Special Issue Review Received 27 April 2012,
Revised 8 November 2012,
Accepted 8 November 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3001
Current status of positron emission tomography radiotracers for serotonin receptors in humans† Luc Zimmera,b* and Didier Le Barsa,c Serotonin (5-HT) neurotransmission plays a key modulatory role in the brain. This system is critical for pathophysiological processes and many drug treatments for brain disorders interact with its 14 subtypes of receptors. Positron emission tomography (PET) is a unique tool for the study of the living brain in translational studies from animal models to patients in neurology or psychiatry. This short review is intended to cover the current status of PET radioligands used for imaging human brain 5-HT receptors. Here, we describe the available PET radioligands for the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT4 and 5-HT6 receptors. Finally, we highlight the future challenges for a functional PET imaging of serotonin receptors, including the research towards specific PET radiotracers for yet unexplored serotonin receptors, the need of radiotracers for endogenous serotonin level measurement and the contribution of agonist radiotracers for functional imaging of 5-HT neurotransmission. Keywords: PET; radiopharmaceutical; serotonin; receptor; brain
General overview of the serotonin receptors
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a
Hospices Civils de Lyon, CERMEP-Imaging Platform, Lyon, France
b University of Lyon 1, INSERM, CNRS, Lyon Neuroscience Research Centre, Lyon, France c
University of Lyon 1, CNRS, Institute of Chemistry and Biochemistry, Villeurbanne, France *Correspondence to: Luc Zimmer & Didier Le Bars, CERMEP-Imagerie du Vivant, Groupement Hospitalier Est, 59 bd Pinel, F-69003 Lyon, France. E-mail: [email protected]; [email protected]
†
This article is published in Journal of Labelled Compounds and Radiopharmaceuticals as a special issue on Carbon-11 and fluorine-18 chemistry devoted to molecular probes for imaging the brain with PET, edited by Frédéric DOLLÉ, Service Hospitalier Frédéric Joliot, Institut d’Imagerie BioMédicale, CEA, 4 Place du Général Leclerc, F-91406 Orsay, France.
Copyright © 2013 John Wiley & Sons, Ltd.
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The serotoninergic (5-HT) system plays a key role in many central nervous system functions. The 5-HT receptors are among the most diverse group of neuro-receptors in the human genome and are also among the phylogenetically oldest systems. 5-HT neurons originate in the dorsal and median raphe nuclei of the pons and upper medulla. This relatively small number of cells produces a dense network of neuronal projections that innervate the entire forebrain to cortex, hippocampus, basal ganglia, limbic system and hypothalamus. On the other direction, caudal cells project to cerebellum, medulla and spinal cord.1 Currently, 14 receptors are structurally and pharmacologically characterised.2 The majority of 5-HT receptors themselves are located extra-synaptically, either pre-synaptically or postsynaptically. The 14 subtypes are divided into seven classes, from 5-HT1 to 5-HT7, according to their structural and functional characteristics. All are members of the trans-membrane GPCR family (G-protein-coupled receptors) except the 5-HT3 receptor, which is a ligand-gated ion channel. Even though functions of these receptors still need to be elucidated, it is known that each of these targets has its own pattern of distribution and role in the CNS. As several reviews on the 5-HT receptors are available, these neurobiological descriptions will be limited to a general overview. Physiologically, 5-HT functions are crucial in the control of sleep, wakefulness, mood, feeding behaviour and the control of sensory transmission. 5-HT dysfunction has been implicated in the aetiology of many psychiatric disorders including depression, anxiety, schizophrenia and other neurological disorders such as Alzheimer’s disease, epilepsy and sleep disorders.3,4 Although our current knowledge of the serotoninergic system is mainly derived from basic research and animal models, the development of non-invasive brain imaging techniques, such as positron emission tomography (PET) allows the study of the
neurotransmission in the human brain, essential for the development of biomarkers.5 PET is often used for quantification of receptor concentration, allowing in vivo pharmacology. PET is also useful for tracking pharmacokinetic and pharmacodynamic properties of drugs and can be used to determine the occupancy of therapeutic drugs, which ultimately can be used to estimate optimal doses in Phase II studies. For that reason, drug discovery in pharmaceutical industry has increasingly taken advantage of this technology to accelerate the development of brain drug candidates.6 Noteworthy, significant discoveries (or confirmation of results obtained in animal models) within the 5-HT system in human brain have been made following the development of selective PET radioligands. However, the full potential of 5-HT-targeted treatments cannot be understood before selective radioligands for 5-HT receptors have been developed and validated in humans. Radioligands for imaging 5-HT receptors are mainly based structurally on receptor antagonists, less often on agonists. In order to generate quantifiable images of brain receptors, radioligands
L. Zimmer and D. Le Bars Biography Luc Zimmer was born in France in 1968 and received a Pharmacist Education at the University of Strasbourg (1986–1992); he completed training during his internship and residency in Radiopharmacy and Radiopharmacology (1993–1999) at the Hospital University of Tours (Nuclear Medicine Department) and at the National Institute for Nuclear Sciences and Technology, Saclay. He received his Pharm.D in Radiopharmacology (1998) and his PhD in Neuroscience (1999) from the University of Tours. He is currently a professor in Pharmacology at the University of Lyon (Université Claude Bernard Lyon 1) and is a radiopharmacist at the University Hospital of Lyon (HCL). He is the head of the Preclinical Department of the CERMEP-imaging platform and is in charge of the Laboratory ‘Radiopharmaceutical and Neurochemical Biomarkers’ at the Lyon Neuroscience Research Center (CRNL). His research interests include PET radiopharmacology and the use of PET radiopharmaceuticals for diagnoses in neurodegenerative diseases. Biography Didier Le Bars was born in France in 1958 and studied Pharmaceutical Sciences at the University of Grenoble (1977–1982); after obtaining his Pharm.D, he completed his advanced studies in Pharmacochemistry and received his PhD in Radiochemistry (1986). After a post-doctoral position in MRC Cyclotron Unit, Hammersmith Hospital, he joined the CERMEP PET facility to develop cyclotron produced short-lived isotopes and labelling of radiopharmaceuticals for positron emission tomography. He is an associate professor in Biophysics at the University of Lyon Medical School (Université Claude Bernard Lyon 1) and a radiopharmacist at the University Hospital of Lyon (HCL), he is currently the head of PET department, radiopharmacy and radiochemistry units of CERMEP-imaging platform. He a member of the Institute of Molecular and Supramolecular Chemistry and Biochemistry (ICBMS, Lyon), his research interests focus on cyclotrons, automation for radiochemistry and new labelled compounds for PET.
