@misc{oai:repo.qst.go.jp:00086448,
 author = {Xiao, Zhiwei and Sun, Jiyun and Masayuki, Fujinaga and Zhao, Chunyu and Haider, Ahmed Haider, Ahmed and Rong, Jian and Shao, Yihan and Xu, Ying and Kent Lloyd, KC and Lu, Wang and Zhang, Ming-Rong and Liang, Steven and Masayuki, Fujinaga and Lu, Wang and Zhang, Ming-Rong},
 month = {Jun},
 note = {Purpose/Background:
Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), belonging to a major class of second messengers, are considered to perform a key role  in signal transduction pathways including a myriad of processes in the central nervous system (CNS), immune system, and cardiovascular system. Accordingly, the super PDEs (cyclic nucleotide phosphodiesterases) family of enzymes regulates a variety of physiological functions by controlling the concentration of cAMP and cGMP. Of all the PDE families, PDE7 is specifically in charge of the degradation of cAMP and has primary expressions in the brain and heart, followed by liver, skeletal muscles, kidneys and pancreas. This broad expression suggests the potential application of PDE7 specific inhibitors in neurological, inflammatory, and immunological disorders. This study was aimed to develop a PDE7 specific radioligand and evaluate its in vitro/in vivo specificity and selectivity.

Methods:
A methoxy analog P7-2104 and the corresponding precursor were synthesized based on the spiro-quinazolinone structure.  The target compound was labeled with carbon-11 using [11C]MeI and further tested for its utility by in vivo PET imaging studies in rodents and non-human primates.

Results:
Target compound and the corresponding precursor were efficiently synthesized with 49.5% and 12.4% overall yields, respectively. [11C]P7-2104 was synthesized in excellent radiochemical purity (>99%) and high molar activities (170 - 220 GBq/µmol) with radiochemical yields of 34±7% (Figure 1A). Rodent PET scans were carried out in C57BL/6 mice and Sprague-Dawley rats. Rapid accumulations were demonstrated in brain in both mice and rats, whereas peak SUV were reached within 2 min p.i. (Figure 1B). Heterogeneous brain uptake, with the highest tracer uptake observed in the striatum and cortex, was shown in rats. Further PET imaging studies in cynomolgus monkeys indicated a rapid penetration cross the BBB and high uptakes in the cortex, putamen and caudate that were consistent with the PDE7 expression profile (Figure 1C).

Conclusion:
In this study, we have successfully developed a PDE7-targeted radioligand [11C]P7-2104 and tested its specificity and stability with in vivo PET imaging studies in rodents and NHP. Further evaluation by blocking PET imaging will be reported in due course., SNMMI2022},
 title = {Synthesis and preclinical evaluation of a novel carbon-11 radiolabeled PDE7 ligand},
 year = {2022}
}