Delforge J, Bottlaender M, Pappata S, Loc'h C, Syrota A
Service Hospitalier Frédéric Joliot, Commissariat à l'Energie Atomique, Orsay, France.
J Cereb Blood Flow Metab. 2001 May;21(5):613-30. doi: 10.1097/00004647-200105000-00016.
The results of several recent papers have shown a significant influence of the endogenous neurotransmitters on the exogenous ligand kinetics measured by positron emission tomography. For example, several groups found that the percentage of D2 receptor sites occupied by the endogenous dopamine ranged from 25% to 40% at basal level. An obvious consequence of this significant occupancy is that the ligand-receptor model parameters, usually estimated by a model that does not take into account the endogenous ligand (EL) kinetics, can be significantly biased. In the current work, the authors studied the biases obtained by using the multiinjection approach. The results showed that in the classical ligand-receptor model, the receptor concentration is correctly estimated and that only the apparent affinity is biased by not taking the EL into account. At present, all absolute quantifications of the EL have been obtained through pharmacologic manipulation of the endogenous transmitter concentration, which is often too invasive a method to be used in patients. A theoretical reasoning showed that a noninvasive approach is necessarily based on both the apparent affinity measurement and on a multiregion approach. The correlation between the receptor concentration and the apparent affinity, previously observed with some ligands, verifies these two conditions; thus, the authors suggest that this correlation could be the result of the EL effect. To test this assumption experimentally, the effect of reserpine-induced dopamine depletion on the interactions between the D2 receptor sites and the FLB 457 is studied. With untreated baboons, the apparent FLB 457 affinity was smaller in the receptor-rich regions (striatum) than in the receptor-poor regions. This discrepancy disappeared after dopamine depletion, strongly suggesting that this affinity difference was related to the EL effect. Therefore, the purpose of the current study was to test the ability to quantify the EL based on the observed correlation between the receptor concentration and the apparent affinity. This approach offers a method for estimating the percentage of receptor sites occupied by the EL and, if its affinity is known, the free EL concentration. From the data obtained using FLB 457 with baboons, the authors found that approximately 53% of the D2 receptor sites are occupied by dopamine in the striatum and that the free dopamine concentration is approximately 120 nmol/L at basal level. This approach is transferable to patients, because the experimental data are obtained without pharmacologically induced modification of the EL.
最近几篇论文的结果表明，内源性神经递质对通过正电子发射断层扫描测量的外源性配体动力学有显著影响。例如，几个研究小组发现，在基础水平下，内源性多巴胺占据的D2受体位点百分比在25%至40%之间。这种显著占据的一个明显后果是，通常由不考虑内源性配体（EL）动力学的模型估计的配体-受体模型参数可能会有显著偏差。在当前的工作中，作者研究了使用多次注射方法获得的偏差。结果表明，在经典的配体-受体模型中，受体浓度估计正确，只有表观亲和力因未考虑EL而产生偏差。目前，所有EL的绝对定量都是通过对内源性递质浓度进行药理学操作获得的，这对于患者来说往往是一种侵入性太强的方法。理论推理表明，非侵入性方法必然基于表观亲和力测量和多区域方法。先前在一些配体中观察到的受体浓度与表观亲和力之间的相关性验证了这两个条件；因此，作者认为这种相关性可能是EL效应的结果。为了通过实验验证这一假设，研究了利血平诱导的多巴胺耗竭对D2受体位点与FLB 457之间相互作用的影响。对于未治疗的狒狒，富含受体的区域（纹状体）中FLB 457的表观亲和力低于受体较少的区域。多巴胺耗竭后这种差异消失，强烈表明这种亲和力差异与EL效应有关。因此，当前研究的目的是测试基于观察到的受体浓度与表观亲和力之间的相关性来量化EL的能力。这种方法提供了一种估计EL占据的受体位点百分比的方法，如果其亲和力已知，则可以估计游离EL浓度。从使用FLB 457对狒狒获得的数据中，作者发现纹状体中约53%的D2受体位点被多巴胺占据，基础水平下的游离多巴胺浓度约为120 nmol/L。这种方法可以应用于患者，因为实验数据是在未对EL进行药理学诱导修饰的情况下获得的。