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must possess certain properties.7 From a radiochemical point of view, radiosynthesis should be as simple and fast as possible, especially with short-lived carbon-11, leading to a high specific radioactivity to avoid any pharmacological blockade of the receptor with unlabelled compound and ensuring therefore the tracer dose principle. From a radiopharmacological point of view, the ligand must possess high affinity toward the receptor, normally in the nanomolar range for 5-HT receptors in accordance to their density value (Bmax). The association rate should be high enough to maximise target to background ratio and the dissociation rate should match to the frame of scanning. The radiotracer must bind selectively to the receptor and this affinity has to compare favourably with affinities of the ligand for a wide spectrum of other receptors and binding sites. The radioligand should also be moderately lipophilic to penetrate adequately the brain and
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should ideally not be a substrate for efflux transporters at the blood–brain barrier, that is, P-glycoprotein. Finally, the radioactive metabolites produced after injection should be excluded from the brain so as not to interfere with the signal measured by the PET camera. This following chapter covers the current status of the PET radioligands for imaging serotoninergic targets. We choose to limit our review to radioligands currently used in humans and possibly transferable to other PET centres because a recent review gave a comprehensive description of 5-HT radioligands.8 Chemical structures are presented with representative carbon-11 and fluorine-18 labelling reactions. An examination of recent literature in PET imaging shows that only five 5-HT receptors can currently be explored in humans with PET radiotracers (see Table 1 and the following section). These serotoninergic targets are 5-HT1A receptors, involved among others in depression and anxiety; 5-HT1B receptors, involved among others in migraine, depression and drug reinforcement; 5-HT2A receptors, involved among others in depression and schizophrenia; 5-HT4 receptors involved in anorexia nervosa and depression; and in a preliminary manner, 5-HT6 receptors, involved in memory, depression and schizophrenia.4
Current PET radiotracers used to image serotonin receptors in humans 5-HT1A receptor radiotracers [11C]WAY100635
The 5-HT1A receptor possesses a high affinity for serotonin and for many synthetic selective agonists and antagonists, some of which have been successfully used in brain imaging. Several highly selective 5-HT1A receptor antagonists have been developed, and WAY100635 (3H-(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-N-(2-pyridyl)cyclohexane-carboxamide) appeared as one of the most promising.9 This piperazine derivate was identified as the first highly selective and potent 5-HT1A receptor antagonist in both ‘presynaptic’ (autoreceptor) and ‘postsynaptic’ (heteroreceptor) locations. Although recent findings suggested that WAY100635 is also a potent D4 agonist,10 this affinity is without consequence for PET imaging as this dopamine receptor density is very low in human brain in comparison to 5-HT1A receptor density. Several derivates were radiolabelled with carbon 11 and evaluated (reviewed in9). [O-methyl-11C]WAY100635 was identified as a potential radioligand for detecting 5-HT1A receptors in rodent and monkeys11 and a later study in human volunteers provided the first delineation of 5-HT1A receptors in living human brain.12 However, in human and primates, [O-methyl-11C]WAY100635 metabolites easily cross the blood–brain barrier and thus increase the level of nonspecific radioactivity in the brain. To circumvent this limitation, labelling was introduced in the cyclohexane carbonyl moiety, [carbonyl-11C]WAY100635 which is degraded into polar radioactive metabolites that do not cross
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L. Zimmer and D. Le Bars Table 1. Overview of used PET radioligands for measurement of 5-HT receptors in human subjects, in more than two research institutions Receptor
Main brain localizations
Maximum density (Bmax)
5-HT1A
Hippocampus, septum, amygdala, raphe, cortex
800–3000 fmol/mg in hippocampus
5-HT1B
Substantia nigra, basal ganglia
400–500 fmol/mg in basal ganglia
5-HT2A
Cortex, olfactory tubercle, claustrum
500 fmol/mg in cortex
5-HT4 5-HT6
Hippocampus, striatum, substantia nigra Striatum, olfactory tubercle, cortex
200 fmol/mg in striatum 200 fmol/mg in striatum
PET radioligands tested in humans [11C]WAY-100635 [carbonyl-11C]DWAY [18F]MPPF [18F]FCWAY [11C]CUMI-101 [11C]AZ10419369 [11C]P943 [18F]setoperone [18F]altanserin [11C]MDL 100,907 [18F]deutoroaltanserin [11C]SB207145 [11C]GSK215083
PET, Positron emission tomography. the blood–brain barrier.13 This elegant but demanding synthesis (Scheme 1) was improved via immobilisation of the Grignard (i.e. immobilised cyclohexylmagnesium chloride in a polypropylene tubing to trap 11CO2 and to obtain the desired [carbonyl-11C] cyclohexanecarbonyl chloride by passing thionyl chloride through the tubing,14] via reduction of excess reagents in a one-pot synthesis15 and through advances in automation.16,17 Despite being well described in the literature,18 [11C] WAY100635 radiosynthesis remains more complex than straightforward methylation as the pivotal Grignard reagent is found somewhat unreliable for many groups. The first database of [11C]WAY100635 in healthy subjects was published in 2002,19 followed by numerous studies with patients suffering from neurological or psychiatric disorders (see20 as a review). Since 2007, more than 20 PET studies have been published in bipolar disorder, panic disorder and anorexia nervosa patients, among others. The main advantage of [11C]WAY100635 is its high target-to-background ratio and its disadvantage is its fast metabolism in plasma, complicating its quantification and justifying other groups investigations on alternative 5-HT1A radiotracers.
Desmethyl-WAY (DWAY) is a minor metabolite of WAY100635.21 DWAY has been labelled with carbon-11 by reaction of desmethyl-WAY100634 with [carbonyl-11C]cyclohexanecarbonyl chloride22 and synthesis was later optimised23 (similar to Scheme 1). It was shown that this radiotracer has very similar radiopharmacological characteristics to [11C]WAY100635. Studies with [carbonyl-11C]DWAY in human volunteers revealed a substantially (75%) greater signal per unit of radioactive dose compared with [carbonyl-11C]WAY100635.24 However, despite these promising results, further human studies using this radiotracer have not been published, perhaps due to the earlier success of [11C]WAY100635. [18F]MPPF
[carbonyl-11C]DWAY In 1994, the laboratory of H.F. Kung described the synthesis of derivatives of 4-(20 -methoxyphenyl)-1-[20 -(N-200 -pyridinyl)-benzamido)ethyl]piperazines25,26 The p-fluoro molecule was tritiated in 1996, and the resulting [3H]MPPF was characterised in vitro, displaying high affinity and selectivity towards 5-HT1A receptors.27 An initial in vivo imaging study with iodinated derivate [123I]MPPI indicated a low binding to 5-HT1A receptors in nonhuman primates,28 because of fast metabolism. Nevertheless,
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Scheme 1. Synthesis of [11C]carbonyl WAY100635 (and derivatives).
