Synthesis, [18F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography

Dong Zhou; Wenhua Chu; Jinbin Xu; Lynne A. Jones; Xin Peng; Shihong Li; Delphine L. Chen; Robert H. Mach

doi:10.1016/j.bmc.2014.01.019

Synthesis, [¹⁸F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography

Dong Zhou, Wenhua Chu, Jinbin Xu, Lynne A. Jones, Xin Peng, Shihong Li, Delphine L. Chen, Robert H. Mach

Research output: Contribution to journal › Article › peer-review

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Abstract

Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be ¹⁸F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC₅₀ = 6.3 nM). [ ¹⁸F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [ ¹⁸F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [¹⁸F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [¹⁸F]12 in the tumor is specific to PARP-1 expression.

Original language	English
Pages (from-to)	1700-1707
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	22
Issue number	5
DOIs	https://doi.org/10.1016/j.bmc.2014.01.019
State	Published - Mar 1 2014

Keywords

Imaging
PARP-1
PET
Radiolabeling

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title = "Synthesis, [18F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography",

abstract = "Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be 18F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50 = 6.3 nM). [ 18F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [ 18F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [18F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [18F]12 in the tumor is specific to PARP-1 expression.",

keywords = "Imaging, PARP-1, PET, Radiolabeling",

author = "Dong Zhou and Wenhua Chu and Jinbin Xu and Jones, {Lynne A.} and Xin Peng and Shihong Li and Chen, {Delphine L.} and Mach, {Robert H.}",

note = "Funding Information: NIH P01 HL13851 (PI: Gropler, Welch) supported this study. The Doris Duke Foundation Clinical Investigator Award (PI: Chen) and NIH R01 HL116389 (PI: Chen) supported DLC{\textquoteright}s effort. We thank Robert Dennett and Brian Wingbermuehle for the production of [ 18 F]fluoride, Justin Rothfuss for conducting the binding affinity assays, and the staff of the Washington University Small Animal Imaging Facility for their technical assistance.",

year = "2014",

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doi = "10.1016/j.bmc.2014.01.019",

language = "English",

volume = "22",

pages = "1700--1707",

journal = "Bioorganic and Medicinal Chemistry",

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AU - Zhou, Dong

AU - Chu, Wenhua

AU - Xu, Jinbin

AU - Jones, Lynne A.

AU - Peng, Xin

AU - Li, Shihong

AU - Chen, Delphine L.

AU - Mach, Robert H.

N1 - Funding Information: NIH P01 HL13851 (PI: Gropler, Welch) supported this study. The Doris Duke Foundation Clinical Investigator Award (PI: Chen) and NIH R01 HL116389 (PI: Chen) supported DLC’s effort. We thank Robert Dennett and Brian Wingbermuehle for the production of [ 18 F]fluoride, Justin Rothfuss for conducting the binding affinity assays, and the staff of the Washington University Small Animal Imaging Facility for their technical assistance.

PY - 2014/3/1

Y1 - 2014/3/1

N2 - Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be 18F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50 = 6.3 nM). [ 18F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [ 18F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [18F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [18F]12 in the tumor is specific to PARP-1 expression.

AB - Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be 18F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50 = 6.3 nM). [ 18F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [ 18F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [18F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [18F]12 in the tumor is specific to PARP-1 expression.

KW - Imaging

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KW - PET

KW - Radiolabeling

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Synthesis, [¹⁸F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography

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