Radiosynthesis, biological evaluation and preliminary microPET study of 18F-labeled 5-resorcinolic triazolone derivative based on ganetespib targeting HSP90
(2018) In Bioorganic & Medicinal Chemistry Letters 28(23-24). p.3658-3664- Abstract
Heat-shock protein 90 (HSP90) is a molecular chaperone that activates oncogenic transformation in several solid tumors, including lung and breast cancers. Ganetespib, a most promising candidate among several HSP90 inhibitors under clinical trials, has entered Phase III clinical trials for cancer therapy. Despite numerous evidences validating HSP90 as a target of anticancer, there are few studies on PET agents targeting oncogenic HSP90. In this study, we synthesized and biologically evaluated a novel 18F-labeled 5-resorcinolic triazolone derivative (1, [18F]PTP-Ganetespib) based on ganetespib. [18F]PTP-Ganetespib was labeled by click chemistry of Ganetespib-PEG-Alkyne (10) and [18F]PEG-N3 (11) with 37.3 ± 5.11% of radiochemical yield and... (More)
Heat-shock protein 90 (HSP90) is a molecular chaperone that activates oncogenic transformation in several solid tumors, including lung and breast cancers. Ganetespib, a most promising candidate among several HSP90 inhibitors under clinical trials, has entered Phase III clinical trials for cancer therapy. Despite numerous evidences validating HSP90 as a target of anticancer, there are few studies on PET agents targeting oncogenic HSP90. In this study, we synthesized and biologically evaluated a novel 18F-labeled 5-resorcinolic triazolone derivative (1, [18F]PTP-Ganetespib) based on ganetespib. [18F]PTP-Ganetespib was labeled by click chemistry of Ganetespib-PEG-Alkyne (10) and [18F]PEG-N3 (11) with 37.3 ± 5.11% of radiochemical yield and 99.7 ± 0.09% of radiochemical purity. [18F]PTP-Ganetespib showed proper LogP (0.96 ± 0.06) and good stability in human serum over 97% for 2 h. [18F]PTP-Ganetespib showed high uptakes in breast cancer cells containing triple negative breast cancer (TNBC) MDA-MB-231 and Her2-negative MCF-7 cells, which are target breast cancer cell lines of HSP90 inhibitor, ganetespib, as an anticancer. Blocking of HSP90 by the pretreatment of ganetespib exhibited significantly decreased accumulation of [18F]PTP-Ganetespib in MDA-MB-231 and MCF-7 cells, indicating the specific binding of [18F]PTP-Ganetespib to MDA-MB-231 and MCF-7 cells with high HSP90 expression. In the biodistribution and microPET imaging studies, the initial uptake into tumor was weaker than in other thoracic and abdominal organs, but [18F]PTP-Ganetespib was retained relatively longer in the tumor than other organs. The uptake of [18F]PTP-Ganetespib in tumors was not sufficient for further development as a tumor-specific PET imaging agent by itself, but this preliminary PET imaging study of [18F]PTP-Ganetespib can be basis for developing new PET imaging agents based on HSP90 inhibitor, ganetespib.
(Less)
- author
- Kang, Julie ; Young Lee, Jun ; Taş, İsa LU ; More, Kunal N ; Kim, Hangun ; Park, Jeong-Hoon and Chang, Dong-Jo
- publishing date
- 2018-12-15
- type
- Contribution to journal
- publication status
- published
- keywords
- Animals, Binding Sites, Cell Line, Tumor, Click Chemistry, Crystallography, X-Ray, Drug Stability, Fluorine Radioisotopes/chemistry, HSP90 Heat-Shock Proteins/chemistry, Humans, Mice, Mice, Nude, Molecular Docking Simulation, Positron-Emission Tomography, Radiopharmaceuticals/blood, Tissue Distribution, Transplantation, Heterologous, Triazoles/blood
- in
- Bioorganic & Medicinal Chemistry Letters
- volume
- 28
- issue
- 23-24
- pages
- 3658 - 3664
- publisher
- Elsevier
- external identifiers
-
- scopus:85055246422
- pmid:30528977
- ISSN
- 0960-894X
- DOI
- 10.1016/j.bmcl.2018.10.035
- language
- English
- LU publication?
