First Evaluation of Superscript11/Superscript

Authors: Saskia P A Wolfensberger Bart N M van Berckel Anu J Airaksinen Kaoru Maruyama Mark Lubberink Ronald Boellaard William D H Carey Wieb Reddingius Dick J Veltman Albert D Windhorst Josée E Leysen Adriaan A Lammertsma

Publish Date: 2009/03/31

Volume: 11, Issue: 4, Pages: 241-245

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Abstract

NK1 receptors have been implicated in various neuropsychiatric and other disorders R116301 is a selective NK1 receptor antagonist In this pilot study 11CR116301 was evaluated as a potential positron emission tomography PET ligand for the NK1 receptorBaseline SUV ratios at 60–90 min after injection ranged from 122 to 170 Following aprepitant administration this specific signal was completely blocked Aprepitant administration did not significantly affect uptake in cerebellum confirming the absence of NK1 receptors in cerebellumTachykinins are a class of neuropeptides that are involved in a variety of biological functions in the central and peripheral nervous systems 1 2 3 Tachykinin receptors have been divided into three subtypes according to their preferred ligands neurokinin 1 NK1 NK2 and NK3 NK1 receptors for which substance P has the highest affinity have been of particular interest because of their potential implication in various neuropsychiatric and other disorders Autoradiography studies of the brain of various species have demonstrated the presence of NK1 receptors in several cerebral structures with the highest density in striatum 4 and negligible density in cerebellum 5 NK1 antagonists could potentially be used for treating a variety of disorders 6 7 8 Originally selective nonpeptide antagonists of the NK1 receptor were studied as potential analgesic compounds 9 Several studies have provided evidence that NK1 receptor antagonists might be effective in the treatment of anxiety disorders and depression 10 11 12 13 although a recent clinical study in depression could not confirm these findings 14 The highly selective NK1 antagonist aprepitant 14 52R3S21R135bistrifluoromethylphenylethoxy34fluorphenyl4morpholinylmethyl12dihydro3H124triazol3one however is effective in the treatment of nausea and emesis after chemotherapy and is already in routine clinical use as an antiemetic agent 15 16 To assess novel drugs targeting the NK1 receptor development of a positron emission tomography PET tracer for this target is warranted as this would provide a unique in vivo means of measuring receptor occupancy In addition in vivo imaging studies might provide new possibilities for studying the role of the NK1 receptor in neuropsychiatric disordersAlthough several NK1 agonists and antagonists have been labeled successfully for in vitro use to date most attempts to develop tracers for in vivo imaging studies have not been successful 17 18 19 For example although the radioiodinated selective NK1 antagonist L703606 was useful for labeling NK1 receptors in vitro 20 it failed to provide a specific signal in vivo in rat and monkey 21 For the high affinity antagonist 11CGR205171 promising results were obtained in monkeys 22 providing images that reflected specific binding to NK1 receptors Its use was limited however by the fact that it did not reach equilibrium within 90 min which is close to the maximum scanning time possible with a carbon11 labeled ligand Recently 218Ffluoromethoxy55trifluoromethyltetrazol1ylbenzyl2S3S2phenylpiperidin3ylamine 18FSPARQ was developed as a fluorine18 labeled alternative SPARQ is structurally related to GR205171 and is a selective highaffinity antagonist of the NK1 receptor 4 21 23 Unfortunately in areas with high receptor densities 18FSPARQ only reached equilibrium after 6 h limiting its use for clinical or intervention studies 5 In addition plasma kinetics of 18FSPARQ were fast and 90 min after injection the amount of parent compound in blood was too low to be measured reliably 5 As such at present there is no “ideal” tracer for human NK1 receptors and therefore alternative compounds need to be investigatedN126Dimethylphenyl242R4S2benzyl135itrifluoromethyl benzoylhexahydro4pyridinylpiperazinoacetamide R116301 is an orally active potent and selective nonpeptide NK1 receptor antagonist with a K i of 045 nM against human NK1 receptors 24 The affinity for human NK2 and NK3 receptors is 1600 and 230fold lower respectively At high concentrations R116301 interacts with rat Na+ and Ca2+ ion channel binding sites K i   2 μM but it does not interact with other receptors ion channels or transporter sites at a concentration of 10 μM R116301 suppresses various aspects of substance P induced behavior in vivo and behaves as a full antagonist in vitro 25 Recently R116301 was labeled with carbon11 24 The present study is the first application of 11CR116301 in humans The aim of the study was to evaluate presence of selective 11CR116301 binding to the NK1 receptor in vivoThree healthy subjects two men aged 46 and 42 and one woman aged 25 were included Subjects were studied within 21 days after eligibility screening which consisted of medical history including Structured Clinical Interview for DSMIV Axis I disorders 26 history of alcohol and drug abuse physical examination vital signs and electrocardiogram laboratory blood and urine assessments and extensive drugs of abuse screening The female subject was practicing an effective method of birth control and pregnancy tests were performed at screening and on the day of the study Volunteers were medicationfree for at least 14 days prior to PET scanning In addition subjects underwent a structural magnetic resonance imaging MRI scan within 14 days prior to the actual PET study to exclude any clinically significant abnormalities and for coregistration with the PET images The study was approved by the Medical Ethics Committee of the VU University Medical Centre Subjects gave written informed consent prior to entering the study

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