Narendran Rajesh, Slifstein Mark, Guillin Olivier, Hwang Yuying, Hwang Dah-Ren, Scher Erica, Reeder Stephanie, Rabiner Eugenii, Laruelle Marc
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York 10032, USA.
Synapse. 2006 Dec 1;60(7):485-95. doi: 10.1002/syn.20325.
[11C]PHNO is a recently introduced agonist to image DA D2-like receptors with Positron Emission Tomography (PET). In cats and humans, [11C]PHNO revealed an atypical distribution compared to radiolabeled D2-like antagonists (such as [11C]raclopride) or other D2-like agonists (such as [11C]NPA), as it displayed unusual high binding in the globus pallidus (GP). The goal of this study was to assess the pharmacological nature of the binding of [11C]PHNO in the GP in nonhuman primates. As previously reported in humans, [11C]PHNO equilibrium specific to nonspecific equilibrium partition coefficients (V3'') in baboons was much higher in GP (3.88 +/- 1.15) than in the dorsal striatum (DST, 2.07 +/- 0.43), whereas the reverse was true for [11C]raclopride (1.48 +/- 0.41 in GP, 2.56 +/- 0.91 in DST) and [11C]NPA (0.87 +/- 0.19 in GP, 1.02 +/- 0.13 in DST). Administration of unlabeled raclopride resulted in similar reductions of [11C] PHNO V3'' and [11C]raclopride V3'' in both the GP and the DST. This observation demonstrated that the [11C]PHNO binding in the GP was specific to D2-like receptors. To evaluate the respective contribution of D3 and D2 receptors to the binding potential (BP) of [11C]PHNO and [11C]raclopride, experiments were carried out with the selective D3 partial agonist 1-(4(2-Napthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCL (BP897). BP897 reduced [11C]raclopride V3'' by 29% +/- 9%, 19% +/- 8%, and 10% +/- 7% in GP, VST, and DST, respectively, a result consistent with expectation from postmortem studies (D3/D2 ratio in GP > VST > DST). BP897 reduced [11C]PHNO V3'' by 57% +/- 11%, 30% +/- 11%, and 13% +/- 8% in GP, VST, and DST, respectively, indicating that the D3 receptor contribution to [11C]PHNO signal is higher than that of [11C]raclopride. From these experiments we conclude that [11C]PHNO is a D3 preferring agonist, and that this property explains the high GP signal not observed with [11C]raclopride or [11C]NPA. This property might contribute to its higher vulnerability to endogenous DA compared to [11C]raclopride and [11C]NPA.
[11C]PHNO是一种最近引入的激动剂，用于通过正电子发射断层扫描（PET）对多巴胺D2样受体进行成像。在猫和人类中，与放射性标记的D2样拮抗剂（如[11C]雷氯必利）或其他D2样激动剂（如[11C]NPA）相比，[11C]PHNO显示出非典型分布，因为它在苍白球（GP）中表现出异常高的结合。本研究的目的是评估[11C]PHNO在非人灵长类动物GP中的结合药理学性质。如先前在人类中报道的那样，狒狒中[11C]PHNO平衡特异性与非特异性平衡分配系数（V3''）在GP中（3.88±1.15）远高于背侧纹状体（DST，2.07±0.43），而[11C]雷氯必利则相反（GP中为1.48±0.41，DST中为2.56±0.91）和[11C]NPA（GP中为0.87±0.19，DST中为1.02±0.13）。给予未标记的雷氯必利导致GP和DST中[11C]PHNO V3''和[11C]雷氯必利V3''的类似降低。该观察结果表明，GP中[11C]PHNO结合对D2样受体具有特异性。为了评估D3和D2受体对[11C]PHNO和[11C]雷氯必利结合潜力（BP）的各自贡献，使用选择性D3部分激动剂1-(4(2-萘甲酰胺基)丁基)-4-(2-甲氧基苯基)-1A-哌嗪盐酸盐（BP897）进行了实验。BP897分别使GP、腹侧纹状体（VST）和DST中[11C]雷氯必利V3''降低29%±9%、19%±8%和10%±7%，这一结果与死后研究的预期一致（GP中的D3/D2比率>VST>DST）。BP897分别使GP、VST和DST中[11C]PHNO V3''降低57%±11%、30%±11%和13%±8%，表明D3受体对[11C]PHNO信号的贡献高于[11C]雷氯必利。从这些实验中我们得出结论，[11C]PHNO是一种优先结合D3的激动剂，并且该特性解释了[11C]雷氯必利或[11C]NPA未观察到的高GP信号。与[11C]雷氯必利和[11C]NPA相比，该特性可能导致其对内源性多巴胺具有更高的敏感性。
