Sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors
First Claim
1. A benzamide compound having a structure shown in the structure in Formula (I):
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Abstract
Novel benzamide compounds of Formula (I), Formula (II) and Formula (III, salts, water soluble salts, analogs and radiolabeled counterparts thereof as sigma-2 receptor radiotracers for imaging the proliferative status of solid tumors. A method for diagnosing a mammal for the presence of a mammalian tumor therein comprises administering to the mammal a diagnostic imaging detectable effective amount of a benzamide compound having a structure illustrated in Formula (I), Formula (II) and Formula (III) and detecting binding of the compound to a tumor in the mammal. A method for diagnostic imaging of a mammalian tissue having cell surface sigma-2 receptors comprising administering to a mammal a diagnostic imaging amount of a compound having a structure illustrated in Formula (I) Formula (II) and Formula (III) and detecting an image of a tissue having an ample cells with sigma-2 receptors.
24 Citations
160 Claims
- 1. A benzamide compound having a structure shown in the structure in Formula (I):
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8. A process for the preparation of a compound selected from one of compounds 1, 2, 3, 4, 5 and 6 of
FIG. 4 which comprises respectively reacting a compound having a formula wherein R is hydrogen or methoxy
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15. A process for the preparation of a compound 7, 8, 9 and 10 of
FIG. 5 which comprises reacting a compound of the formula
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16. In an aspect X comprises at least one of methyl and bromide.
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21. A process for the preparation of a compound depicted as 11 and 12 which comprises:
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(c) reacting a compound of the formula (d) with bromoacetonitrile to produce a compound of the formula (d) hydrogenating that compound over palladium on charcoal to provide a compound of the formula and condensing that compound with either one of 2-methoxy-5-bromonaphthoyl chloride or 5-bromo-2,3-dimethoxybenzoic acid respectively to produce compound 11 and compound 12.
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- 24. A method for diagnosing a mammal for the presence of a cancer comprises administering to the mammal a diagnostic imaging detectable effective amount of a novel benzamide detectably labeled compound having a structure selected from at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 structurally depicted in Formula (II) and compound 14 structurally depicted in Formula (III) and detecting binding of the at least one benzamide compound to a tumor in the mammal;
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32. A marker for cancer comprising a detectably-labeled benzamide compound having a structure of at least one of the structures illustratively depicted of benzamide compounds illustratively depicted in Formula (I) including compound 23, compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and having an explicit provocative binding efficacy to a tumor in a living mammal and in an aspect the detectably labeled benzamide compound is a highly selective σ
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2 radioligand having the aforementioned structure appended with a radioactive ligand;
- View Dependent Claims (33, 34, 35, 36, 37, 39, 40)
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2 radioligand having the aforementioned structure appended with a radioactive ligand;
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38. Radiolabel compounds of Formula (I), Formula (II) and Formula (III) including compound 23 having at least one of tritium and/or iodine 125 radiolabels using standard radiolabeling conditions to produce at least one of a tritiated and iodine 125 labeled analog that can be used in the invitro detection of sigma 2 receptors in tumors and normal tissue.
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41. A pharmaceutical composition comprising a benzamide compound having as a structure at least one of structures shown for novel benzamide compounds illustratively depicted in Formula (I) compound, 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and a pharmaceutically acceptable diluent or carrier;
- conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (42, 43, 44, 45, 46)
- conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
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47. A bezamide composition comprising a detectably labeled benzamide compound further comprising a highly selective σ
- 2 radioligand.
- 48. A pharmaceutical composition effective for treating human or non-human neoplastic disorder comprises a detectably labeled pharmaceutically effective amount of at least one compound having a structure of at least one of the structures illustratively depicted in one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) in a composition including a pharmaceutically acceptable carrier.
- 55. A method for determining the proliferative status of a cancer cell in a living mammal comprises administering to a living mammal afflicted with a solid malignant tumor, an effective amount of a detectably-labeled benzamide compound having a structure of at least of at least one of the one of the benzamide compounds illustratively depicted in Formula (I) compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and determining the extent to which the detectably-labeled benzamide compound binds to cells of a tumor in the mammal, the extent providing a measure of the proliferative status of the cells.
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62. Radiolabel compounds and compositions of Formula (I), Formula (II) and Formula (III) including compound 23 wherein at least one benzamide compound(s) is radiolabeled with at least one of tritium and/or iodine 125 radiolabels using standard radiolabeling conditions to produce at least one of a tritiated and iodine 125 labeled analog that can be used in the invitro detection of sigma 2 receptors in tumors and normal tissue.
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66. A method for pharmacologically treating a mammalian tumor as a disorder in a mammal comprises administering to a mammal having a tumor a composition including a tumor-inhibiting amount of at least one detectably-labeled benzamide compound having a structure of the structure shown of at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) In an aspect the mammal is a human;
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (67, 68, 69, 70, 71)
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
- 72. A method for diagnostic imaging of a mammalian tissue having ample cell surface sigma-2 receptors comprising administering to the tissue of the mammal a diagnostic imaging amount of at least one compound having a structure of at least one benzamide compound illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) and detecting an image of a tissue having an ample cells with sigma-2 receptors and including those compounds having a structure shown in the structure in Formula (I):
- 78. A method for in vitro detection of a cancer cell in living mammalian tissue sample comprising contacting a mammalian tissue sample comprising a cell with an in vitro diagnostic imaging amount of at least one detectably labeled benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) for a time and under conditions sufficient and effective for binding of the compound to the cell and detecting such binding indicative of an association with the present of cancer.