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L. Zimmer and D. Le Bars
Scheme 2. Synthesis of [18F]MPPF by nucleophilic aromatic substitution.
despite these negative results, the p-fluoro MPPF compound was successfully radiolabelled with fluorine-18 for PET studies.29 The radiochemical pathway of [18F]MPPF relies on the nucleophilic aromatic substitution of a nitro-precursor. Shiue’s procedure was optimised by Le Bars et al.,30 leading to a simple procedure, easy to automate, affording [18F]MPPF in good yields and high specific activity. This synthesis (Scheme 2), with conventional or micro-wave heating, is now well described,31 automated on most commercial systems.32 Passchier et al.33,34 demonstrated the suitability of [18F]MPPF as a PET radiotracer to label 5-HT1A receptors in human. The paucity of 5-HT1A receptors in cerebellum allowed the use of a simplified reference tissue model to estimate [18F]MPPF binding potential in regions of interest.35 Costes et al.36 proposed a simplified protocol without arterial blood sampling more suitable for clinical research. A normative [18F]MPPF PET database was built in different age groups, for both healthy men and women.37 The first clinical PET study with [18F]MPPF in patients was carried out in epileptic subjects.38 More recent clinical studies measured 5-HT1A receptor densities in patients suffering from Alzheimer’s disease,39–41 from migraine42,43 and depression in epileptic patients44 or in Parkinson patients.45
reaction with the intermediate amine, WAY100634. The drawback of this compound was its difficult synthesis, because of the low yield of 4-fluorocyclo-hexanecarboxylic acid. Vuong et al.47 developed an automated one-pot synthesis with reduction of impurities (Scheme 3), starting from a methanesulfonate precursor and single-step nucleophilic substitution with [18F] fluoride. [18F]FCWAY was used to quantify 5-HT1A receptors in epileptic patients48–50 and patients with panic disorders.51 The main disadvantage of [18F]FCWAY is defluorination, leading to bone radioactivity uptake, although this defluorination can be limited following administration of disulfiram.52 [11C]CUMI-101
[18F]FCWAY
A series of fluorocyclohexyl analogues of WAY-100635 were developed by Lang et al.46 in an attempt to provide a fluorinated analogue of WAY-100635. In this series, 4-trans-F-18 FCWAY [18F] trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N(2-pyridyl)cyclohexane carboxamide was proven to possess the best properties for measuring receptor density given its high affinity for 5-HT1A and its high hippocampus to cerebellum ratio. This selected radiotracer was initially prepared with a multistep reaction sequence using the 4-nosylate derivative of the pentamethylbenzyl ester of cyclohexanecarboxylic acid, radiolabelling with fluorine-18, preparation of acid chloride and
All currently available 5-HT1A radiopharmaceuticals for clinical PET are antagonists and many efforts have already been devoted to develop an agonist radioligand in order to explore functional 5-HT1A receptors.20 Initial studies reported the successful use of CUMI-101, a 11C-labelled agonist tracer, in rat, primate and man.53–55 The radiosynthesis of [11C]CUMI-101 (previously named [11C]MMP, cf. Scheme 4), involves standard 11C-methylation of the corresponding desmethyl precursor 2-(4-(4-(2-hydroxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione with [11C]CH3OTf in acetone in the presence of NaOH and HPLC purification. Human distribution, dosimetry and first 5-HT1A quantification using this agonist in healthy subjects were recently described.55,56 Although modelling parameters of this radiotracer were thoroughly explored for 5-HT1A imaging, its pharmacological properties were recently questioned as [11C]CUMI-101 exhibits only partial agonism at 5-HT1A receptors.57 This pharmacological drawback could limit the dissemination of this radiotracer and justify the research of other alternative PET 5-HT1A agonists.58,59
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Scheme 3. Synthesis of [18F]FCWAY by nucleophilic aliphatic substitution.
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Scheme 4. Synthesis of [11C]CUMI-101 by methylation.
5-HT1B receptor radiotracers
5-HT2A receptor radiotracers
[11C]AZ10419369
[18F]Setoperone
The radiosynthesis of [11C]AZ10419369 (5-methyl-8-(4-methylpiperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-morpholin-4-yl-phenylamide), recently reported by Pierson et al.,60 involved the standard 11C-N-methylation of the corresponding desmethyl precursor with [11C]CH3OTf in acetone in the presence of NaOH. The first human PET study with [11C]AZ10419369 showed a rapid brain uptake, a binding distribution in accordance with 5-HT1B distribution and no brain radiometabolites.61,62 All these characteristics encourage pursuing the use of this radiotracer. [11C]P943
The structure of setoperone is close to ketanserin, developed in PET as [11C]ketanserin but never published in human studies. [18F]Setoperone (6-[2-[4-(4-[18F]fluoro benzoyl) piperidin-1-yl] ethyl]-7-methyl-2,3-dihydro-1,3thiazolo[3,2-a]pyrimidin-5-one), first synthesised by Crouzel et al.68 showed in its first studies in baboon brain a high binding in areas rich in 5-HT2A receptors such as cortex but also in striatum.69 If the cortical binding is blocked by pre-treatment with 5-HT2A antagonists, the striatum binding was significantly because of D2 receptors. However, with regard to the differential localization of the 5-HT2A relative to D2 receptors, this relative lack of specificity of [18F]setoperone did not stop it from becoming the first successful 5-HT2A PET ligand. [18F]setoperone has been used to estimate the 5-HT2A drug occupancy by antipsychotics70–72 and also to explore possible changes in 5-HT2A density in Alzheimer’s disease,73 migraine (,74 stroke,75 and depression.76,77 [18F]altanserin
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P943 (R-1-[4-(2-methoxy-isopropyl)-phenyl]-3-[2-(4-methylpiperazin-1-yl)benzyl]-pyrrolidin-2-one) is a potent 5-HT1B antagonist recently described.63 [11C]P943 is radiolabelled using [11C]methyl triflate alkylation of desmethyl-P943 in DMF, purified by preparative RP-HPLC. The first study in human included modelling approaches and even if the specificity of this radiotracer has to be confirmed in vivo, [11C]P943 appears to be suited for the quantification of 5-HT1B receptors.63 The first applications in patients are in addiction to alcohol64 and to gambling65 in which 5-HT1B seems to be involved. Other studies conducted by the same team are interested in depression66 and in the consequences of brain trauma.67
Altanserin is a fluorobenzoyl derivative, structurally close to setoperone and ketanserin. The original radiosynthesis of [18F] altanserin involved nucleophilic substitution of 3-[2-[4-(4-nitrobenzoyl)-1-piperidyl]ethyl]-2-sulfanyl-3H-quinazolin-4-one with K[18F]F/ Kryptofix 2.2.2 in dimethyl sulfoxide, followed by HPLC purification.78 Its automation in a commercial module with a solid phase work-up procedure involved the acidification of the crude reaction mixture and a C18 solid phase separation before the final HPLC purification.79 Pharmacologically, altanserin has a lower affinity for D2 receptor than setoperone and therefore it is assumed that the majority of the PET signal of [18F]altanserin can be attributed to 5-HT2A receptor binding. The first [18F]altanserin study in humans was published in 199480 and numerous studies in patients followed. More recently, a more complex kinetic modelling of this radiotracer was proposed because its brain radiometabolites contribute possibly to the nonspecific binding.81,82 This model was simplified by different bolusinfusion paradigms83,84 and a database of 5-HT2A binding in
L. Zimmer and D. Le Bars healthy volunteers has been published in 2004.85 These validation studies in healthy subjects allowed an extensive use of [18F]altanserin to determine 5-HT2A receptor status in patients suffering from cognitive decline86,87 and several psychiatric diseases.88,89
5-HT4 receptor radiotracers [11C]SB207145
[18F]deutoroaltanserin
As previously mentioned, the formation of lipophilic radiometabolites from [18F]altanserin was considered as a major disadvantage because of their interactions in data analysis. This justified the development of a PET radioligand related to [18F] altanserin but without production of radiometabolites crossing the blood–brain barrier. The team of Innis proposed [18F]deuteroaltanserin in which two deuterium atoms on the ethyl chain were supposed to limit the radiometabolism,90 on the basis of a carbon–deuterium bond more difficult to break than a carbon– hydrogen bond. This initial study in human indicated a brain uptake increased by 26% above [18F]altanserin. Only few further studies have been published using [18F]deuteroaltanserin in humans91 and this radiotracer failed obviously to replace [18F] altanserin.
