Synthesis and in vivo evaluation of [11C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis

Zhude Tu; Wenhua Chu; Jun Zhang; Carmen S. Dence; Michael J. Welch; Robert H. Mach

doi:10.1016/j.nucmedbio.2005.03.001

Synthesis and in vivo evaluation of [¹¹C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis

Zhude Tu, Wenhua Chu, Jun Zhang, Carmen S. Dence, Michael J. Welch, Robert H. Mach

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

48 Scopus citations

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme of eukaryotic cells that has been implicated in response to DNA injury. PARP-1 detects single-strand DNA breaks induced by a variety of genotoxic insults. A hyperactivation of PARP-1 is believed to play a critical role in tissues undergoing cellular death by necrosis. Therefore, a radiotracer that could image PARP-1 levels with PET could provide a useful tool in measuring necrosis in a variety of pathological conditions. The phenanthridinone derivative, 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2-yl)acetamide (PJ34), has a high affinity for PARP-1 (IC₅₀=20 nM) and is a suitable lead compound for PET radiotracer development. The synthesis of [¹¹C]PJ34 was accomplished by base-catalyzed reaction of the corresponding des-methyl precursor, N-(5,6-dihydro-6-oxophenanthridin-2-yl)-2-(methylamino)acetamide with [¹¹C]methyl iodide in DMF. The radiolabeling yield was 60% and the specific activity was ∼2000 mCi/μmol (decay corrected to E.O.B.). The total radiosynthesis time was approximately 50 min. Preliminary in vivo biodistribution studies in a rodent model of diabetes indicate that [ ¹¹C]PJ34 displays a high uptake in tissues where PARP-1 is hyperactivated. These data indicate that [¹¹C]PJ34 may be a useful radiotracer for imaging tissues undergoing cellular death via necrosis.

Original language	English
Pages (from-to)	437-443
Number of pages	7
Journal	Nuclear Medicine and Biology
Volume	32
Issue number	5
DOIs	https://doi.org/10.1016/j.nucmedbio.2005.03.001
State	Published - Jul 2005

Keywords

C-radiolabeling
Necrosis
PARP-1
PET

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10.1016/j.nucmedbio.2005.03.001

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@article{a4e909cbaab243b893cd5964a0f80736,

title = "Synthesis and in vivo evaluation of [11C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis",

abstract = "Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme of eukaryotic cells that has been implicated in response to DNA injury. PARP-1 detects single-strand DNA breaks induced by a variety of genotoxic insults. A hyperactivation of PARP-1 is believed to play a critical role in tissues undergoing cellular death by necrosis. Therefore, a radiotracer that could image PARP-1 levels with PET could provide a useful tool in measuring necrosis in a variety of pathological conditions. The phenanthridinone derivative, 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2-yl)acetamide (PJ34), has a high affinity for PARP-1 (IC50=20 nM) and is a suitable lead compound for PET radiotracer development. The synthesis of [11C]PJ34 was accomplished by base-catalyzed reaction of the corresponding des-methyl precursor, N-(5,6-dihydro-6-oxophenanthridin-2-yl)-2-(methylamino)acetamide with [11C]methyl iodide in DMF. The radiolabeling yield was 60% and the specific activity was ∼2000 mCi/μmol (decay corrected to E.O.B.). The total radiosynthesis time was approximately 50 min. Preliminary in vivo biodistribution studies in a rodent model of diabetes indicate that [ 11C]PJ34 displays a high uptake in tissues where PARP-1 is hyperactivated. These data indicate that [11C]PJ34 may be a useful radiotracer for imaging tissues undergoing cellular death via necrosis.",

keywords = "C-radiolabeling, Necrosis, PARP-1, PET",

author = "Zhude Tu and Wenhua Chu and Jun Zhang and Dence, {Carmen S.} and Welch, {Michael J.} and Mach, {Robert H.}",

note = "Funding Information: This work was supported by grant HL1385 awarded by the National Institutes of Health. The immunochemistry of PAR was supported in part by Digestive Disease Research Cores Center in Washington University School of Medicine with NIH grant P30 DK52574. The authors would like to thank Terry Sharp, Lynne Jones and Pat Margenau for their excellent technical assistance. We would also like to thank Dr. Jinbin Xu for conducting the statistical analysis of the biodistribution data.",

year = "2005",

month = jul,

doi = "10.1016/j.nucmedbio.2005.03.001",

language = "English",

volume = "32",

pages = "437--443",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

number = "5",

}

TY - JOUR

T1 - Synthesis and in vivo evaluation of [11C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis

AU - Tu, Zhude

AU - Chu, Wenhua

AU - Zhang, Jun

AU - Dence, Carmen S.

