Brain uptake and receptor binding of two [¹¹C]labelled selective high affinity NK1-antagonists, GR203040 and GR205171 — PET studies in rhesus monkey

Abstract

Two high affinity and selective NK1-receptor antagonists, GR203040 and GR205171, were labelled with ¹¹C and used in a series of experiments in rhesus monkeys. The purpose of these studies was to evaluate the brain uptake pattern and to explore the potential use of these compounds as PET ligands to characterise NK1-receptor binding. Seventeen studies were carried out with [¹¹C]GR205171 and five experiments with [¹¹C]GR203040, including baseline studies and studies performed after a 5 min infusion of cold compound at doses between 0.05 and 1 mg/kg. Both compounds demonstrated a significant and rapid uptake in the brain, but the uptake of [¹¹C]GR205171 was more than double the uptake of [¹¹C]GR203040. At tracer doses of [¹¹C]GR205171 and all doses of [¹¹C]GR203040 the uptake reached a plateau with no washout during the examination time, whereas [¹¹C]GR205171 after pre-treatment with cold GR205171 showed a significant washout. Using a model with the cerebellum as reference, a method for quantitation was applied to the studies with [¹¹C]GR205171 and the results indicated that the highest specific binding was in the striatum. The pre-treatment dose of cold GR205171 needed for 50% inhibition of binding was less than 0.04 mg/kg. The studies indicated that [¹¹C]GR205171 could be used for the in vivo characterisation of NK1-receptor binding.

Introduction

Positron emission tomography (PET) is a unique method for the in vivo assessment of drug distribution and interaction with biochemical target systems. In the field of neuroscience, this method is increasingly applied as a research tool in the exploration of brain function in healthy and disease conditions. PET is also proving to have an important role in drug development, with the potential of giving important pharmacokinetic information, notably blood–brain barrier penetration, and pharmacodynamic information, such as the degree and duration of interaction of a drug with cerebral receptor and enzyme systems. Several studies have demonstrated that PET can give more accurate information to guide dosage regimes than can be obtained from drug pharmacokinetics alone (Bergström et al., 1997, Bench et al., 1991, Fowler et al., 1993). There is a growing interest to develop drugs that are antagonists of the NK1-receptor (neurokinin 1) system. This receptor system uses substance P as its prime agonist. The possible therapeutic applications of these agents have not yet been fully defined; however, their potential is being explored in a range of disorders, including emesis, pain, inflammation and psychiatric diseases (Gardner et al., 1995, Kramer et al., 1998). For the optimal planning of clinical trials with NK1-receptor antagonists it would be desirable to have available a PET method which would allow the assessment of blood–brain barrier penetration and degree of NK1-receptor occupancy. Some attempts to find an in vivo imaging method have been made (Del-Rosario et al., 1993, Livni et al., 1995, Breeman et al., 1996). GR203040 and GR205171 are high affinity selective NK1-receptor antagonists developed by GlaxoWellcome (Beattie et al., 1995, Gardner et al., 1995, Gardner et al., 1996, Ward et al., 1995). Methods for labelling these compounds with ¹¹C were developed at the Uppsala University PET Centre, and a series of studies were performed in rhesus monkeys to characterise their pharmacokinetics and to assess their potential as PET ligands for the characterisation of the NK1-receptor system in the brain.