SB207145 is a 5-HT4 receptor antagonist radiolabelled with carbon-11 by Gee et al. in 2008.98 This team described the 11Cmethylation of SB206453 (hydrochloride salt) with [11C]iodomethane, performed inside an HPLC sample loop. First preliminary data in a few healthy subjects indicated that [11C]SB207145 was distributed into the brain according to known 5-HT4 receptor distribution. A later study explored radioligand metabolism and binding kinetics in pig brain, revealing a slow but reversible kinetics of [11C] SB207145 in 5-HT4 brain regions and the validity of the simplified reference tissue model.99 In more recent studies, a comprehensive quantification of the brain binding of [11C]SB207145 in the human brain was further provided, demonstrating good test–retest reproducibility and time-stability; a database exploring the effect of age and sex was provided.100,101 To date, [11C]SB207145 is the only PET radiotracer that can be used for quantitative PET measurements of 5-HT4 receptors in the human brain. 5-HT6 receptor radiotracers [11C]GSK215083
[11C]MDL 100,907
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MDL 100,907 ((R)-(+)-4-(hydroxy-(2,3-dimethoxyphenyl) methyl)-N-2-(4-fluorophenyl)ethylpiperidine is a potent and a highly selective 5-HT2A receptor antagonist in vitro. The preparation of (R)-(+)-[3-methoxy-11C]MDL 100,907 is performed by O-methylation of the 3-hydroxy precursor (MDL 105,725) with [11C]methyl iodide in acetone and sodium hydroxide followed by a semi-preparative normal-phase HPLC separation.92 The first PET study reported in humans revealed favourable characteristics for [11C]MDL 100,907 with a moderate lipophilicity and a binding 4–6 times higher in neocortex than in cerebellum.93 Further studies validated the methodology for modelling [11C] MDL 100,907 binding in PET studies, with the use of metabolite-corrected arterial plasma radioactivity concentration for one94 and a more simple non-invasive graphical analysis for the other.95 In fact, [11C]MDL 100,907 has only been used in a limited number of clinical studies including depressed patients96 and patients with obsessive–compulsive disorders.97
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Two 5-HT6 antagonists theoretically suitable for PET studies were recently identified.102,103 On the basis of a common 3-benzenesulfonyl-8-piperazin-1-yl-quinoline structure, [11C]GSK215083 and [11C]GSK224558 were both investigated in pig brain. [11C] GSK215083 was selected as the more potent despite its high affinity for 5-HT2A receptors (in vitro Ki, 0.79 nM). However, given the differential localization of these two receptors in the central nervous system, the authors considered that the striatum binding can be attributed to 5-HT6 receptors. Despite this limit, [11C] GSK215083 represents the only available 5-HT6 PET radioligand to date.104
Future challenges for a functional PET imaging of serotonin receptors Specific PET radiotracers for unexplored serotonin receptors There is still a need for research into PET radiotracers for an accurate delineation and quantification of 5-HT receptors in humans including healthy subjects and patients in neurology or psychiatry. According to the International Union of Basic and Clinical
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L. Zimmer and D. Le Bars Pharmacology database, there are 14 currently known 5-HT receptors and more than a hundred of 5-HT ligands including molecules with therapeutic actions, that is, antipsychotics, antiemetic and antimigraine agents.2 Despite this large number of pharmacological ligands, it has to be kept in mind that many 5-HT receptor families do not have yet their own PET radiotracers and if they have, there is still a bottleneck between the available PET tracer candidates and the PET radiotracer usable in humans. As mentioned earlier, only five 5-HT receptors have their own PET radiotracer used in humans and eight 5-HT receptors are not yet investigable by PET in humans: 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5 and 5-HT7 receptors. Different situations can be described. The first is that the receptor has not yet a selective ligand, that is, a ligand targeting one specific 5-HT family with a higher affinity than for other 5-HT families or other targets. Indeed, if it is relatively easy to select a list of ligands with a high affinity for a dedicated receptor, not every molecule is selective for only one receptor: for example, the 5-HT1E receptors do not have yet selective ligands. The other situation is that the radioligand candidate was tested in animal models but failed at this stage because of the characteristics of its pharmacokinetics (rapid metabolism. . .), its pharmacodynamics (brain exclusion via efflux transporter. . .) or unknown reasons (low target-to-background ratio despite favourable characteristics. . .). Finally, it has to be highlighted that the transfer of a radiotracer used in animals to humans requires ever increasing and demanding radiopharmaceutical prerequisites. All these diverse situations explain the high attrition rate in the development of new PET radiopharmaceuticals for 5-HT brain imaging. Radiotracers for endogenous serotonin level measurement Another need for research into 5-HT radiotracers is the development and validation of radiotracers able to measure endogenous 5-HT fluctuations. Under certain circumstances indeed, PET can provide a dynamic measure of neurotransmission by measuring acute fluctuations in synaptic neurotransmitter concentrations in vivo. This function is based on the principle of competition between a particular radioligand and a neurotransmitter.105 Several reports demonstrate that PET, using a ligand with a relatively low affinity for the said receptor, might be able to evaluate the release of a neurotransmitter after a pharmacological challenge. This explains that the search for the ideal PET radiotracer designed to measure in vivo serotonin fluctuations is still ongoing. Numerous studies performed in animal models or in humans investigated the susceptibility of serotonin receptor radiotracers to manipulation of endogenous serotonin. The most studied radiotracers in humans were [18F]MPPF for the 5-HT1A receptors,106 [18F]altanserin for the 5-HT2A receptors,107 a single study with [11C]SB207145 for the 5-HT4 receptors100 and [11C] AZ10419369 for 5-HT1B receptors.60,108 However, as these results obtained with antagonists are contradictory, we suggest that agonist radiotracers, more sensitive to extracellular change in neurotransmitters, could open a perspective.
