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 pathophysiology of emesis and depression. Autoradiographic studies in monkey and human brains have shown a high expression of NK1 receptors in regions important for the regulation of affective behaviors and the neurochemical response to stress. Furthermore, clinical studies demonstrated that treatment with the SP (NK1 receptor) antagonist (SPA) aprepitant (also known as MK-0869) significantly improves depression symptoms and reduces the incidence of chemotherapy-induced nausea and vomiting. An important objective of all neuroscience drug discovery and development programs is to establish the correlation between dose, receptor occupancy, and the observed clinical effect (the dose-response relationship). These goals can be achieved using radioactive receptor-specific tracers and dynamic noninvasive 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 high affinity for the NK1 receptor, low nonspecific binding, and good blood-brain barrier penetration. PET imaging studies in rhesus monkeys and humans confirmed these tracer features and established the usefulness of this probe for in vivo NK1 receptor occupancy studies. Subsequent PET occupancy studies in humans predicted that very high levels of central NK1 receptor occupancy (> 90%) were associated with therapeutically significant antidepressant and antiemetic effects. Future PET imaging studies will focus on quantification of NK1 receptor expression in depressed patients, both before and after successful treatment with antidepressants.