- no
- additional info
- Copyright © 2018 Elsevier Ltd. All rights reserved.
- id
- 9e209812-7847-4732-8f60-b766f6a7ebc9
- date added to LUP
- 2022-08-25 14:38:14
- date last changed
- 2024-03-20 13:37:15
@article{9e209812-7847-4732-8f60-b766f6a7ebc9,
abstract = {{<p>Heat-shock protein 90 (HSP90) is a molecular chaperone that activates oncogenic transformation in several solid tumors, including lung and breast cancers. Ganetespib, a most promising candidate among several HSP90 inhibitors under clinical trials, has entered Phase III clinical trials for cancer therapy. Despite numerous evidences validating HSP90 as a target of anticancer, there are few studies on PET agents targeting oncogenic HSP90. In this study, we synthesized and biologically evaluated a novel 18F-labeled 5-resorcinolic triazolone derivative (1, [18F]PTP-Ganetespib) based on ganetespib. [18F]PTP-Ganetespib was labeled by click chemistry of Ganetespib-PEG-Alkyne (10) and [18F]PEG-N3 (11) with 37.3 ± 5.11% of radiochemical yield and 99.7 ± 0.09% of radiochemical purity. [18F]PTP-Ganetespib showed proper LogP (0.96 ± 0.06) and good stability in human serum over 97% for 2 h. [18F]PTP-Ganetespib showed high uptakes in breast cancer cells containing triple negative breast cancer (TNBC) MDA-MB-231 and Her2-negative MCF-7 cells, which are target breast cancer cell lines of HSP90 inhibitor, ganetespib, as an anticancer. Blocking of HSP90 by the pretreatment of ganetespib exhibited significantly decreased accumulation of [18F]PTP-Ganetespib in MDA-MB-231 and MCF-7 cells, indicating the specific binding of [18F]PTP-Ganetespib to MDA-MB-231 and MCF-7 cells with high HSP90 expression. In the biodistribution and microPET imaging studies, the initial uptake into tumor was weaker than in other thoracic and abdominal organs, but [18F]PTP-Ganetespib was retained relatively longer in the tumor than other organs. The uptake of [18F]PTP-Ganetespib in tumors was not sufficient for further development as a tumor-specific PET imaging agent by itself, but this preliminary PET imaging study of [18F]PTP-Ganetespib can be basis for developing new PET imaging agents based on HSP90 inhibitor, ganetespib.</p>}},
author = {{Kang, Julie and Young Lee, Jun and Taş, İsa and More, Kunal N and Kim, Hangun and Park, Jeong-Hoon and Chang, Dong-Jo}},
issn = {{0960-894X}},
keywords = {{Animals; Binding Sites; Cell Line, Tumor; Click Chemistry; Crystallography, X-Ray; Drug Stability; Fluorine Radioisotopes/chemistry; HSP90 Heat-Shock Proteins/chemistry; Humans; Mice; Mice, Nude; Molecular Docking Simulation; Positron-Emission Tomography; Radiopharmaceuticals/blood; Tissue Distribution; Transplantation, Heterologous; Triazoles/blood}},
language = {{eng}},
month = {{12}},
number = {{23-24}},
pages = {{3658--3664}},
publisher = {{Elsevier}},
series = {{Bioorganic & Medicinal Chemistry Letters}},
title = {{Radiosynthesis, biological evaluation and preliminary microPET study of 18F-labeled 5-resorcinolic triazolone derivative based on ganetespib targeting HSP90}},
url = {{http://dx.doi.org/10.1016/j.bmcl.2018.10.035}},
doi = {{10.1016/j.bmcl.2018.10.035}},
volume = {{28}},
year = {{2018}},
}