Molecular NeuroImaging, LLC, New Haven, Connecticut; and
Molecular NeuroImaging, LLC, New Haven, Connecticut; and.
J Nucl Med. 2014 Aug;55(8):1297-304. doi: 10.2967/jnumed.113.122895. Epub 2014 Jun 4.
Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A.
Eleven healthy volunteers participated in this study ((18)F-MNI-654 test-retest, 2 men; (18)F-MNI-659 test-retest, 4 men and 1 woman; (18)F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for (18)F-MNI-654 and over 3.5 h for (18)F-MNI-659, and pharmacokinetic modeling with plasma- and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for (18)F-MNI-659 and radiation dosimetry estimated with OLINDA.
Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time-activity data demonstrated that (18)F-MNI-654 kinetics were much slower than (18)F-MNI-659 kinetics. For (18)F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BPND), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The (18)F-MNI-659 effective dose was estimated at 0.024 mSv/MBq.
PET imaging in the human brain with 2 novel PDE10A (18)F tracers is being reported. Noninvasive quantification of (18)F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, (18)F-MNI-659 kinetics are fast enough for a good estimate of BPND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, (18)F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.
报告两种新型 PDE10A 放射性配体 2-(2-(3-(1-(2-氟乙基)-1H-吲唑-6-基)-7-甲基-4-氧代-3,4-二氢喹唑啉-2-基)乙基)-4-异丙氧基异吲哚啉-1,3-二酮（(18)F-MNI-654）和 2-(2-(3-(4-(2-氟乙氧基)苯基)-7-甲基-4-氧代-3,4-二氢喹唑啉-2-基)乙基)-4-异丙氧基异吲哚啉-1,3-二酮（(18)F-MNI-659）在人体内的首次特征描述，旨在选择最适合用于未来研究神经精神疾病病理生理变化并辅助 PDE10A 靶向药物开发的配体。
11 名健康志愿者参与了这项研究（(18)F-MNI-654 测试-重测，2 名男性；(18)F-MNI-659 测试-重测，4 名男性和 1 名女性；(18)F-MNI-659 剂量测定，2 名男性和 2 名女性）。(18)F-MNI-654 的脑 PET 图像采集时间为 5.5 小时，(18)F-MNI-659 的采集时间为 3.5 小时，采用基于血浆和参考区（小脑皮质）的方法进行药代动力学建模。(18)F-MNI-659 的全身 PET 图像采集时间为 6 小时，采用 OLINDA 估计放射性剂量。
两种放射性示踪剂的代谢方式相似，注射后 120 分钟时仍有 20%左右的完整母体。PET 时间活性数据表明，(18)F-MNI-654 的动力学比(18)F-MNI-659 的动力学慢得多。对于(18)F-MNI-659，Logan 和简化参考组织模型的非结合性结合潜能（BPND）具有良好的一致性，支持非侵入性定量，测试-重测变异性小于 10%，组内相关系数大于 0.9。(18)F-MNI-659 的有效剂量估计为 0.024 mSv/MBq。
报告了两种新型 PDE10A（18）F 示踪剂在人体大脑中的 PET 成像。使用小脑作为参考的简化参考组织模型可以对（18）F-MNI-659 进行非侵入性定量。此外，（18）F-MNI-659 的动力学足够快，可以在 90 分钟的数据中很好地估计 BPND，其值在基底节周围约为 3.0。最后，（18）F-MNI-659 的放射性剂量是有利的，与目前在人体中使用的其他 PET 放射性示踪剂的放射性剂量一致。
