Radiosynthesis and Preclinical Evaluation of a Carbon-11 Labeled Phosphodiesterase 7 Inhibitor for PET Neuroimaging

Dysfunction of cyclic nucleotide phosphodiesterase 7 (PDE7) has been associated with excess intracellular cAMP concentrations, fueling pathogenic processes that are implicated in neurodegenerative disorders. This study aimed to develop a suitable positron emission tomography (PET) probe that allows noninvasive mapping of PDE7 in the mammalian brain. Based on a spiro cyclohexane-1,4'-quinazolinone scaffold with known inhibitory properties toward PDE7, we designed and synthesized a carbon-11 labeling tolerant methoxy analog. The resulting PET probe, code named [<sup>11</sup>C]-P7-2104 (<b>27</b>), was synthesized in high molar activities (170-220 GBq/μmol) with decay-corrected radiochemical yields of 34 ± 7%. <i>In vitro</i> cell uptake of [<sup>11</sup>C]<b>27</b> was 6-7-fold higher in PDE7 overexpressing cells compared to the controls, whereas an <i>in vitro</i> specificity of up to 90% was measured. <i>Ex vivo</i> metabolite studies revealed a high fraction of intact parent in the rat brain (98% at 5 min and 75% at 30 min postinjection). Considerable brain penetration was further corroborated by <i>ex vivo</i> biodistribution and PET imaging studies, the latter showing heterogenic brain uptake. While marginal blockade was observed by PET studies in rodents, a moderate, but dose-dependent, blockade was observed in the non-human primate brain following pretreatment with nonradioactive <b>27</b>. Accordingly, [<sup>11</sup>C]<b>27</b> will serve as a valuable lead compound for the development of a new arsenal of PDE7-targeted probes.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-08-18
DOI
https://doi.org/10.1021/acsmedchemlett.5c00385
Citations
1
Primary Topic
Phosphodiesterase function and regulation
Type
article
Field-Weighted Citation Impact
0.81

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article

Radiosynthesis and Preclinical Evaluation of a Carbon-11 Labeled Phosphodiesterase 7 Inhibitor for PET Neuroimaging

Tomoteru Yamasaki, Ahmed Haider, Zhiwei Xiao, Yihan Shao et al.
1 citations
ACS Medicinal Chemistry Letters
Phosphodiesterase function and regulation
0.81
article

Radiosynthesis and Preclinical Evaluation of a Carbon-11 Labeled Phosphodiesterase 7 Inhibitor for PET Neuroimaging

Tomoteru Yamasaki, Ahmed Haider, Zhiwei Xiao, Yihan Shao, Steven H. Liang, Erick Calderon Leon, Shi Kuang, Chunyu Zhao, Ming‐Rong Zhang, Jiyun Sun, Yi Xu, Huiyi Wei, Wakana Mori, Masayuki Fujinaga, Junjie Wei, Chongzhao Ran, Lin Xie, Richard Van, Han‐Ting Zhang, Ying Xu, Lu Wang, Jiahui Chen, Jian Rong, Yiding Zhang, Kuan Hu, KC Kent Lloyd
article en
1 citations

Abstract

Dysfunction of cyclic nucleotide phosphodiesterase 7 (PDE7) has been associated with excess intracellular cAMP concentrations, fueling pathogenic processes that are implicated in neurodegenerative disorders. This study aimed to develop a suitable positron emission tomography (PET) probe that allows noninvasive mapping of PDE7 in the mammalian brain. Based on a spiro cyclohexane-1,4'-quinazolinone scaffold with known inhibitory properties toward PDE7, we designed and synthesized a carbon-11 labeling tolerant methoxy analog. The resulting PET probe, code named [<sup>11</sup>C]-P7-2104 (<b>27</b>), was synthesized in high molar activities (170-220 GBq/μmol) with decay-corrected radiochemical yields of 34 ± 7%. <i>In vitro</i> cell uptake of [<sup>11</sup>C]<b>27</b> was 6-7-fold higher in PDE7 overexpressing cells compared to the controls, whereas an <i>in vitro</i> specificity of up to 90% was measured. <i>Ex vivo</i> metabolite studies revealed a high fraction of intact parent in the rat brain (98% at 5 min and 75% at 30 min postinjection). Considerable brain penetration was further corroborated by <i>ex vivo</i> biodistribution and PET imaging studies, the latter showing heterogenic brain uptake. While marginal blockade was observed by PET studies in rodents, a moderate, but dose-dependent, blockade was observed in the non-human primate brain following pretreatment with nonradioactive <b>27</b>. Accordingly, [<sup>11</sup>C]<b>27</b> will serve as a valuable lead compound for the development of a new arsenal of PDE7-targeted probes.

ACS Medicinal Chemistry LettersVol. 16(9)
Rutgers, The State University of New Jersey (US), West Virginia University (US), Harvard University (US), Petronas (Malaysia) (MY), National Institute of Advanced Studies (IN), Massachusetts General Hospital (US), Blanchette Rockefeller Neurosciences Institute (US), National Institutes for Quantum Science and Technology (JP), Athinoula A. Martinos Center for Biomedical Imaging (US), First Affiliated Hospital of Jinan University (CN), University of California, Davis (US), University of Oklahoma (US)
Harvard Medical School, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Japan Society for the Promotion of Science, Moonshot Research and Development Program
Openalex Percentile: Top 25%
Phosphodiesterase function and regulation
0.81
DOIOpen Access PDFOpenAlex
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