Dataset Information

Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

ABSTRACT: We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 (t_1/2 = 20.4 min) for evaluation with PET in monkey. Whereas two of these radioligands did not provide PDE4D-specific signal in monkey brain, two others, [¹¹C]T1660 and [¹¹C]T1650, provided sizable specific signal, as judged by pharmacological challenge using rolipram or a selective PDE4D inhibitor (BPN14770) and subsequent biomathematical analysis. Specific binding was highest in prefrontal cortex, temporal cortex, and hippocampus, regions that are important for cognitive function. [¹¹C]T1650 was progressed to evaluation in humans with PET, but the output measure of brain enzyme density (V_T) increased with scan duration. This instability over time suggests that radiometabolite(s) were accumulating in the brain. BPN14770 blocked PDE4D uptake in human brain after a single dose, but the percentage occupancy was difficult to estimate because of the unreliability of measuring V_T. Overall, these results show that imaging of PDE4D in primate brain is feasible but that further radioligand refinement is needed, most likely to avoid problematic radiometabolites.

SUBMITTER: Wakabayashi Y

PROVIDER: S-EPMC7444660 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

Wakabayashi Yuichi Y Telu Sanjay S Dick Rachel M RM Fujita Masahiro M Ooms Maarten M Morse Cheryl L CL Liow Jeih-San JS Hong Jinsoo S JS Gladding Robert L RL Manly Lester S LS Zoghbi Sami S SS Mo Xuesheng X D'Amato Emily C EC Sindac Janice A JA Nugent Richard A RA Marron Brian E BE Gurney Mark E ME Innis Robert B RB Pike Victor W VW

ACS chemical neuroscience 20200408 9

We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 (<i>t</i><sub>1/2</sub> = 20.4 min) for evaluation with PET in monkey. Whereas two ...[more]

PMID: 32212718

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Dataset Information

Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

Publications

Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

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