Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2)

被引：2

作者：

Chen, Zhen ^{[1
,2
,3
]}

Chen, Jiahui ^{[2
,3
,4
]}

Mori, Wakana ^{[5
]}

Yi, Yongjia ^{[1
]}

Rong, Jian ^{[2
,3
,4
]}

Li, Yinlong ^{[2
,3
,4
]}

Leon, Erick R. Calderon ^{[6
]}

Shao, Tuo ^{[2
,3
]}

Song, Zhendong ^{[4
]}

Yamasaki, Tomoteru ^{[5
]}

Ishii, Hideki ^{[5
]}

Zhang, Yiding ^{[5
]}

Kokufuta, Tomomi ^{[5
]}

Hu, Kuan ^{[5
]}

Xie, Lin ^{[5
]}

Josephson, Lee ^{[2
,3
]}

Van, Richard ^{[6
]}

Shao, Yihan ^{[6
]}

Factor, Stewart ^{[7
]}

Zhang, Ming-Rong ^{[5
]}

Liang, Steven H. ^{[2
,3
,4
]}

机构：

[1] Nanjing Forestry Univ, Coll Chem Engn, Int Innovat Ctr Forest Chem & Mat, Jiangsu Key Lab Biomass Based Green Fuels & Chem,J, Nanjing 210037, Jiangsu, Peoples R China

[2] Harvard Med Sch, Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA

[3] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA

[4] Emory Univ, Dept Radiol & Imaging Sci, 1364 Clifton Rd, Atlanta, GA 30322 USA

[5] Natl Inst Radiol Sci, Natl Inst Quantum & Radiol Sci & Technol, Dept Radiopharmaceut Dev, Chiba 2638555, Japan

[6] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA

[7] Emory Univ, Dept Neurol, Jean & Paul Amos Parkinsons Dis & Movement Disorde, Sch Med, Atlanta, GA 30322 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 04期

关键词：

PARKINSONS-DISEASE; DISCOVERY; MUTATIONS;

D O I：

10.1021/acs.jmedchem.3c01687

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Parkinson's disease (PD) is one of the most highly debilitating neurodegenerative disorders, which affects millions of people worldwide, and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved in the pathogenesis of PD. Developing a potent LRRK2 positron emission tomography (PET) tracer would allow for in vivo visualization of LRRK2 distribution and expression in PD patients. In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [C-11]3 ([C-11]PF-06447475) and [F-18]4 ([F-18]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [F-18]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers.

引用

页码：2559 / 2569

页数：11

共 50 条

[1] Dependence of Leucine-rich Repeat Kinase 2 (LRRK2) Kinase Activity on Dimerization
Sen, Saurabh
Webber, Philip J.
West, Andrew B.
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (52) : 36346 - 36356
[2] Effect of leucine-rich repeat kinase 2 (LRRK2) on protein synthesis
Kim, Hyejung
Son, Ilhong
Seol, Wongi
ANIMAL CELLS AND SYSTEMS, 2018, 22 (01) : 15 - 21
[3] Chemical Biology of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors
Estrada, Anthony A.
Sweeney, Zachary K.
JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (17) : 6733 - 6746
[4] Evaluation of Current Methods to Detect Cellular Leucine-Rich Repeat Kinase 2 (LRRK2) Kinase Activity
Fernandez, Belen
Chittoor-Vinod, Vinita G.
Kluss, Jillian H.
Kelly, Kaela
Bryant, Nicole
Nguyen, An Phu Tran
Bukhari, Syed A.
Smith, Nathan
Ordonez, Antonio Jesus Lara
Fdez, Elena
Chartier-Harlin, Marie-Christine
Montine, Thomas J.
Wilson, Mark A.
Moore, Darren J.
West, Andrew B.
Cookson, Mark R.
Nichols, R. Jeremy
Hilfiker, Sabine
JOURNAL OF PARKINSONS DISEASE, 2022, 12 (05) : 1423 - 1447
[5] The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease
Cookson, Mark R.
NATURE REVIEWS NEUROSCIENCE, 2010, 11 (12) : 791 - 797
[6] Leucine-rich repeat kinase 2 (LRRK2) deficiency diminishes the development of EAU
Wandu, Sylvia
Shi, Guangpu
Ogbeifun, Osato
Nugent, Lindsey
Cai, Huaibin
Gery, Igal
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2014, 55 (13)
[7] Leucine-rich repeat kinase 2 (LRRK2) regulates α-synuclein clearance in microglia
Maekawa, Tatsunori
Sasaoka, Toshikuni
Azuma, Sadahiro
Ichikawa, Takafumi
Melrose, Heather L.
Farrer, Matthew J.
Obata, Fumiya
BMC NEUROSCIENCE, 2016, 17
[8] Leucine-rich repeat kinase 2 (LRRK2) regulates α-synuclein clearance in microglia
Tatsunori Maekawa
Toshikuni Sasaoka
Sadahiro Azuma
Takafumi Ichikawa
Heather L. Melrose
Matthew J. Farrer
Fumiya Obata
BMC Neuroscience, 17
[9] Characterization of Autophosphorylation in the Leucine-Rich Repeat Kinase 2 (LRRK2) GTPase Domain
West, A.
Webber, P. J.
Smith, A.
Sen, S.
Biskup, S.
Yue, Z.
Mobley, J. A.
Horton, B.
MOVEMENT DISORDERS, 2010, 25 : S611 - S611
[10] A review of modifiers of Parkinsonism in the Leucine-rich repeat kinase 2 (LRRK2) population
Staisch, J.
MOVEMENT DISORDERS, 2018, 33 : S622 - S622

← 1 2 3 4 5 →