Synthesis and evaluation of an AZD2461 [                         18                         F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant

Sean W. Reilly; Laura N. Puentes; Alexander Schmitz; Chia Ju Hsieh; Chi Chang Weng; Catherine Hou; Shihong Li; Yin Ming Kuo; Prashanth Padakanti; Hsiaoju Lee; Aladdin A. Riad; Mehran Makvandi; Robert H. Mach

doi:10.1016/j.bioorg.2018.10.015

Synthesis and evaluation of an AZD2461 [ ¹⁸ F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant

Sean W. Reilly
, Laura N. Puentes
, Alexander Schmitz
, Chia Ju Hsieh
, Chi Chang Weng
, Catherine Hou
, Shihong Li
, Yin Ming Kuo
, Prashanth Padakanti
, Hsiaoju Lee
, Aladdin A. Riad
, Mehran Makvandi^*
, Robert H. Mach

^*Corresponding author for this work

University of Pennsylvania

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

22 Scopus citations

Abstract

Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer's and Parkinson's. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC ₅₀ = 3.9 ± 1.2 nM), which was further evaluated as a potential ¹⁸ F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [ ¹⁸ F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.

Original language	English
Pages (from-to)	242-249
Number of pages	8
Journal	Bioorganic Chemistry
Volume	83
DOIs	https://doi.org/10.1016/j.bioorg.2018.10.015
State	Published - 03 2019
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

AZD2461
Blood-brain barrier
MicroPET imaging
P-glycoprotein
PARP-1 inhibitor

Access to Document

10.1016/j.bioorg.2018.10.015

Cite this

Reilly, S. W., Puentes, L. N., Schmitz, A., Hsieh, C. J., Weng, C. C., Hou, C., Li, S., Kuo, Y. M., Padakanti, P., Lee, H., Riad, A. A., Makvandi, M., & Mach, R. H. (2019). Synthesis and evaluation of an AZD2461 [ ¹⁸ F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant Bioorganic Chemistry, 83, 242-249. https://doi.org/10.1016/j.bioorg.2018.10.015

@article{6490946548c64659a1912bcc33a7c657,

title = " Synthesis and evaluation of an AZD2461 [ 18 F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant ",

abstract = " Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer's and Parkinson's. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC 50 = 3.9 ± 1.2 nM), which was further evaluated as a potential 18 F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [ 18 F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.",

keywords = "AZD2461, Blood-brain barrier, MicroPET imaging, P-glycoprotein, PARP-1 inhibitor",

author = "Reilly, \{Sean W.\} and Puentes, \{Laura N.\} and Alexander Schmitz and Hsieh, \{Chia Ju\} and Weng, \{Chi Chang\} and Catherine Hou and Shihong Li and Kuo, \{Yin Ming\} and Prashanth Padakanti and Hsiaoju Lee and Riad, \{Aladdin A.\} and Mehran Makvandi and Mach, \{Robert H.\}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = mar,

doi = "10.1016/j.bioorg.2018.10.015",

language = "英语",

volume = "83",

pages = "242--249",

journal = "Bioorganic Chemistry",

issn = "0045-2068",

publisher = "Academic Press Inc.",

}

Reilly, SW, Puentes, LN, Schmitz, A, Hsieh, CJ, Weng, CC, Hou, C, Li, S, Kuo, YM, Padakanti, P, Lee, H, Riad, AA, Makvandi, M & Mach, RH 2019, ' Synthesis and evaluation of an AZD2461 [ ¹⁸ F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant ', Bioorganic Chemistry, vol. 83, pp. 242-249. https://doi.org/10.1016/j.bioorg.2018.10.015

Synthesis and evaluation of an AZD2461 [ ¹⁸ F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant . / Reilly, Sean W.; Puentes, Laura N.; Schmitz, Alexander et al.
In: Bioorganic Chemistry, Vol. 83, 03.2019, p. 242-249.

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

TY - JOUR

T1 - Synthesis and evaluation of an AZD2461 [ 18 F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant

AU - Reilly, Sean W.

AU - Puentes, Laura N.

AU - Schmitz, Alexander

AU - Hsieh, Chia Ju

AU - Weng, Chi Chang

AU - Hou, Catherine

AU - Li, Shihong

AU - Kuo, Yin Ming

AU - Padakanti, Prashanth

AU - Lee, Hsiaoju

AU - Riad, Aladdin A.

AU - Makvandi, Mehran

AU - Mach, Robert H.

PY - 2019/3

Y1 - 2019/3

N2 - Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer's and Parkinson's. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC 50 = 3.9 ± 1.2 nM), which was further evaluated as a potential 18 F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [ 18 F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.

AB - Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer's and Parkinson's. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC 50 = 3.9 ± 1.2 nM), which was further evaluated as a potential 18 F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [ 18 F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.

KW - AZD2461

KW - Blood-brain barrier

KW - MicroPET imaging

KW - P-glycoprotein

KW - PARP-1 inhibitor

UR - https://www.scopus.com/pages/publications/85055744462

U2 - 10.1016/j.bioorg.2018.10.015

DO - 10.1016/j.bioorg.2018.10.015

M3 - 文章

C2 - 30390553

AN - SCOPUS:85055744462

SN - 0045-2068

VL - 83

SP - 242

EP - 249

JO - Bioorganic Chemistry

JF - Bioorganic Chemistry

ER -

Reilly SW, Puentes LN, Schmitz A, Hsieh CJ, Weng CC, Hou C et al. Synthesis and evaluation of an AZD2461 [ ¹⁸ F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant Bioorganic Chemistry. 2019 Mar;83:242-249. doi: 10.1016/j.bioorg.2018.10.015