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

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.