedure of the 99m Tc-containing species on a region of interest (ROI) of the subject; and
performing a TI-201-thallous chloride SPECT imaging procedure of the TI-201-thallous chloride on the ROI,
wherein said 99m Tc-containing species has the formula 99m TcX(Y) 3 Z, wherein:
X is an anion;
each Y, which is independently chosen, is a vicinal dioxime having the formula HON═C(R 1 )C(R 2 )═NOH or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R 1 and R 2 are —(CR 8 CR 9 ) n — wherein n is 3, 4, 5 or 6 and R 8 and R 9 are each independently hydrogen or alkyl; and
Z is a boron derivative of the formula B—R 3
wherein R 3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R 4 R 5 N)-alkyl and R 4 and R 5 are each independently hydrogen, alkyl, or arylalkyl, or R 4 and R 5 when taken together with the nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle.
33. The method according to claim 32 , wherein performing the TI-201-thallous chloride SPECT imaging procedure comprises performing the TI-201-thallous chloride SPECT imaging procedure after administering the 99m Tc-containing species.
34. The method according to claim 32 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises simultaneously performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures.
35. The method according to claim 32 , wherein performing the TI-201-thallous chloride SPECT imaging procedure comprises performing the TI-201-thallous chloride SPECT imaging procedure before performing the 99m Tc-containing species SPECT imaging procedure.
36. The method according to claim 32 , wherein performing the 99m Tc-containing species SPECT imaging procedure comprises performing the 99m Tc-containing species SPECT imaging procedure before performing the TI-201-thallous chloride SPECT imaging procedure.
37. The method according to claim 32 , wherein administering the 99m Tc-containing species and administering the TI-201-thallous chloride comprise (a) administering one of the 99m Tc-containing species and the TI-201-thallous chloride while the subject is at rest, and (b) administering the other of the 99m Tc-containing species and the TI-201-thallous chloride while subjecting the subject to stress.
38. The method according to claim 37 , wherein administering the 99m Tc-containing species comprises administering the 99m Tc-containing species while the subject is at rest, and wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride while subjecting the subject to the stress.
39. The method according to claim 38 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises simultaneously performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures.
40. The method according to claim 38 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing the 99m Tc-containing species SPECT imaging procedure before performing the TI-201-thallous chloride SPECT imaging procedure.
41. The method according to claim 38 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing TI-201-thallous chloride SPECT imaging procedure before performing the 99m Tc-containing species SPECT imaging procedure.
42. The method according to claim 38 , wherein performing the TI-201-thallous chloride SPECT imaging procedure comprises performing the TI-201-thallous chloride SPECT imaging procedure for a duration of between 3 and 5 minutes.
43. The method according to claim 37 , wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride while the subject is at rest, and wherein administering the 99m Tc-containing species comprises administering the 99m Tc-containing species while subjecting the subject to the stress.
44. The method according to claim 43 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises simultaneously performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures.
45. The method according to claim 43 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing the 99m Tc-containing species SPECT imaging procedure before performing the TI-201-thallous chloride SPECT imaging procedure.
46. The method according to claim 43 , wherein performing the 99m Tc-containing species and the TI-201-thallous chloride SPECT imaging procedures comprises performing TI-201-thallous chloride SPECT imaging procedure before performing the 99m Tc-containing species SPECT imaging procedure.
47. The method according to claim 37 , wherein subjecting the subject to the stress comprises subjecting the subject to pharmacological stress.
48. The method according to claim 37 , wherein subjecting the subject to the stress comprises subjecting the subject to exercise stress.
49. The method according to claim 32 , wherein administering the TI-201-thallous chloride comprises administering the TI-201-thallous chloride having a radioactivity of between 3 and 5 mCi at a time of the administering.
50. The method according to claim 32 , wherein administering the 99m Tc-containing species, administering the TI-201-thallous chloride, performing the 99m Tc-containing species SPECT imaging procedure, and performing the TI-201-thallous chloride imaging procedure comprise administering the 99m Tc-containing species, administering the TI-201-thallous chloride, performing the 99m Tc-containing species SPECT imaging procedure, and performing the TI-201-thallous chloride SPECT imaging procedure while the subject remains in place at a camera of an imaging system.
51. The method according to claim 32 wherein administering the 99m Tc-containing species and administering the TI-201-thallous chloride comprise administering the 99m Tc-containing species and the TI-201-thallous chloride using an automated administration system that is configured to receive imaging protocol information for use with the 99m Tc-containing species and the TI-201-thallous chloride, and to administer the 99m Tc-containing species and the TI-201-thallous chloride into the subject at least in part responsively to the protocol information.
52. The method according to claim 32 , wherein the ROI is a cardiac ROI, and wherein performing the 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures comprises performing the 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures on the cardiac ROI.
53. The method according to claim 32 , wherein performing the 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures comprises performing dynamic 99m Tc-containing species SPECT and TI-201-thallous chloride imaging procedures.
