2. Academic Validation
  3. Radiosynthesis and Preclinical Evaluation of a Novel 11C‑Labeled Pyrazolopyrimidine Derivative for Positron Emission Tomography Imaging of Phosphodiesterase 2A

Radiosynthesis and Preclinical Evaluation of a Novel 11C‑Labeled Pyrazolopyrimidine Derivative for Positron Emission Tomography Imaging of Phosphodiesterase 2A

  • ACS Med Chem Lett. 2025 Dec 12;17(1):218-225. doi: 10.1021/acsmedchemlett.5c00649.
Yinlong Li 1,  Wakana Mori 2,  Zhendong Song 1,  Tomoteru Yamasaki 2,  Taoqian Zhao 1,  Jiahui Chen 1,  Yiding Zhang 2,  Xin Zhou 1,  Lin Xie 2,  Tomomi Kokufuta 2,  Kuan Hu 2,  Qilong Hu 1,  Masayuki Fujinaga 2,  Xiaoyan Li 1,  Katsushi Kumata 2,  Chongjiao Li 1,  Zhenkun Sun 3,  Yabiao Gao 1,  Danielle E Hoyle 3,  Jimmy S Patel 1 4,  Hongjie Yuan 3,  Ming-Rong Zhang 2,  Steven H Liang 1
Affiliations

Affiliations

  • 1 Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, Georgia 30322, United States.
  • 2 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
  • 3 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
  • 4 Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, United States.
PMID: 41531954 DOI: 10.1021/acsmedchemlett.5c00649
Abstract

Phosphodiesterase 2A (PDE2A) plays a vital role in regulating cyclic nucleotide signaling by hydrolyzing cAMP and cGMP in the central nervous system (CNS). This enzymatic activity is essential for neuronal function, and PDE2A has emerged as a molecular target for neuroimaging in neuropsychiatric disorders and neurodegenerative diseases. In this study, we evaluated the novel 11C-labeled positron emission tomography (PET) radioligand [11C]1 derived from a pyrazolopyrimidine-based PDE2A inhibitor. The radiosynthesis of [11C]1 was accomplished via [11C]-methyl iodide-mediated methylation of precursor 9 under mild conditions, yielding [11C]1 with high purity (99%) and high molar activity (154 ± 66 GBq/μmol). In vitro autoradiography demonstrated high radiotracer accumulation in regions with abundant PDE2A expression, including the striatum and substantia nigra. However, dynamic PET imaging in rats showed a relatively uniform distribution throughout the brain and no significant blocking effects. Further optimization in medicinal chemistry is necessary to improve the in vivo performance of the pyrazolopyrimidine-based PDE2A tracer scaffold.

Keywords

Brain imaging; Carbon-11; Phosphodiesterase 2A; Positron emission tomography; Radioligand.

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