Conclusions This review presented the PET radiotracers currently injectable in humans for the exploration of 5-HT receptors. Validated radiotracers for imaging the 5-HT system exist for 5-HT1A, 5-HT1B, 5-HT2A, 5-HT4 and 5-HT6 receptors. Among these radiotracers, several are well validated and used in clinical research (i.e. [11C]WAY100635, [18F]MPPF, [18F]altanserin) and other are currently emerging with preliminary evaluations in humans (i.e. [11C]CUMI-101, [11C] AZ10419369, [11C]P943, and [11C]SB207145). Despite numerous characterizations of radiotracer-candidates, there are currently no PET radioligands for the exploration of 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5 and 5-HT7 receptor in humans. The availability of new selective antagonists and agonists for many of these receptors should facilitate the emergence of PET radiotracers for future studies of the 5-HT neurotransmission.
Conflict of Interest The authors did not report any conflict of interest.
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A large majority of PET radiotracers currently used for the 5-HT receptor exploration are antagonists (see Section 2: 12 out of 13 PET radiotracers used in humans). It is known that pharmacological properties distinguishing antagonist and agonist have possible consequences in PET imaging. The principle is that
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agonists preferentially bind to receptors that are coupled to G-proteins, whereas antagonists are believed to label receptors indiscriminately. Growing evidence suggests that G-protein receptor-coupling (corresponding to the functional receptors) may be involved in both the pathogenesis and treatment of mood disorders109 or in neurodegenerative disorders.110 Therefore, the comparison between a PET antagonist binding (thought to label a receptor family indiscriminately) and an agonist (thought to label G-protein coupled receptors of this family) could reflect the proportion of functional receptors, particularly in the field of 5-HT neurotransmission. Theoretically, 5-HT agonist radiotracers may be more sensitive to 5-HT extracellular levels because 5-HT binds preferentially to the high affinity state of the receptor and could fully displace a PET agonist bound to the same receptor population. Development of this concept comes, among others, from 5-HT1A agonists tested as radiopharmaceuticals in animal models and in healthy human subjects.53–55,58,59 However, the proof of concept of this promising approach has still to be provided.
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Copyright © 2013 John Wiley & Sons, Ltd.
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Revised 8 November 2012,
Accepted 8 November 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3001
Current status of positron emission tomography radiotracers for serotonin receptors in humans† Luc Zimmera,b* and Didier Le Barsa,c Serotonin (5-HT) neurotransmission plays a key modulatory role in the brain. This system is critical for pathophysiological processes and many drug treatments for brain disorders interact with its 14 subtypes of receptors. Positron emission tomography (PET) is a unique tool for the study of the living brain in translational studies from animal models to patients in neurology or psychiatry. This short review is intended to cover the current status of PET radioligands used for imaging human brain 5-HT receptors. Here, we describe the available PET radioligands for the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT4 and 5-HT6 receptors. Finally, we highlight the future challenges for a functional PET imaging of serotonin receptors, including the research towards specific PET radiotracers for yet unexplored serotonin receptors, the need of radiotracers for endogenous serotonin level measurement and the contribution of agonist radiotracers for functional imaging of 5-HT neurotransmission. Keywords: PET; radiopharmaceutical; serotonin; receptor; brain
General overview of the serotonin receptors
J. Label Compd. Radiopharm 2013, 56 105–113
a
Hospices Civils de Lyon, CERMEP-Imaging Platform, Lyon, France
b University of Lyon 1, INSERM, CNRS, Lyon Neuroscience Research Centre, Lyon, France c
University of Lyon 1, CNRS, Institute of Chemistry and Biochemistry, Villeurbanne, France *Correspondence to: Luc Zimmer & Didier Le Bars, CERMEP-Imagerie du Vivant, Groupement Hospitalier Est, 59 bd Pinel, F-69003 Lyon, France. E-mail: [email protected]; [email protected]
†
This article is published in Journal of Labelled Compounds and Radiopharmaceuticals as a special issue on Carbon-11 and fluorine-18 chemistry devoted to molecular probes for imaging the brain with PET, edited by Frédéric DOLLÉ, Service Hospitalier Frédéric Joliot, Institut d’Imagerie BioMédicale, CEA, 4 Place du Général Leclerc, F-91406 Orsay, France.
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The serotoninergic (5-HT) system plays a key role in many central nervous system functions. The 5-HT receptors are among the most diverse group of neuro-receptors in the human genome and are also among the phylogenetically oldest systems. 5-HT neurons originate in the dorsal and median raphe nuclei of the pons and upper medulla. This relatively small number of cells produces a dense network of neuronal projections that innervate the entire forebrain to cortex, hippocampus, basal ganglia, limbic system and hypothalamus. On the other direction, caudal cells project to cerebellum, medulla and spinal cord.1 Currently, 14 receptors are structurally and pharmacologically characterised.2 The majority of 5-HT receptors themselves are located extra-synaptically, either pre-synaptically or postsynaptically. The 14 subtypes are divided into seven classes, from 5-HT1 to 5-HT7, according to their structural and functional characteristics. All are members of the trans-membrane GPCR family (G-protein-coupled receptors) except the 5-HT3 receptor, which is a ligand-gated ion channel. Even though functions of these receptors still need to be elucidated, it is known that each of these targets has its own pattern of distribution and role in the CNS. As several reviews on the 5-HT receptors are available, these neurobiological descriptions will be limited to a general overview. Physiologically, 5-HT functions are crucial in the control of sleep, wakefulness, mood, feeding behaviour and the control of sensory transmission. 5-HT dysfunction has been implicated in the aetiology of many psychiatric disorders including depression, anxiety, schizophrenia and other neurological disorders such as Alzheimer’s disease, epilepsy and sleep disorders.3,4 Although our current knowledge of the serotoninergic system is mainly derived from basic research and animal models, the development of non-invasive brain imaging techniques, such as positron emission tomography (PET) allows the study of the
neurotransmission in the human brain, essential for the development of biomarkers.5 PET is often used for quantification of receptor concentration, allowing in vivo pharmacology. PET is also useful for tracking pharmacokinetic and pharmacodynamic properties of drugs and can be used to determine the occupancy of therapeutic drugs, which ultimately can be used to estimate optimal doses in Phase II studies. For that reason, drug discovery in pharmaceutical industry has increasingly taken advantage of this technology to accelerate the development of brain drug candidates.6 Noteworthy, significant discoveries (or confirmation of results obtained in animal models) within the 5-HT system in human brain have been made following the development of selective PET radioligands. However, the full potential of 5-HT-targeted treatments cannot be understood before selective radioligands for 5-HT receptors have been developed and validated in humans. Radioligands for imaging 5-HT receptors are mainly based structurally on receptor antagonists, less often on agonists. In order to generate quantifiable images of brain receptors, radioligands