54. The method according to claim 32 , wherein said Tc-99m-containing species has the structure:
55. The method according to claim 32 , comprising mixing:
(i) a source of anion;
(ii) a boronic acid derivative, or compounds which can react in situ to form a boronic acid derivative, having the formula R 3 B(OR 7 )(OR 7 ) or a pharmaceutically acceptable salt thereof, wherein R 3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxy-alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl, or R 4 R 5 N-alkyl and R 4 and R 5 are each independently hydrogen, alkyl, or arylalkyl, or R 4 and R 5 when taken together with nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle, and each R 7 is independently selected from hydrogen, alkyl and aryl;
(iii) at least one dioxime having the formula HON═C(R 1 )C(R 2 )═NOH or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R 1 and R 2 are —(CR 8 R 9 ) n — wherein n is 3, 4, 5 or 6 and R 8 and R 9 are each independently hydrogen or alkyl;
(iv) a reducing agent; and
(v) a source of 99m Tc;
whereby to obtain the 99m Tc-containing species,
wherein administering comprises administering the 99m Tc-containing species thus obtained.
56. The method according to claim 55 , wherein said mixing further comprises mixing hydroxypropyl gamma cyclodextrin with said source of anion, said boronic acid derivative, said dioxime and said reducing agent.
57. A method of imaging, comprising:
administering a 99m Tc-containing species to an adult human subject;
administering TI-201-thallous chloride to the subject; and
performing simultaneous SPECT imaging of the 99m Tc-containing species and the TI-201-thallous chloride on a region of interest (ROI) of the subject,
wherein said 99m Tc-containing species has the formula 99m TcX(Y) 3 Z, wherein:
X is an anion;
each Y, which is independently chosen, is a vicinal dioxime having the formula HON═C(R 1 )C(R 2 )═NOH or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R 1 and R 2 are —(CR 8 CR 9 ) n — wherein n is 3, 4, 5 or 6 and R 8 and R 9 are each independently hydrogen or alkyl; and
Z is a boron derivative of the formula B—R 3
wherein R 3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R 4 R 5 N)-alkyl and R 4 and R 5 are each independently hydrogen, alkyl, or arylalkyl, or R 4 and R 5 when taken together with the nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle.
58. The method according to claim 57 , wherein administering the 99m Tc-containing species and the TI-201-thallous chloride comprises administering the 99m Tc-containing species and the TI-201-thallous chloride as a mixture.
59. The method according to claim 58 , wherein administering the mixture comprises administering the mixture before performing the simultaneous SPECT imaging.
60. The method according to claim 58 , wherein administering the mixture comprises administering the mixture during the simultaneous SPECT imaging.
61. The method according to claim 57 , wherein administering the 99m Tc-containing species and the TI-201-thallous chloride comprises administering the 99m Tc-containing species and the TI-201-thallous chloride before performing the simultaneous SPECT imaging.
62. The method according to claim 57 , wherein administering the 99m Tc-containing species and the TI-201-thallous chloride comprises administering the 99m Tc-containing species and the TI-201-thallous chloride during the simultaneous SPECT imaging.
63. The method according to claim 57 , wherein the ROI is a cardiac ROI, and wherein performing the simultaneous SPECT imaging comprises performing the simultaneous SPECT imaging on the cardiac ROI.
64. The method according to claim 63 , wherein performing the simultaneous SPECT imaging comprises performing a dynamic myocardial perfusion study.
65. The method according to claim 64 , wherein performing the dynamic myocardial perfusion study comprises analyzing different kinetics of the 99m Tc-containing species and the TI-201-thallous chloride.
66. The method according to claim 64 , wherein performing the dynamic myocardial perfusion study comprises performing a rest dynamic myocardial perfusion study.
67. The method according to claim 64 , wherein performing the dynamic myocardial perfusion study comprises performing a stress dynamic myocardial perfusion study.
68. The method according to claim 64 , further comprising administering a pharmacological stress agent.
69. The method according to claim 57 , wherein said Tc-99m-containing species has the structure:
70. The method according to claim 57 , comprising mixing:
(i) a source of anion;
(ii) a boronic acid derivative, or compounds which can react in situ to form a boronic acid derivative, having the formula R 3 B(OR 7 )(OR 7 ) or a pharmaceutically acceptable salt thereof, wherein R 3 is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxy-alkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl, or R 4 R 5 N-alkyl and R 4 and R 5 are each independently hydrogen, alkyl, or arylalkyl, or R 4 and R 5 when taken together with nitrogen atom to which they are attached form a 5 or 6-membered nitrogen containing heterocycle, and each R 7 is independently selected from hydrogen, alkyl and aryl;
(iii) at least one dioxime having the formula HON═C(R 1 )C(R 2 )═NOH or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, halogen, alkyl, aryl, amino or a 5 or 6-membered nitrogen or oxygen containing heterocycle, or together R 1 and R 2 are —(CR 8 R 9 ) n — wherein n is 3, 4, 5 or 6 and R 8 and R 9 are each independently hydrogen or alkyl;
(iv) a reducing agent; and
(v) a source of 99m Tc;
whereby to obtain the 99m Tc-containing species,
wherein administering comprises administering the 99m Tc-containing species thus obtained.
71. The method according to claim 70 , wherein said mixing further comprises mixing hydroxypropyl gamma cyclodextrin with said source of anion, said boronic acid derivative, said dioxime and said reducing agent.