Visualization and Quantification of Neurokinin-1 (NK1) Receptors in the Human Brain

Abstract

[F-18]SPA-RQ is a novel tool for exploration of the functions of NK(1) receptors in man. [F-18]SPA-RQ can be used to define receptor pharmacodynamics and focus dose selection of novel NK(1) receptor antagonists in clinical trials thereby ensuring adequate proof of concept testing particularly in therapeutic applications related to CNS dysfunction.

Voxel-based NK1 Receptor Occupancy Measurements with [18F]SPA-RQ and Positron Emission Tomography: A Procedure for Assessing Errors from Image Reconstruction and Physiological Modeling

“…There are three known NK-receptor subtypes, NK1 [formerly called substance P (SP) receptor], NK2 (formerly substance K/ substance E receptor), and NK3 (formerly NK B receptor) receptors, but the effects of SP in the brain are mediated primarily via the NK1 receptor subtype [9]. The highest density of NK1 receptors can be found in the caudate and putamen (the structures of interest in the present study), intermediate densities in the cortical regions, and negligible density in the human cerebellum [10]. Because of this, the cerebellum can be used as a reference region in the reference tissue modeling approach with [ 18 F]SPA-RQ [3,10,11] (see Slifstein and Laruelle [12] for possible models for PET reversible radiotracers with reference tissue input).…”

“…The highest density of NK1 receptors can be found in the caudate and putamen (the structures of interest in the present study), intermediate densities in the cortical regions, and negligible density in the human cerebellum [10]. Because of this, the cerebellum can be used as a reference region in the reference tissue modeling approach with [ 18 F]SPA-RQ [3,10,11] (see Slifstein and Laruelle [12] for possible models for PET reversible radiotracers with reference tissue input). The distribution of SP and NK1 receptors in the human nervous system (see Hietala et al [10] and Caberlotto et al [13]) and the targeted disruption of the NK1 receptor in mice have provided information about the possible functions of SP.…”

“…Because of this, the cerebellum can be used as a reference region in the reference tissue modeling approach with [ 18 F]SPA-RQ [3,10,11] (see Slifstein and Laruelle [12] for possible models for PET reversible radiotracers with reference tissue input). The distribution of SP and NK1 receptors in the human nervous system (see Hietala et al [10] and Caberlotto et al [13]) and the targeted disruption of the NK1 receptor in mice have provided information about the possible functions of SP. It is believed that SP is involved in the regulation of emesis, movement, emotions, reward, stress responses, neurogenesis, and vigilance [14Y19].…”

“…Previous [ 18 F]SPA-RQ PET studies indicate that this tracer is suitable for noninvasive imaging of central NK1 receptors [3, 10, 11, 21Y24]. The tracer can also be used to define receptor pharmacodynamics and guide dose-finding (by means of receptor occupancy) of novel NK1 receptor antagonists in clinical trials [3,10,23]. In the present study, we used a pharmacologically well characterized competitive NK1 receptor antagonist drug, which has been investigated in human studies [25].…”

“…However, these tests have not been done for phantoms describing full dynamic receptor studies. In this study, our aim was to investigate the effect of image reconstruction methods and model calculation methods in a dynamic NK1 receptor antagonist, [ 18 F]SPA-RQ [10], study (Fig. 1).…”