AU - Welch, Michael J.

AU - Mach, Robert H.

N1 - Funding Information: This work was supported by grant HL1385 awarded by the National Institutes of Health. The immunochemistry of PAR was supported in part by Digestive Disease Research Cores Center in Washington University School of Medicine with NIH grant P30 DK52574. The authors would like to thank Terry Sharp, Lynne Jones and Pat Margenau for their excellent technical assistance. We would also like to thank Dr. Jinbin Xu for conducting the statistical analysis of the biodistribution data.

PY - 2005/7

Y1 - 2005/7

N2 - Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme of eukaryotic cells that has been implicated in response to DNA injury. PARP-1 detects single-strand DNA breaks induced by a variety of genotoxic insults. A hyperactivation of PARP-1 is believed to play a critical role in tissues undergoing cellular death by necrosis. Therefore, a radiotracer that could image PARP-1 levels with PET could provide a useful tool in measuring necrosis in a variety of pathological conditions. The phenanthridinone derivative, 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2-yl)acetamide (PJ34), has a high affinity for PARP-1 (IC50=20 nM) and is a suitable lead compound for PET radiotracer development. The synthesis of [11C]PJ34 was accomplished by base-catalyzed reaction of the corresponding des-methyl precursor, N-(5,6-dihydro-6-oxophenanthridin-2-yl)-2-(methylamino)acetamide with [11C]methyl iodide in DMF. The radiolabeling yield was 60% and the specific activity was ∼2000 mCi/μmol (decay corrected to E.O.B.). The total radiosynthesis time was approximately 50 min. Preliminary in vivo biodistribution studies in a rodent model of diabetes indicate that [ 11C]PJ34 displays a high uptake in tissues where PARP-1 is hyperactivated. These data indicate that [11C]PJ34 may be a useful radiotracer for imaging tissues undergoing cellular death via necrosis.

AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme of eukaryotic cells that has been implicated in response to DNA injury. PARP-1 detects single-strand DNA breaks induced by a variety of genotoxic insults. A hyperactivation of PARP-1 is believed to play a critical role in tissues undergoing cellular death by necrosis. Therefore, a radiotracer that could image PARP-1 levels with PET could provide a useful tool in measuring necrosis in a variety of pathological conditions. The phenanthridinone derivative, 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2-yl)acetamide (PJ34), has a high affinity for PARP-1 (IC50=20 nM) and is a suitable lead compound for PET radiotracer development. The synthesis of [11C]PJ34 was accomplished by base-catalyzed reaction of the corresponding des-methyl precursor, N-(5,6-dihydro-6-oxophenanthridin-2-yl)-2-(methylamino)acetamide with [11C]methyl iodide in DMF. The radiolabeling yield was 60% and the specific activity was ∼2000 mCi/μmol (decay corrected to E.O.B.). The total radiosynthesis time was approximately 50 min. Preliminary in vivo biodistribution studies in a rodent model of diabetes indicate that [ 11C]PJ34 displays a high uptake in tissues where PARP-1 is hyperactivated. These data indicate that [11C]PJ34 may be a useful radiotracer for imaging tissues undergoing cellular death via necrosis.

KW - C-radiolabeling

KW - Necrosis

KW - PARP-1

KW - PET

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U2 - 10.1016/j.nucmedbio.2005.03.001

DO - 10.1016/j.nucmedbio.2005.03.001

M3 - Article

C2 - 15982573

AN - SCOPUS:20744452940

SN - 0969-8051

VL - 32

SP - 437

EP - 443

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 5

ER -

Synthesis and in vivo evaluation of [¹¹C]PJ34, a potential radiotracer for imaging the role of PARP-1 in necrosis

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Keywords

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