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.

磷酸二酯酶-4D (PDE4D) 已成为治疗神经精神疾病的重要靶标，但目前尚无 PET 放射性配体可用于稳健量化人脑 PDE4D 以协助生物医学研究和药物发现。先前的候选 PDE4D PET 放射性配体，即 [ ¹¹ C]T1650，在人类身上失败了，因为大脑 PDE4D 特异性信号（以总分布体积为索引）的时间稳定性差，可能是由于放射性代谢物在大脑中积聚所致。它的硝基被认为是脑放射性代谢物的来源。方法：我们从之前的结构-活性关系研究中选择了 5 种高亲和力和选择性的 PDE4D 抑制剂（不含硝基），用于评估作为 PET 放射性配体。结果：所有 5 种放射性配体均以有用的产率和高摩尔活性用¹¹ C标记（半衰期，20.4 分钟）。所有这些都在恒河猴大脑中显示出相当大的 PDE4D 特异性信号。值得注意的是，[ ¹¹ C]JMJ-81和[ ¹¹ C]JMJ-129表现出优异的信号时间稳定性（总分布体积）。此外，例如，[ ¹¹ C]JMJ-81被发现在离体猴脑中不含放射性代谢物，证实该放射性配体可以通过PET对脑PDE4D进行可靠的定量。结论：鉴于 [ ¹¹ C]JMJ-81 和 [ ¹¹ C]JMJ-129在结构和代谢谱上高度相似，都值得在人类受试者中进行进一步评估。 [ ¹¹ C]JMJ-129 显示出更高的 PDE4D 特异性与非特异性结合比率，将是第一个进行评估的。