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Imaging Substance P Receptors (NK1) in the Living Human Brain Using Positron Emission Tomography

Article Abstract

Substance P (SP)-neurokinin-1 (NK1) receptor pathways have been implicated in the pathophysiologyof emesis and depression. Autoradiographic studies in monkey and human brains have shown ahigh expression of NK1 receptors in regions important for the regulation of affective behaviors and theneurochemical response to stress. Furthermore, clinical studies demonstrated that treatment withthe SP (NK1 receptor) antagonist (SPA) aprepitant (also known as MK-0869) significantly improvesdepression symptoms and reduces the incidence of chemotherapy-induced nausea and vomiting. Animportant objective of all neuroscience drug discovery and development programs is to establish thecorrelation between dose, receptor occupancy, and the observed clinical effect (the dose-responserelationship). These goals can be achieved using radioactive receptor-specific tracers and dynamicnoninvasive brain imaging modalities, such as positron emission tomography (PET). In the SPA program,a tracer [18F]SPA-RQ was chosen for PET studies on the basis of several criteria, including highaffinity for the NK1 receptor, low nonspecific binding, and good blood-brain barrier penetration. PETimaging studies in rhesus monkeys and humans confirmed these tracer features and established theusefulness of this probe for in vivo NK1 receptor occupancy studies. Subsequent PET occupancy studiesin humans predicted that very high levels of central NK1 receptor occupancy (> 90%) were associatedwith therapeutically significant antidepressant and antiemetic effects. Future PET imaging studieswill focus on quantification of NK1 receptor expression in depressed patients, both before and aftersuccessful treatment with antidepressants.

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