L. Zimmer and D. Le Bars Biography Luc Zimmer was born in France in 1968 and received a Pharmacist Education at the University of Strasbourg (1986–1992); he completed training during his internship and residency in Radiopharmacy and Radiopharmacology (1993–1999) at the Hospital University of Tours (Nuclear Medicine Department) and at the National Institute for Nuclear Sciences and Technology, Saclay. He received his Pharm.D in Radiopharmacology (1998) and his PhD in Neuroscience (1999) from the University of Tours. He is currently a professor in Pharmacology at the University of Lyon (Université Claude Bernard Lyon 1) and is a radiopharmacist at the University Hospital of Lyon (HCL). He is the head of the Preclinical Department of the CERMEP-imaging platform and is in charge of the Laboratory ‘Radiopharmaceutical and Neurochemical Biomarkers’ at the Lyon Neuroscience Research Center (CRNL). His research interests include PET radiopharmacology and the use of PET radiopharmaceuticals for diagnoses in neurodegenerative diseases. Biography Didier Le Bars was born in France in 1958 and studied Pharmaceutical Sciences at the University of Grenoble (1977–1982); after obtaining his Pharm.D, he completed his advanced studies in Pharmacochemistry and received his PhD in Radiochemistry (1986). After a post-doctoral position in MRC Cyclotron Unit, Hammersmith Hospital, he joined the CERMEP PET facility to develop cyclotron produced short-lived isotopes and labelling of radiopharmaceuticals for positron emission tomography. He is an associate professor in Biophysics at the University of Lyon Medical School (Université Claude Bernard Lyon 1) and a radiopharmacist at the University Hospital of Lyon (HCL), he is currently the head of PET department, radiopharmacy and radiochemistry units of CERMEP-imaging platform. He a member of the Institute of Molecular and Supramolecular Chemistry and Biochemistry (ICBMS, Lyon), his research interests focus on cyclotrons, automation for radiochemistry and new labelled compounds for PET.
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must possess certain properties.7 From a radiochemical point of view, radiosynthesis should be as simple and fast as possible, especially with short-lived carbon-11, leading to a high specific radioactivity to avoid any pharmacological blockade of the receptor with unlabelled compound and ensuring therefore the tracer dose principle. From a radiopharmacological point of view, the ligand must possess high affinity toward the receptor, normally in the nanomolar range for 5-HT receptors in accordance to their density value (Bmax). The association rate should be high enough to maximise target to background ratio and the dissociation rate should match to the frame of scanning. The radiotracer must bind selectively to the receptor and this affinity has to compare favourably with affinities of the ligand for a wide spectrum of other receptors and binding sites. The radioligand should also be moderately lipophilic to penetrate adequately the brain and
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should ideally not be a substrate for efflux transporters at the blood–brain barrier, that is, P-glycoprotein. Finally, the radioactive metabolites produced after injection should be excluded from the brain so as not to interfere with the signal measured by the PET camera. This following chapter covers the current status of the PET radioligands for imaging serotoninergic targets. We choose to limit our review to radioligands currently used in humans and possibly transferable to other PET centres because a recent review gave a comprehensive description of 5-HT radioligands.8 Chemical structures are presented with representative carbon-11 and fluorine-18 labelling reactions. An examination of recent literature in PET imaging shows that only five 5-HT receptors can currently be explored in humans with PET radiotracers (see Table 1 and the following section). These serotoninergic targets are 5-HT1A receptors, involved among others in depression and anxiety; 5-HT1B receptors, involved among others in migraine, depression and drug reinforcement; 5-HT2A receptors, involved among others in depression and schizophrenia; 5-HT4 receptors involved in anorexia nervosa and depression; and in a preliminary manner, 5-HT6 receptors, involved in memory, depression and schizophrenia.4
Current PET radiotracers used to image serotonin receptors in humans 5-HT1A receptor radiotracers [11C]WAY100635
The 5-HT1A receptor possesses a high affinity for serotonin and for many synthetic selective agonists and antagonists, some of which have been successfully used in brain imaging. Several highly selective 5-HT1A receptor antagonists have been developed, and WAY100635 (3H-(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-N-(2-pyridyl)cyclohexane-carboxamide) appeared as one of the most promising.9 This piperazine derivate was identified as the first highly selective and potent 5-HT1A receptor antagonist in both ‘presynaptic’ (autoreceptor) and ‘postsynaptic’ (heteroreceptor) locations. Although recent findings suggested that WAY100635 is also a potent D4 agonist,10 this affinity is without consequence for PET imaging as this dopamine receptor density is very low in human brain in comparison to 5-HT1A receptor density. Several derivates were radiolabelled with carbon 11 and evaluated (reviewed in9). [O-methyl-11C]WAY100635 was identified as a potential radioligand for detecting 5-HT1A receptors in rodent and monkeys11 and a later study in human volunteers provided the first delineation of 5-HT1A receptors in living human brain.12 However, in human and primates, [O-methyl-11C]WAY100635 metabolites easily cross the blood–brain barrier and thus increase the level of nonspecific radioactivity in the brain. To circumvent this limitation, labelling was introduced in the cyclohexane carbonyl moiety, [carbonyl-11C]WAY100635 which is degraded into polar radioactive metabolites that do not cross
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L. Zimmer and D. Le Bars Table 1. Overview of used PET radioligands for measurement of 5-HT receptors in human subjects, in more than two research institutions Receptor
Main brain localizations
Maximum density (Bmax)
5-HT1A
Hippocampus, septum, amygdala, raphe, cortex
800–3000 fmol/mg in hippocampus
5-HT1B
Substantia nigra, basal ganglia
400–500 fmol/mg in basal ganglia
5-HT2A
Cortex, olfactory tubercle, claustrum
500 fmol/mg in cortex
5-HT4 5-HT6
Hippocampus, striatum, substantia nigra Striatum, olfactory tubercle, cortex
200 fmol/mg in striatum 200 fmol/mg in striatum
PET radioligands tested in humans [11C]WAY-100635 [carbonyl-11C]DWAY [18F]MPPF [18F]FCWAY [11C]CUMI-101 [11C]AZ10419369 [11C]P943 [18F]setoperone [18F]altanserin [11C]MDL 100,907 [18F]deutoroaltanserin [11C]SB207145 [11C]GSK215083
PET, Positron emission tomography. the blood–brain barrier.13 This elegant but demanding synthesis (Scheme 1) was improved via immobilisation of the Grignard (i.e. immobilised cyclohexylmagnesium chloride in a polypropylene tubing to trap 11CO2 and to obtain the desired [carbonyl-11C] cyclohexanecarbonyl chloride by passing thionyl chloride through the tubing,14] via reduction of excess reagents in a one-pot synthesis15 and through advances in automation.16,17 Despite being well described in the literature,18 [11C] WAY100635 radiosynthesis remains more complex than straightforward methylation as the pivotal Grignard reagent is found somewhat unreliable for many groups. The first database of [11C]WAY100635 in healthy subjects was published in 2002,19 followed by numerous studies with patients suffering from neurological or psychiatric disorders (see20 as a review). Since 2007, more than 20 PET studies have been published in bipolar disorder, panic disorder and anorexia nervosa patients, among others. The main advantage of [11C]WAY100635 is its high target-to-background ratio and its disadvantage is its fast metabolism in plasma, complicating its quantification and justifying other groups investigations on alternative 5-HT1A radiotracers.
