Trifunctional constructs with tunable pharmacokinetics useful in imaging and anti-tumor therapies
The present technology provides compounds, as well as compositions including such compounds, useful for imaging and/or treatment of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary, gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and/or a prostate cancer. The compounds are represented by the following formula or a pharmaceutically acceptable salt thereof.
1 . A compound optionally chelating a radionuclide where the compound is
(((1S)-1-carboxy-5-(3-(3-(1-((23S,26S)-26-carboxy-33-(4-iodophenyl)-21,24,32-trioxo-23-(4-(3-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)thioureido)butyl)-3,6,9,12,15,18-hexaoxa-22,25,31-triazatritriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid;
(((1S)-1-carboxy-5-(3-(3-(1-((17S,20S)-20-carboxy-27-(4-iodophenyl)-15,18,26-trioxo-17-(4-(3-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)thioureido)butyl)-3,6,9,12-tetraoxa-16,19,25-triazaheptacosyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid;
(((1S)-1-carboxy-5-(3-(3-(1-((14S,17S)-17-carboxy-24-(4-iodophenyl)-12,15,23-trioxo-14-(4-(3-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)thioureido)butyl)-3,6,9-trioxa-13,16,22-triazatetracosyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid;
(((1S)-1-carboxy-5-(3-(3-(1-((29S,32S)-32-carboxy-39-(4-iodophenyl)-27,30,38-trioxo-29-(4-(3-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)thioureido)butyl)-3,6,9,12,15, 18,21,24-octaoxa-28,31,37-triazanonatriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid;
(((1S)-1-carboxy-5-(3-(3-(1-((41S,44S)-44-carboxy-51-(4-iodophenyl)-39,42,50-trioxo-41-(4-(3-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)thioureido)butyl)-3,6,9,12,15,18,21,24,27,30,33,36-dodecaoxa-40,43,49-triazahenpentacontyl)-1H-1,2,3-triazol-5-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid;
(((1S)-1-carboxy-5-(3-(3-(1-(2-(((2S)-1-(((S)-1-carboxy-5-(2-(4-iodophenyl)acetamido)pentyl)amino)-1-oxo-6-(3-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)thioureido)hexan-2-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-5-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid;
(((S)-1-Carboxy-5-(3-(3-(1-((14S,45S)-45-carboxy-14-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-54-(4-iodophenyl)-12,15,43,51-tetraoxo-3,6,9,19,22,25,28,31,34,37,40-undecaoxa-13,16,44,50-tetraazatetrapentacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid;
or a pharmaceutically acceptable salt and/or solvate thereof.
2 . The compound of claim 1 , wherein the compound chelates the radionuclide.
3 . The compound of claim 2 , wherein the radionuclide is 177 Lu 3+ , 175 Lu 3+ , 45 Sc 3+ , 66 Ga 3+ , 67 Ga 3+ , 68 Ga 3+ , 69 Ga 3+ , 71 Ga 3+ , 89 Y 3+ , 86 Y 3+ , 89 Zr 4+ , 90 Y 3+ , 99m Tc +1 , 111 In 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 152 Dy 3+ , 149 Th 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , 160 Gd 3+ , 188 Re +1 , 186 Re +1 , 213 Bi 3+ , 211 At + , 217 At + , 227 Th 4+ , 226 Th 4+ , 225 Ac 3+ , 233 Ra 2+ , 152 Dy 3+ , 213 Bi 3+ , 212 Bi 3+ , 211 Bi 3+ , 212 Pb 2+ , 212 Pb 4+ , 255 Fm 3+ , or uranium-230.
4 . The compound of claim 2 , wherein the radionuclide is an alpha-emitting radionuclide selected from 213 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2+ , 212 Pb 2+ , and 212 Pb 4+ .
5 . A method comprising
administering to a subject an effective amount of a compound of claim 2 , for imaging a cancer; and
subsequent to the administering, detecting one or more of positron emission, gamma rays from positron emission and annihilation, and Cerenkov radiation due to positron emission.
6 . The method of claim 5 , wherein the cancer comprises one or more of a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary, gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
7 . The method of claim 5 , wherein administering the compound comprises parenteral administration.
8 . A method comprising
administering to a subject an effective amount of a compound of claim 2 , for treating a cancer.
9 . The method of claim 8 , wherein the cancer comprises one or more of glioma, cervical carcinoma, vulvar carcinoma, endometrial carcinoma, primary ovarian carcinoma, metastatic ovarian carcinoma, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary, gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer.
10 . The method of claim 8 , wherein administering the compound comprises parenteral administration.