Facile synthesis of carbon-11-labeled sEH/PDE4 dual inhibitors as new potential PET agents for imaging of sEH/PDE4 enzymes in neuroinflammation

Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

“…[58], and the PDE4D inhibitor BPN14770 [59]. For PET imaging of neuroinflammation, two novel 11 C-labeled radioligands that are dual specific for the soluble epoxidase hydrolase (sEH) and PDE4 were reported in 2019 by Jia et al [56]. Multi-target drugs for treatment of complex diseases are regarded to be more efficient than the traditional single-target approach because therapeutics often interact with multiple targets [60][61][62][63][64].…”

“…Both, sEH and PDE4, are critical enzymes in neuroinflammation and play an important role in the progression of various neurodegenerative diseases including Alzheimer´s disease [57]. Thus, Jia et al selected the recently developed bioavailable sEH/PDE4 dual inhibitors MPPA (compound 6) and a related derivative (compound 7) for treatment of inflammatory pain as lead compounds [56,57] (see Figure 3). Starting from the respective phenol precursors, the sEH/PDE4 radioligands [ 11 C]6 and For PET imaging of neuroinflammation, two novel 11 C-labeled radioligands that are dual specific for the soluble epoxidase hydrolase (sEH) and PDE4 were reported in 2019 by Jia et al [56].…”

“…Thus, Jia et al selected the recently developed bioavailable sEH/PDE4 dual inhibitors MPPA (compound 6) and a related derivative (compound 7) for treatment of inflammatory pain as lead compounds [56,57] (see Figure 3). Starting from the respective phenol precursors, the sEH/PDE4 radioligands [ 11 C]6 and For PET imaging of neuroinflammation, two novel 11 C-labeled radioligands that are dual specific for the soluble epoxidase hydrolase (sEH) and PDE4 were reported in 2019 by Jia et al [56]. Multi-target drugs for treatment of complex diseases are regarded to be more efficient than the traditional single-target approach because therapeutics often interact with multiple targets [60][61][62][63][64].…”

“…Both, sEH and PDE4, are critical enzymes in neuroinflammation and play an important role in the progression of various neurodegenerative diseases including Alzheimer's disease [57]. Thus, Jia et al selected the recently developed bioavailable sEH/PDE4 dual inhibitors MPPA (compound 6) and a related derivative (compound 7) for treatment of inflammatory pain as lead compounds [56,57] (see Figure 3). Starting from the respective phenol precursors, the sEH/PDE4 radioligands [ 11 C]6 and [ 11 C]7 have been synthesized in a home-built automated multi-purpose 11 C-radiosynthesis module [56] Jia et al reported that their radiosynthesis approach enabled the automated 11 C-labeling reaction as well as purification and formulation for routine production suitable for preparation of clinical doses of the radioligands [56].…”

“…Starting from the corresponding desmethyl precursors, the respective radioligands have been synthesized by O-or N-methylation using [ 11 C]CH3I [58] (see Scheme 6). Jia et al reported that their radiosynthesis approach enabled the automated 11 Clabeling reaction as well as purification and formulation for routine production suitable for preparation of clinical doses of the radioligands [56]. This facilitates future studies for the planned biological evaluation of [ 11 C]6 and [ 11 C]7.…”