Imaging Substance P Receptors (NK1) in the Living Human Brain Using Positron Emission Tomography
J Clin Psychiatry 2002;63(suppl 11):18-24
© Copyright 2016 Physicians Postgraduate Press, Inc.
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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.