- 82. A method for in vitro detection of a cancer cell in a living mammalian tissue sample comprising contacting a mammalian tissue sample with an in vitro diagnostic imaging detectable and acquisitionable amount of at least one detectably labeled benzamide compound having as a structure a structure of at least one of the benzamide compounds including compound 23 illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) for a time and under cellular conditions functionally sufficient and effective for binding of the compound to the cancer cell and detecting such binding.
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85. Radiolabel compounds of Formula (I), Formula (II) and Formula (III) including compound 23 are radiolabeled with at least one of tritium and iodine 125 radiolabels using standard radiolabeling conditions to produce at least one of a tritiated and iodine 125 labeled analog that can be used in the in vitro detection of sigma 2 receptors in tumors and normal tissue.
- 86. Benzamide compounds having a structure shown in the structure in Formula (I):
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95. A method for determining proliferation and progression of a cancer as a disorder in a living mammal comprising administering to a living mammal a diagnostic imaging detectable amount of at least one detectably-labeled benzamide compound having as a structure a structure of at least one of the benzamide compounds illustratively structurally depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first selected time, detecting an image of a tissue having ample cells with sigma-2 receptors at a second selected (later) time respectively detecting an image of a tissue having ample cells with sigma-2 receptors at both times, comparing the images and determining if the detected image at the later time is smaller than the detected image at the first time;
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (96, 97, 98, 99, 100, 101, 102, 103, 104)
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
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105. A method for identifying a modulating effect (and regression effect) of a cancer in a living mammal with a disorder, comprising administering to the mammal a diagnostic imaging detectable amount of at least one detectably-labeled benzamide compound having a structure of at least one of the structures illustrated in Formula (I) Formula (II) and Formula (III) at a first time, detecting and acquisitioning an image of a tissue having ample available cells with sigma-2 receptors, administering a detectably-labeled benzamide compound having a structure of at least one of the compound structures illustrated in Formula (I), Formula (II) and Formula (III) to the mammal and at a second (later) time respectively detecting and acquisitioning an image of a tissue having an abundance of cells with sigma receptors, comparing the respective images and determining that there has been an prophylactic effect and/or regression.;
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (106, 107, 109, 110, 111, 112, 113, 114, 115, 116)
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
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108. A compound in accordance with claim 108 wherein the compound is radiolabeled with at least one of 123I, 124I, 125I and tritium.
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117. A method for diagnosing and determining the response of a mammalian patient(s) with a disorder to tailored drug therapy comprising administering to a mammal a diagnostic imaging detectable amount of at least one detectably labeled benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first and second (later) times respectively, detecting an image of a tissue having an abundance of cells with sigma receptors at both times, comparing the images and determining if the image at a later time is larger than the image at the first time that there has been a proliferative effect and progression of cancer;
- novel conformationally flexible benzamide compounds including those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (118, 119, 120, 121, 122, 123, 124, 125, 126)
- novel conformationally flexible benzamide compounds including those compounds having a structure shown in the structure in Formula (I);
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127. A method of screening candidate chemicals for toxicity/lethality to cancer comprising administering to a mammal a diagnostic imaging detectable amount of at least one detectably labeled benzamide compound selected from the benzamide compounds illustratively depicted in Formula (I), compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first time, detecting and acquisitioning an image of a tissue having ample cells with sigma-2 receptors, administering to the mammal a candidate chemical, detecting and acquisitioning an image of tissue having ample cells with sigma-2 receptors, comparing the detected images and making a determination as to whether there has been a proliferative effect and progression of the cancer;
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (128, 129, 130, 131, 132, 133, 134, 135)
- novel conformationally flexible benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
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136. A medical treatment for a mammal and a method of medically treating a mammal comprising administering to a mammal a diagnostic imaging detectable amount of at least one benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I) compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) at a first and second (later) time respectively, detecting an image of a tissue having ample cells with sigma receptors at the first and second times, comparing the images taken respectively and determining if the image at the later time is larger than the image at the first time that there has been a proliferative effect and progression of the cancer;
- wherein benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (137, 138, 139, 140, 141, 142, 143, 144)
- wherein benzamide compounds include those compounds having a structure shown in the structure in Formula (I);
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145. A method of customizing drug therapy for a living mammalian subject comprising administering to the subject to the mammal undergoing drug therapy a diagnostic imaging detectable amount of at least benzamide compound having a structure of at least one of the benzamide compounds illustratively depicted in Formula (I) compound 13 depicted in Formula (II) and compound 14 depicted in Formula (III) detecting an image of a tumor having ample sigma-2 receptors and making a determination regarding the drug therapy based on the captured images;
- having conformationally flexible benzamide compounds including those compounds having a structure shown in the structure in Formula (I);
- View Dependent Claims (146, 147, 148, 149, 150, 151, 152)
- having conformationally flexible benzamide compounds including those compounds having a structure shown in the structure in Formula (I);
- 153. A compound having a structure depicted as
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155. A process for the preparation of a compound having a structure depicted as compound 23, which comprises reacting the corresponding phenol with 1-bromo-2-fluoroethane.
Specification