Substance P (SP) is a neurotransmitter serving numerous different functions in human central and peripheral nervous system. SP acts mainly through neurokinin‑1 receptors (NK1R). SP and NK1R are widely distributed in the human central nervous system. This neurotransmitter system modulates other neurotransmitter systems and adjusts network balances. The SP system regulates a wide variety of functions such as mood, stress, pain, inflammation, anxiety, and satiety. Therefore, this system is implicated in many pathological conditions such as major depression, anxiety, nausea and emesis, addiction and obesity. Our knowledge of the SP and NK1R systems derive mostly from animal studies, whereas human data is lacking., Direct in vivo research of SP and NK1R functions in man has become possible by using molecular imaging techniques such as positron emission tomography and specific neurokinin receptor tracers. 

We had three main aims in this study: First, we validated a method to visualize and quantify NK1 receptors in human brain in vivo using PET and a fluorine‑18 labeled substance P antagonist receptor ligand [18F]SPA‑RQ. Second, we studied normal healthy subjects and tested if age or gender affect the availability of these receptors in human brain. Third, as this neurotransmitter system, and more specifically, NK1R antagonists, have been implicated in the treatment of major depressive disorder (MDD), we studied patients with MDD to see if these patients have changes in their brain NK1R availability. 

We validated a method to image and quantify NK1R in human brain in vivo using [18F]SPA‑RQ. Reasonable scan time was determined as 240 minutes, cerebellum was available as a reference region as it was devoid of NK1Rs, and simplified reference tissue model (SRTM) was validated as a reliable method to model the data. Healthy volunteers had age‑related decrease of 7% per decade in NK1R availability in many brain regions. Females had lower brain NK1R1 availability than males with no statistical evidence for regional specificity. Patients with MDD did not have differences in their NK1R availability compared to healthy controls, but their rated symptoms on overall depression and anxiety correlated with NK1R binding in some brain regions. 

These studies validated a method to image and quantify NK1R availability in human brain in vivo using PET. The application potential of this method is obvious in drug development (mechanism of action and dose‑finding) and in vivo studies of human physiology and disease processes related to the substance P system. In applied studies of this thesis, we found a decrease in NK1R availability during aging that follows the same rate that has been previously reported for many other receptor systems, such as the dopamine system. The detailed mechanisms in NK1 receptor sex differences are not know, but hormonal differences are likely to contribute. We found no difference on NK1R availability between patients with MDD and matched healthy controls, consistent with lack of efficacy of substance P antagonists in clinical trials in MDD and anxiety disorders. However, NK1 receptors did modulate the affective symptom domain in patients with MDD, however, NK1 receptor antagonism alone may be insufficient for clinical treatment of MDD.