Radiosynthesis and Preclinical Evaluation of a Novel <sup>11</sup> C-Labeled Pyrazolopyrimidine Derivative for Positron Emission Tomography Imaging of Phosphodiesterase 2A
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 <sup>11</sup>C-labeled positron emission tomography (PET) radioligand [<sup>11</sup>C]<b>1</b> derived from a pyrazolopyrimidine-based PDE2A inhibitor. The radiosynthesis of [<sup>11</sup>C]<b>1</b> was accomplished via [<sup>11</sup>C]-methyl iodide-mediated methylation of precursor <b>9</b> under mild conditions, yielding [<sup>11</sup>C]<b>1</b> with high purity (99%) and high molar activity (154 ± 66 GBq/μmol). <i>In vitro</i> 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 <i>in vivo</i> performance of the pyrazolopyrimidine-based PDE2A tracer scaffold.
Authors
- Tomoteru Yamasaki (ORCID: https://orcid.org/0000-0001-7773-3665)
- Zhendong Song (ORCID: https://orcid.org/0000-0002-1657-6325)
- Steven H. Liang (ORCID: https://orcid.org/0000-0003-1413-6315)
- Qi-Long Hu (ORCID: https://orcid.org/0000-0002-5844-9252)
- Taoqian Zhao
- Chongjiao Li
- Xiangyang Li (ORCID: https://orcid.org/0009-0001-3360-7381)
- Ming‐Rong Zhang (ORCID: https://orcid.org/0000-0002-3001-9605)
- Xin Mu Zhou (ORCID: https://orcid.org/0000-0002-1820-7830)
- Yinlong Li (ORCID: https://orcid.org/0000-0002-8864-1712)
- Tomomi Kokufuta
- Wakana Mori
- Katsushi Kumata
- Hongjie Yuan
- Masayuki Fujinaga (ORCID: https://orcid.org/0000-0002-0418-229X)
- Zhenkun Sun (ORCID: https://orcid.org/0000-0002-5130-283X)
- Jiahui Chen (ORCID: https://orcid.org/0000-0001-9186-1110)
- Yiding Zhang (ORCID: https://orcid.org/0000-0002-3500-1586)
- Jimmy S. Patel (ORCID: https://orcid.org/0000-0002-7322-7578)
- Yabiao Gao (ORCID: https://orcid.org/0000-0001-7600-9982)
- Lin Xie (ORCID: https://orcid.org/0000-0002-6472-322X)
- Kuan Hu (ORCID: https://orcid.org/0009-0004-2549-629X)
- Danielle E. Hoyle
Institutions
- Emory University (US)
- Cancer Institute (WIA) (IN)
- National Institutes for Quantum Science and Technology (JP)
- Institute for Advanced Medical Research (US)
- Advanced Medical Research Institute (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00649
- Primary Topic
- Phosphodiesterase function and regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00