PT  - JOURNAL ARTICLE
AU  - Jiang, Meijuan
AU  - Tang, Shiyu
AU  - Jenkins, Madeline D.
AU  - Lee, Adrian C.
AU  - Kenou, Bruny
AU  - Knoer, Carson
AU  - Santamaria, Jose Montero
AU  - Wu, Shawn
AU  - Liow, Jeih-San
AU  - Zoghbi, Sami S.
AU  - Zanotti-Fregonara, Paolo
AU  - Innis, Robert B.
AU  - Telu, Sanjay
AU  - Pike, Victor W.
TI  - Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and <sup>11</sup>C-Labeled Radioligands That Avoid Radiometabolite Contamination
AID  - 10.2967/jnumed.123.266750
DP  - 2024 Feb 29
TA  - Journal of Nuclear Medicine
PG  - jnumed.123.266750
4099  - http://jnm.snmjournals.org/content/early/2024/02/29/jnumed.123.266750.short
4100  - http://jnm.snmjournals.org/content/early/2024/02/29/jnumed.123.266750.full
AB  - Phosphodiesterase-4D (PDE4D) has emerged as a significant target for treating neuropsychiatric disorders, but no PET radioligand currently exists for robustly quantifying human brain PDE4D to assist biomedical research and drug discovery. A prior candidate PDE4D PET radioligand, namely [11C]T1650, failed in humans because of poor time stability of brain PDE4D-specific signal (indexed by total volume of distribution), likely due to radiometabolites accumulating in brain. Its nitro group was considered to be a source of the brain radiometabolites. Methods: We selected 5 high-affinity and selective PDE4D inhibitors, absent of a nitro group, from our prior structure–activity relationship study for evaluation as PET radioligands. Results: All 5 radioligands were labeled with 11C (half-time, 20.4 min) in useful yields and with high molar activity. All displayed sizable PDE4D-specific signals in rhesus monkey brain. Notably, [11C]JMJ-81 and [11C]JMJ-129 exhibited excellent time stability of signal (total volume of distribution). Furthermore, as an example, [11C]JMJ-81 was found to be free of radiometabolites in ex vivo monkey brain, affirming that this radioligand can provide robust quantification of brain PDE4D with PET. Conclusion: Given their high similarity in structures and metabolic profiles, both [11C]JMJ-81 and [11C]JMJ-129 warrant further evaluation in human subjects. [11C]JMJ-129 shows a higher PDE4D specific-to-nonspecific binding ratio and will be the first to be evaluated.