Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Nicholas J. Lodge; Yu Wen Li; Frederick T. Chin; Douglas D. Dischino; Sami S. Zoghbi; Jeffrey A. Deskus; Ronald J. Mattson; Masao Imaizumi; Rick Pieschl; Thaddeus F. Molski; Masahiro Fujita; Heidi Dulac; Robert Zaczek; Joanne J. Bronson; John E. Macor; Robert B. Innis; Victor W. Pike

doi:10.1016/j.nucmedbio.2014.03.005

Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

Nicholas J. Lodge, Yu Wen Li, Frederick T. Chin, Douglas D. Dischino, Sami S. Zoghbi, Jeffrey A. Deskus, Ronald J. Mattson, Masao Imaizumi, Rick Pieschl, Thaddeus F. Molski, Masahiro Fujita, Heidi Dulac, Robert Zaczek, Joanne J. Bronson, John E. Macor, Robert B. Innis, Victor W. Pike

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

12 Scopus citations

Abstract

Introduction: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF₁ receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF₁ receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. Methods: CRF₁ receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF₁ receptors (displacement of [¹²⁵I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF₁ receptor density (B_max) was assessed in rhesus brain cortical and cerebellum membranes with the CRF₁ receptor ligand, [³H]BMS-728300. Results: The three ligands selected for development showed high binding affinity (IC₅₀ values, 0.3-8nM) at CRF₁ receptors and moderate lipophilicity (LogD, 2.8-4.4). [³H]BMS-728300 and the two ¹⁸F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF₁ receptor B_max in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [¹⁸F]BMS-721313, [¹⁸F]BMS-732098 and [¹¹C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions: Candidate CRF₁ receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF₁ receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF₁ receptors.

Original language	English (US)
Pages (from-to)	524-535
Number of pages	12
Journal	Nuclear Medicine and Biology
Volume	41
Issue number	6
DOIs	https://doi.org/10.1016/j.nucmedbio.2014.03.005
State	Published - Jul 2014

Keywords

Autoradiography
Corticotropin-releasing factor (CRF)
Positron emission tomography (PET)
Rhesus monkey

ASJC Scopus subject areas

Molecular Medicine
Radiology Nuclear Medicine and imaging
Cancer Research

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10.1016/j.nucmedbio.2014.03.005

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Lodge, N. J., Li, Y. W., Chin, F. T., Dischino, D. D., Zoghbi, S. S., Deskus, J. A., Mattson, R. J., Imaizumi, M., Pieschl, R., Molski, T. F., Fujita, M., Dulac, H., Zaczek, R., Bronson, J. J., Macor, J. E., Innis, R. B., & Pike, V. W. (2014). Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors. Nuclear Medicine and Biology, 41(6), 524-535. https://doi.org/10.1016/j.nucmedbio.2014.03.005

Lodge, NJ, Li, YW, Chin, FT, Dischino, DD, Zoghbi, SS, Deskus, JA, Mattson, RJ, Imaizumi, M, Pieschl, R, Molski, TF, Fujita, M, Dulac, H, Zaczek, R, Bronson, JJ, Macor, JE, Innis, RB & Pike, VW 2014, 'Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors', Nuclear Medicine and Biology, vol. 41, no. 6, pp. 524-535. https://doi.org/10.1016/j.nucmedbio.2014.03.005

@article{23a292de773044feb9a74e12bf8d768a,

title = "Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors",

abstract = "Introduction: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. Methods: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [125I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [3H]BMS-728300. Results: The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [3H]BMS-728300 and the two 18F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [18F]BMS-721313, [18F]BMS-732098 and [11C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.",

keywords = "Autoradiography, Corticotropin-releasing factor (CRF), Positron emission tomography (PET), Rhesus monkey",

author = "Lodge, {Nicholas J.} and Li, {Yu Wen} and Chin, {Frederick T.} and Dischino, {Douglas D.} and Zoghbi, {Sami S.} and Deskus, {Jeffrey A.} and Mattson, {Ronald J.} and Masao Imaizumi and Rick Pieschl and Molski, {Thaddeus F.} and Masahiro Fujita and Heidi Dulac and Robert Zaczek and Bronson, {Joanne J.} and Macor, {John E.} and Innis, {Robert B.} and Pike, {Victor W.}",

note = "Funding Information: The authors are indebted to Yuan Tian (Dept. of Radiochemistry, Bristol-Myers Squibb) for providing the [ 3 H]BMS-728300. Authors affiliated to the National Institutes of Health (NIH) were supported by the Intramural Research Program of the NIH (National Institute of Mental Health; NIMH) . This project was conducted under a cooperative research and development agreement (CRADA) between Bristol-Myers-Squibb Research Laboratories and the NIMH.",

year = "2014",

month = jul,

doi = "10.1016/j.nucmedbio.2014.03.005",

language = "English (US)",

volume = "41",

pages = "524--535",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

AU - Lodge, Nicholas J.

AU - Li, Yu Wen

AU - Chin, Frederick T.

AU - Dischino, Douglas D.

AU - Zoghbi, Sami S.

AU - Deskus, Jeffrey A.

AU - Mattson, Ronald J.

AU - Imaizumi, Masao

AU - Pieschl, Rick

AU - Molski, Thaddeus F.

AU - Fujita, Masahiro

AU - Dulac, Heidi

AU - Zaczek, Robert

AU - Bronson, Joanne J.

AU - Macor, John E.

AU - Innis, Robert B.

AU - Pike, Victor W.

N1 - Funding Information: The authors are indebted to Yuan Tian (Dept. of Radiochemistry, Bristol-Myers Squibb) for providing the [ 3 H]BMS-728300. Authors affiliated to the National Institutes of Health (NIH) were supported by the Intramural Research Program of the NIH (National Institute of Mental Health; NIMH) . This project was conducted under a cooperative research and development agreement (CRADA) between Bristol-Myers-Squibb Research Laboratories and the NIMH.

PY - 2014/7

Y1 - 2014/7

N2 - Introduction: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. Methods: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [125I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [3H]BMS-728300. Results: The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [3H]BMS-728300 and the two 18F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [18F]BMS-721313, [18F]BMS-732098 and [11C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.

AB - Introduction: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. Methods: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [125I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [3H]BMS-728300. Results: The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [3H]BMS-728300 and the two 18F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [18F]BMS-721313, [18F]BMS-732098 and [11C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. Conclusions: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.

KW - Autoradiography

KW - Corticotropin-releasing factor (CRF)

KW - Positron emission tomography (PET)

KW - Rhesus monkey

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Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors

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