Converse Alexander K, Krasko Maryann N, Rudisch Denis Michael, Slesarev Maxim S, Szot John C, Gallagher Catherine L, Ciucci Michelle R
Waisman Center, University of Wisconsin-Madison Madison, Wisconsin 53705
Department of Communication Science and Disorders, University of Wisconsin-Madison Madison, Wisconsin 53706.
J Neurosci. 2025 Jul 16;45(29):e0259252025. doi: 10.1523/JNEUROSCI.0259-25.2025.
Evidence suggests that the neurotransmitter norepinephrine may play an important role in Parkinson disease (PD). The norepinephrine transporter (NET) regulates noradrenergic signaling and can serve as an index of noradrenergic innervation in neuroimaging studies. The rat model, which exhibits many signs similar to PD, notably in the nonmotor domain, exhibits abnormal noradrenergic markers. Here, we sought to (1) implement reference region pharmacokinetic modeling of positron emission tomography (PET) imaging with the novel NET ligand [F]NS12137, (2) validate the resulting indices of NET concentration, and (3) characterize NET in the model. Long-Evans male rats were imaged by PET with [F]NS12137 at 9 and 11 months and compared with wild-type (WT) controls. An additional group of WT rats of both sexes were imaged with [F]NS12137 PET after pretreatment with the specific and selective NET ligand nisoxetine. Binding in locus coeruleus (LC), thalamus (Thal), and prelimbic area (PrL), regions rich in NET, was analyzed by a two-tissue compartment reversible binding model using a cerebellar reference region. [F]NS12137 binding exhibited moderate test-retest reproducibility in LC, Thal, and PrL. Nisoxetine blockade yielded substantial reductions of [F]NS12137 binding in LC. Compared with WT controls, rats exhibited reduced binding in Thal and PrL. Pharmacokinetic analysis of [F]NS12137 PET provides a reproducible and specific measure of NET binding and indicates reduced NET in PD-related brain regions in rats. Noninvasive in vivo [F]NS12137 PET imaging is therefore a promising method for the study of potential therapies in the rat.
有证据表明，神经递质去甲肾上腺素可能在帕金森病（PD）中起重要作用。去甲肾上腺素转运体（NET）调节去甲肾上腺素能信号传导，并且在神经影像学研究中可作为去甲肾上腺素能神经支配的指标。该大鼠模型表现出许多与PD相似的症状，尤其是在非运动领域，其去甲肾上腺素能标记物异常。在此，我们试图（1）用新型NET配体[F]NS12137对正电子发射断层扫描（PET）成像进行参考区域药代动力学建模，（2）验证所得的NET浓度指标，以及（3）在该模型中对NET进行表征。对Long-Evans雄性大鼠在9个月和11个月时用[F]NS12137进行PET成像，并与野生型（WT）对照进行比较。另一组雌雄WT大鼠在用特异性和选择性NET配体尼索西汀预处理后，用[F]NS12137 PET成像。使用小脑参考区域，通过双组织隔室可逆结合模型分析富含NET的蓝斑（LC）、丘脑（Thal）和前边缘区（PrL）中的结合情况。[F]NS12137结合在LC、Thal和PrL中表现出中等的重测重现性。尼索西汀阻断使LC中[F]NS12137结合大幅减少。与WT对照相比，该大鼠在Thal和PrL中的结合减少。[F]NS12137 PET的药代动力学分析提供了一种可重现且特异的NET结合测量方法，并表明该大鼠与PD相关脑区中的NET减少。因此，非侵入性体内[F]NS12137 PET成像对于研究该大鼠的潜在治疗方法是一种有前景的方法。