Desmethyl-WAY (DWAY) is a minor metabolite of WAY100635.21 DWAY has been labelled with carbon-11 by reaction of desmethyl-WAY100634 with [carbonyl-11C]cyclohexanecarbonyl chloride22 and synthesis was later optimised23 (similar to Scheme 1). It was shown that this radiotracer has very similar radiopharmacological characteristics to [11C]WAY100635. Studies with [carbonyl-11C]DWAY in human volunteers revealed a substantially (75%) greater signal per unit of radioactive dose compared with [carbonyl-11C]WAY100635.24 However, despite these promising results, further human studies using this radiotracer have not been published, perhaps due to the earlier success of [11C]WAY100635. [18F]MPPF
[carbonyl-11C]DWAY In 1994, the laboratory of H.F. Kung described the synthesis of derivatives of 4-(20 -methoxyphenyl)-1-[20 -(N-200 -pyridinyl)-benzamido)ethyl]piperazines25,26 The p-fluoro molecule was tritiated in 1996, and the resulting [3H]MPPF was characterised in vitro, displaying high affinity and selectivity towards 5-HT1A receptors.27 An initial in vivo imaging study with iodinated derivate [123I]MPPI indicated a low binding to 5-HT1A receptors in nonhuman primates,28 because of fast metabolism. Nevertheless,
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Scheme 1. Synthesis of [11C]carbonyl WAY100635 (and derivatives).
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L. Zimmer and D. Le Bars
Scheme 2. Synthesis of [18F]MPPF by nucleophilic aromatic substitution.
despite these negative results, the p-fluoro MPPF compound was successfully radiolabelled with fluorine-18 for PET studies.29 The radiochemical pathway of [18F]MPPF relies on the nucleophilic aromatic substitution of a nitro-precursor. Shiue’s procedure was optimised by Le Bars et al.,30 leading to a simple procedure, easy to automate, affording [18F]MPPF in good yields and high specific activity. This synthesis (Scheme 2), with conventional or micro-wave heating, is now well described,31 automated on most commercial systems.32 Passchier et al.33,34 demonstrated the suitability of [18F]MPPF as a PET radiotracer to label 5-HT1A receptors in human. The paucity of 5-HT1A receptors in cerebellum allowed the use of a simplified reference tissue model to estimate [18F]MPPF binding potential in regions of interest.35 Costes et al.36 proposed a simplified protocol without arterial blood sampling more suitable for clinical research. A normative [18F]MPPF PET database was built in different age groups, for both healthy men and women.37 The first clinical PET study with [18F]MPPF in patients was carried out in epileptic subjects.38 More recent clinical studies measured 5-HT1A receptor densities in patients suffering from Alzheimer’s disease,39–41 from migraine42,43 and depression in epileptic patients44 or in Parkinson patients.45
reaction with the intermediate amine, WAY100634. The drawback of this compound was its difficult synthesis, because of the low yield of 4-fluorocyclo-hexanecarboxylic acid. Vuong et al.47 developed an automated one-pot synthesis with reduction of impurities (Scheme 3), starting from a methanesulfonate precursor and single-step nucleophilic substitution with [18F] fluoride. [18F]FCWAY was used to quantify 5-HT1A receptors in epileptic patients48–50 and patients with panic disorders.51 The main disadvantage of [18F]FCWAY is defluorination, leading to bone radioactivity uptake, although this defluorination can be limited following administration of disulfiram.52 [11C]CUMI-101
[18F]FCWAY
A series of fluorocyclohexyl analogues of WAY-100635 were developed by Lang et al.46 in an attempt to provide a fluorinated analogue of WAY-100635. In this series, 4-trans-F-18 FCWAY [18F] trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N(2-pyridyl)cyclohexane carboxamide was proven to possess the best properties for measuring receptor density given its high affinity for 5-HT1A and its high hippocampus to cerebellum ratio. This selected radiotracer was initially prepared with a multistep reaction sequence using the 4-nosylate derivative of the pentamethylbenzyl ester of cyclohexanecarboxylic acid, radiolabelling with fluorine-18, preparation of acid chloride and
All currently available 5-HT1A radiopharmaceuticals for clinical PET are antagonists and many efforts have already been devoted to develop an agonist radioligand in order to explore functional 5-HT1A receptors.20 Initial studies reported the successful use of CUMI-101, a 11C-labelled agonist tracer, in rat, primate and man.53–55 The radiosynthesis of [11C]CUMI-101 (previously named [11C]MMP, cf. Scheme 4), involves standard 11C-methylation of the corresponding desmethyl precursor 2-(4-(4-(2-hydroxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione with [11C]CH3OTf in acetone in the presence of NaOH and HPLC purification. Human distribution, dosimetry and first 5-HT1A quantification using this agonist in healthy subjects were recently described.55,56 Although modelling parameters of this radiotracer were thoroughly explored for 5-HT1A imaging, its pharmacological properties were recently questioned as [11C]CUMI-101 exhibits only partial agonism at 5-HT1A receptors.57 This pharmacological drawback could limit the dissemination of this radiotracer and justify the research of other alternative PET 5-HT1A agonists.58,59
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Scheme 3. Synthesis of [18F]FCWAY by nucleophilic aliphatic substitution.
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Scheme 4. Synthesis of [11C]CUMI-101 by methylation.
