vofopitant and (2-methoxy-5-tetrazol-1-ylbenzyl)(2-phenylpiperidin-3-yl)amine

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.

Topics: Animals; Brain; Carbon Radioisotopes; Ligands; Macaca mulatta; Neurokinin-1 Receptor Antagonists; Piperidines; Protein Binding; Receptors, Neurokinin-1; Tetrazoles; Tomography, Emission-Computed

It has been demonstrated recently that antagonists of the tachykinin NK1 receptor, specifically CP-99,994 and GR203040, possess anti-emetic activity in a range of species. To optimise this activity, a series of analogues based around the structure of GR203040 have been synthesised and their affinity at the human tachykinin NK1 receptor determined. In addition, the potency of these analogues to inhibit emesis induced in the ferret by whole-body X-irradiation has been examined. A range of substitution at the C-1 position of the tetrazole moiety in GR203040 were explored in vitro and in vivo. The trifluoromethyl compound, GR205171, was the most potent antagonist with regard to the ability to inhibit emesis induced by X-irradiation. This compound was demonstrated to have a broad spectrum of anti-emetic activity, inhibiting emesis in the ferret induced by cisplatin, cyclophosphamide, morphine, ipecacuanha and copper sulphate. Furthermore, emesis was also inhibited in the house-musk shrew, Suncus murinus, when induced by either motion or cisplatin, and in the dog when induced by ipecacuanha. GR205171 has the most potent anti-emetic activity of any tachykinin NK1 receptor antagonist described to date. The compound is orally active in the ferret and dog, long-lasting, and warrants further investigation as a potential broad-spectrum anti-emetic agent.

Topics: Administration, Oral; Animals; Antiemetics; Cisplatin; Dogs; Dose-Response Relationship, Drug; Ferrets; Humans; Male; Motor Activity; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Shrews; Stereoisomerism; Tetrazoles