Radiosynthesis and preclinical evaluation of a carbon-11 labeled PET ligand for imaging metabotropic glutamate receptor 7

Yinlong Li; Zhiwei Xiao; Wakana Mori; Jiyun Sun; Tomoteru Yamasaki; Jian Rong; Masayuki Fujinaga; Jiahui Chen; Katsushi Kumata; Chunyu Zhao; Yiding Zhang; Thomas L Collier; Kuan Hu; Lin Xie; Xin Zhou; Wei Zhang; Zhendong Song; Yabiao Gao; Zhenkun Sun; Kuo Zhang; Jimmy S Patel; Chongzhao Ran; Ahmad Chaudhary; Douglas J Sheffler; Nicholas Dp Cosford; Linqi Zhang; Chuangyan Zhai; Ahmed Haider; Hongjie Yuan; Ming-Rong Zhang; Steven H Liang

doi:10.62347/PUAI9230

Radiosynthesis and preclinical evaluation of a carbon-11 labeled PET ligand for imaging metabotropic glutamate receptor 7

Am J Nucl Med Mol Imaging. 2024 Oct 15;14(5):306-315. doi: 10.62347/PUAI9230. eCollection 2024.

Authors

Yinlong Li^{1

2}, Zhiwei Xiao^{1

2}, Wakana Mori³, Jiyun Sun², Tomoteru Yamasaki³, Jian Rong^{1

2}, Masayuki Fujinaga³, Jiahui Chen^{1

2}, Katsushi Kumata³, Chunyu Zhao^{1

2}, Yiding Zhang³, Thomas L Collier^{1

2}, Kuan Hu³, Lin Xie³, Xin Zhou¹, Wei Zhang¹, Zhendong Song¹, Yabiao Gao¹, Zhenkun Sun⁴, Kuo Zhang¹, Jimmy S Patel^{1

5}, Chongzhao Ran⁶, Ahmad Chaudhary¹, Douglas J Sheffler⁷, Nicholas Dp Cosford⁷, Linqi Zhang¹, Chuangyan Zhai¹, Ahmed Haider^{1

2}, Hongjie Yuan⁴, Ming-Rong Zhang³, Steven H Liang^{1

2}

Affiliations

¹ Department of Radiology and Imaging Sciences, Emory University Atlanta, GA 30322, USA.
² Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School Boston, MA 02114, USA.
³ Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology Chiba 263-8555, Japan.
⁴ Department of Pharmacology and Chemical Biology, Emory University School of Medicine Atlanta, GA 30322, USA.
⁵ Department of Radiation Oncology, Winship Cancer Institute of Emory University Atlanta, GA 30322, USA.
⁶ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School Boston, MA 02114, USA.
⁷ Cancer Molecular Therapeutics Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Prebys Medical Discovery Institute La Jolla, CA 92037, USA.

Abstract

Metabotropic glutamate receptor 7 (mGlu₇) is a G protein-coupled receptor that is preferentially found in the active zone of neurotransmitter release in the central nervous system (CNS). mGlu₇ plays a vital role in memory, learning, and neuronal development, rendering it a potential target for treating epilepsy, depression, and anxiety. The development of noninvasive imaging ligands targeting mGlu₇ could help elucidate the functional significance of mGlu₇ and accelerate drug discovery for neurological and psychiatric disorders. In this report, a novel carbon-11 labeled positron emission tomography (PET) tracer designated [¹¹C]18 (codenamed MG7-2109) was synthesized via ¹¹C-methylation in 23% decay-corrected radiochemical yield (RCY). In vitro serum stability, serum protein binding, in vitro autoradiography and ex vivo biodistribution studies of [¹¹C]18 were conducted. Preliminary PET imaging results revealed a homogeneous distribution of [¹¹C]18 and rapid clearance in rodent brains. This study provides valuable insights into the development of mGlu₇-targeted PET tracer based on an isoxazolo(5,4-c)pyridine scaffold.

Keywords: mGlu7; negative allosteric modulator; positron emission tomography; radioligand.