| Autor: |
Xiao, Zhiwei, Sun, Jiyun, Masayuki, Fujinaga, Zhao, Chunyu, Haider Haider, Ahmed, Rong, Jian, Shao, Yihan, Lee Collier, Thomas, C Kent Lloyd, K, Lu, Wang, Zhang, Ming-Rong, Liang, Steven |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Zdroj: |
Nuclear Medicine and Biology. |
| ISSN: |
0969-8051 |
| Popis: |
Background: The intracellular second messengers, cAMP and cGMP, play a substantial role in signal transduction pathways involving a myriad of processes in the central nervous system (CNS), immune system, and cardiovascular system. Cyclic nucleotide phosphodiesterases (PDEs) constitute a superfamily of enzymes that degrade cAMP and cGMP to regulate the functions of these second messengers. Among the PDE subfamilies (PDE1-PDE11), PDE7 is cAMP-specific and found to be primarily expressed in the brain and heart, followed by liver, skeletal muscles, kidneys and pancreas. Due to the broad expression, PDE7 inhibitors recently have gained increasing attention for their potential applications in neurological, inflammatory, and immunological disorders. This study was aimed to develop a novel PDE7 specific radioligand for PET neuroimaging. Methods: Based on the spiro-quinazolinone structure which has shown PDE7 inhibitory properties, a methoxy analog P7-2104 was designed and synthesized. The target compound was labeled with carbon-11 using [11C]MeI from the respective desmethyl precursor and tested for its utility by cell uptake studies, ex vivo biodistribution and radiometabolite studies. Results: From commercially available chemicals, target compound and the corresponding precursor were efficiently synthesized with 49.5% and 12.4% overall yields, respectively (Scheme 1A). After the condensation between 2-chloro-5-methoxyaniline and potassium isocyanate, target compound was synthesized by intermolecular spirocyclization, while the respective precursor was then obtained through demethylation of target compound using hydrobromic acid. [11C]P7-2104 was synthesized in high molar activities (170 - 220 GBq/µmol) with radiochemical yields of 34±7% (Scheme 1B). Compared with HEK293 control cells, higher uptake was found in HEK293-PDE7B recombinant cells which revealed PDE7 specific binding, and ex vivo metabolite studies showed the excellent in vivo stability in rat brain (75% of intact parent at 30 min post injection). In whole body ex vivo biodistribution in CD-1 mice, significant radioactivity accumulation was found in the brain and heart that was consistent with the PDE7 expression profile. Conclusion: Based on the spiro-quinazolinone scaffold, we have successfully developed a PDE7-targeted radioligand [11C]P7-2104 with excellent specificity and stability. Further evaluation by PET imaging in rodents will be reported in due course. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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