aprepitant and vofopitant

1 In this study, [(3)H]GR205171 (3(S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine), a potent and selective NK1 receptor antagonist, was characterised in autoradiographic studies in gerbil brain and in binding experiments on homogenates from gerbil and human brain cortex and striatum. 2 In autoradiographic studies in gerbil brain, highest levels of [(3)H]GR205171 binding sites were observed in caudate putamen, nucleus accumbens, medial and cortical nuclei of the amygdala and intermediate levels were detected in the hypothalamus, basolateral amygdala, septum, and cortex. 3 Saturation experiments in homogenates of brain striatum from gerbil showed that [(3)H]GR205171 binds to a single receptor population with a pK(d) value of 10.8+/-0.2 and a B(max) value of 607+/-40 fmol mg(-1). A lower number of NK1 receptor sites was found in cortex, where a B(max) of 94+/-6 fmol mg(-1) protein was obtained. Saturation experiments performed on homogenates from brain striatum of two human subjects and brain cortex of three human subjects showed that [(3)H]GR205171 binds with pK(d) values not different from gerbil and B(max) values ranging from 318+/-51 to 432+/-27 fmol mg(-1) protein in striatum and from 59+/-1 to 74+/-21 fmol mg(-1) protein in cortex. The natural ligand [(3)H]Substance P (SP) bound with sub-nanomolar affinity to 15 and 6% sites compared to [(3)H]GR205171 in gerbil and human striatum, respectively. 4 In competition binding experiments, GR205171 and the NK1 receptor antagonists aprepitant (MK-869), L-733,060 and NKP-608 bound with similar pK(i) values in gerbil and human striatum, irrespective of the use of [(3)H]GR205171 or [(3)H]SP as radioligand. The following rank order was found in terms of pK(i) values: GR205171>aprepitant> or =L-733,060>NKP-608. In homologous displacement experiments in gerbil and human striatum, SP showed nanomolar affinity, whereas in [(3)H]GR205171 competition experiments SP bound with pIC(50) values in the micromolar range and Hill slopes significantly lower than one. 5 It is concluded that the similarities of [(3)H]GR205171 binding characteristics and pharmacology between gerbil and human in cortex and striatum support the use of gerbil in preclinical models to study the effects of NK1 receptor antagonists in the central nervous system.

Topics: Adolescent; Aged, 80 and over; Animals; Aprepitant; Autoradiography; Binding, Competitive; Brain; Female; Gerbillinae; Humans; In Vitro Techniques; Kinetics; Ligands; Male; Middle Aged; Models, Animal; Morpholines; Piperidines; Radioligand Assay; Receptors, Neurokinin-1; Substance P; Tetrazoles; Tritium

High performance liquid chromatography combined with either single quad or triple quad mass spectral detectors (LC/MS) was used to measure the brain distribution of receptor occupancy tracers targeting dopamine D2, serotonin 5-HT2A and neurokinin NK-1 receptors using the ligands raclopride, MDL-100907 and GR205171, respectively. All three non-radiolabeled tracer molecules were easily detectable in discrete rat brain areas after intravenous doses of 3, 3 and 30 microg/kg, respectively. These levels showed a differential brain distribution caused by differences in receptor density, as demonstrated by the observation that pretreatment with compounds that occupy these receptors reduced this differential distribution in a dose-dependent manner. Intravenous, subcutaneous and oral dose-occupancy curves were generated for haloperidol at the dopamine D2 receptor as were oral curves for the antipsychotic drugs olanzapine and clozapine. In vivo dose-occupancy curves were also generated for orally administered clozapine, olanzapine and haloperidol at the cortical 5-HT2A binding site. In vivo occupancy at the striatal neurokinin NK-1 binding site by various doses of orally administered MK-869 was also measured. Our results demonstrate the utility of LC/MS to quantify tracer distribution in preclinical brain receptor occupancy studies.

Topics: Animals; Antipsychotic Agents; Aprepitant; Benzodiazepines; Brain; Chromatography, High Pressure Liquid; Clozapine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Evaluation, Preclinical; Fluorobenzenes; Gerbillinae; Haloperidol; Male; Mass Spectrometry; Morpholines; Neurokinin-1 Receptor Antagonists; Olanzapine; Piperidines; Raclopride; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Receptors, Neurokinin-1; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Tetrazoles