GlaxoSmithKline, Clinical Imaging Centre Hammersmith Hospital, London, W12 0NN, UK.
Nucl Med Biol. 2011 Aug;38(6):875-84. doi: 10.1016/j.nucmedbio.2011.02.005. Epub 2011 Mar 30.
The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [(11)C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET.
A procedure was developed for labeling MP-10 with carbon-11. [(11)C]MP-10 was evaluated in vivo both in the pig and baboon brain.
Alkylation of the corresponding desmethyl compound with [(11)C]methyl iodide produced [(11)C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [(11)C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [(11)C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [(11)C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [(11)C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V(T)) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP(ND)) as the outcome measure of specific binding. Quantification of [(11)C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP(ND) estimates consistent with those obtained by the two-tissue compartment model.
We demonstrated that [(11)C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.
本研究旨在通过正电子发射断层扫描（PET）评估一种新型报道的放射性配体[(11)C]MP-10，这是一种在体内对中枢磷酸二酯酶 10A 酶（PDE10A）具有强大和选择性抑制作用的化合物。
开发了一种用碳-11标记 MP-10 的方法。[(11)C]MP-10 在猪和狒狒大脑中进行了体内评估。
用[(11)C]甲基碘对相应的去甲基化合物进行烷基化，产生了具有良好放射化学产率和比活度的[(11)C]MP-10。在猪的 PET 研究中，[(11)C]MP-10 迅速进入大脑，在给药后 1-2 分钟达到组织浓度峰值，随后从组织中洗脱。给予选择性 PDE10A 抑制剂可将所有脑区的结合降低至小脑水平，证明了[(11)C]MP-10 结合的饱和性和选择性。在非人类灵长类动物中，[(11)C]MP-10 的脑组织动力学较慢，在给药后 30-60 分钟达到组织浓度峰值。在这两种物种中，观察到的脑区信号的顺序为纹状体>间脑>皮质区=小脑，与 PDE10A 的已知分布和浓度一致。[(11)C]MP-10 脑动力学通过双组织室模型得到了很好的描述，并获得了总分布容积（V(T)）的估计值。用未标记的 MP-10 进行阻断研究揭示了小脑作为参考组织的适用性，并使区域结合潜力（BP(ND)）的估计成为特异性结合的结果测量。使用简化的参考组织模型和小脑输入函数对[(11)C]MP-10 结合的定量分析产生了与双组织室模型获得的 BP(ND)估计值一致的结果。
我们证明了[(11)C]MP-10 具有通过 PET 对大脑中的 PDE10A 进行体内定量的良好特性。
