RT Journal Article SR Electronic T1 Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET and 11C-Labeled Radioligands That Avoid Radiometabolite Contamination JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 788 OP 793 DO 10.2967/jnumed.123.266750 VO 65 IS 5 A1 Jiang, Meijuan A1 Tang, Shiyu A1 Jenkins, Madeline D. A1 Lee, Adrian C. A1 Kenou, Bruny A1 Knoer, Carson A1 Montero Santamaria, Jose A1 Wu, Shawn A1 Liow, Jeih-San A1 Zoghbi, Sami S. A1 Zanotti-Fregonara, Paolo A1 Innis, Robert B. A1 Telu, Sanjay A1 Pike, Victor W. YR 2024 UL http://jnm.snmjournals.org/content/65/5/788.abstract 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.