5-HT1B receptor radiotracers
5-HT2A receptor radiotracers
[11C]AZ10419369
[18F]Setoperone
The radiosynthesis of [11C]AZ10419369 (5-methyl-8-(4-methylpiperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid 4-morpholin-4-yl-phenylamide), recently reported by Pierson et al.,60 involved the standard 11C-N-methylation of the corresponding desmethyl precursor with [11C]CH3OTf in acetone in the presence of NaOH. The first human PET study with [11C]AZ10419369 showed a rapid brain uptake, a binding distribution in accordance with 5-HT1B distribution and no brain radiometabolites.61,62 All these characteristics encourage pursuing the use of this radiotracer. [11C]P943
The structure of setoperone is close to ketanserin, developed in PET as [11C]ketanserin but never published in human studies. [18F]Setoperone (6-[2-[4-(4-[18F]fluoro benzoyl) piperidin-1-yl] ethyl]-7-methyl-2,3-dihydro-1,3thiazolo[3,2-a]pyrimidin-5-one), first synthesised by Crouzel et al.68 showed in its first studies in baboon brain a high binding in areas rich in 5-HT2A receptors such as cortex but also in striatum.69 If the cortical binding is blocked by pre-treatment with 5-HT2A antagonists, the striatum binding was significantly because of D2 receptors. However, with regard to the differential localization of the 5-HT2A relative to D2 receptors, this relative lack of specificity of [18F]setoperone did not stop it from becoming the first successful 5-HT2A PET ligand. [18F]setoperone has been used to estimate the 5-HT2A drug occupancy by antipsychotics70–72 and also to explore possible changes in 5-HT2A density in Alzheimer’s disease,73 migraine (,74 stroke,75 and depression.76,77 [18F]altanserin
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P943 (R-1-[4-(2-methoxy-isopropyl)-phenyl]-3-[2-(4-methylpiperazin-1-yl)benzyl]-pyrrolidin-2-one) is a potent 5-HT1B antagonist recently described.63 [11C]P943 is radiolabelled using [11C]methyl triflate alkylation of desmethyl-P943 in DMF, purified by preparative RP-HPLC. The first study in human included modelling approaches and even if the specificity of this radiotracer has to be confirmed in vivo, [11C]P943 appears to be suited for the quantification of 5-HT1B receptors.63 The first applications in patients are in addiction to alcohol64 and to gambling65 in which 5-HT1B seems to be involved. Other studies conducted by the same team are interested in depression66 and in the consequences of brain trauma.67
Altanserin is a fluorobenzoyl derivative, structurally close to setoperone and ketanserin. The original radiosynthesis of [18F] altanserin involved nucleophilic substitution of 3-[2-[4-(4-nitrobenzoyl)-1-piperidyl]ethyl]-2-sulfanyl-3H-quinazolin-4-one with K[18F]F/ Kryptofix 2.2.2 in dimethyl sulfoxide, followed by HPLC purification.78 Its automation in a commercial module with a solid phase work-up procedure involved the acidification of the crude reaction mixture and a C18 solid phase separation before the final HPLC purification.79 Pharmacologically, altanserin has a lower affinity for D2 receptor than setoperone and therefore it is assumed that the majority of the PET signal of [18F]altanserin can be attributed to 5-HT2A receptor binding. The first [18F]altanserin study in humans was published in 199480 and numerous studies in patients followed. More recently, a more complex kinetic modelling of this radiotracer was proposed because its brain radiometabolites contribute possibly to the nonspecific binding.81,82 This model was simplified by different bolusinfusion paradigms83,84 and a database of 5-HT2A binding in
L. Zimmer and D. Le Bars healthy volunteers has been published in 2004.85 These validation studies in healthy subjects allowed an extensive use of [18F]altanserin to determine 5-HT2A receptor status in patients suffering from cognitive decline86,87 and several psychiatric diseases.88,89
5-HT4 receptor radiotracers [11C]SB207145
[18F]deutoroaltanserin
As previously mentioned, the formation of lipophilic radiometabolites from [18F]altanserin was considered as a major disadvantage because of their interactions in data analysis. This justified the development of a PET radioligand related to [18F] altanserin but without production of radiometabolites crossing the blood–brain barrier. The team of Innis proposed [18F]deuteroaltanserin in which two deuterium atoms on the ethyl chain were supposed to limit the radiometabolism,90 on the basis of a carbon–deuterium bond more difficult to break than a carbon– hydrogen bond. This initial study in human indicated a brain uptake increased by 26% above [18F]altanserin. Only few further studies have been published using [18F]deuteroaltanserin in humans91 and this radiotracer failed obviously to replace [18F] altanserin.
SB207145 is a 5-HT4 receptor antagonist radiolabelled with carbon-11 by Gee et al. in 2008.98 This team described the 11Cmethylation of SB206453 (hydrochloride salt) with [11C]iodomethane, performed inside an HPLC sample loop. First preliminary data in a few healthy subjects indicated that [11C]SB207145 was distributed into the brain according to known 5-HT4 receptor distribution. A later study explored radioligand metabolism and binding kinetics in pig brain, revealing a slow but reversible kinetics of [11C] SB207145 in 5-HT4 brain regions and the validity of the simplified reference tissue model.99 In more recent studies, a comprehensive quantification of the brain binding of [11C]SB207145 in the human brain was further provided, demonstrating good test–retest reproducibility and time-stability; a database exploring the effect of age and sex was provided.100,101 To date, [11C]SB207145 is the only PET radiotracer that can be used for quantitative PET measurements of 5-HT4 receptors in the human brain. 5-HT6 receptor radiotracers [11C]GSK215083
[11C]MDL 100,907
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MDL 100,907 ((R)-(+)-4-(hydroxy-(2,3-dimethoxyphenyl) methyl)-N-2-(4-fluorophenyl)ethylpiperidine is a potent and a highly selective 5-HT2A receptor antagonist in vitro. The preparation of (R)-(+)-[3-methoxy-11C]MDL 100,907 is performed by O-methylation of the 3-hydroxy precursor (MDL 105,725) with [11C]methyl iodide in acetone and sodium hydroxide followed by a semi-preparative normal-phase HPLC separation.92 The first PET study reported in humans revealed favourable characteristics for [11C]MDL 100,907 with a moderate lipophilicity and a binding 4–6 times higher in neocortex than in cerebellum.93 Further studies validated the methodology for modelling [11C] MDL 100,907 binding in PET studies, with the use of metabolite-corrected arterial plasma radioactivity concentration for one94 and a more simple non-invasive graphical analysis for the other.95 In fact, [11C]MDL 100,907 has only been used in a limited number of clinical studies including depressed patients96 and patients with obsessive–compulsive disorders.97
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Two 5-HT6 antagonists theoretically suitable for PET studies were recently identified.102,103 On the basis of a common 3-benzenesulfonyl-8-piperazin-1-yl-quinoline structure, [11C]GSK215083 and [11C]GSK224558 were both investigated in pig brain. [11C] GSK215083 was selected as the more potent despite its high affinity for 5-HT2A receptors (in vitro Ki, 0.79 nM). However, given the differential localization of these two receptors in the central nervous system, the authors considered that the striatum binding can be attributed to 5-HT6 receptors. Despite this limit, [11C] GSK215083 represents the only available 5-HT6 PET radioligand to date.104
Future challenges for a functional PET imaging of serotonin receptors Specific PET radiotracers for unexplored serotonin receptors There is still a need for research into PET radiotracers for an accurate delineation and quantification of 5-HT receptors in humans including healthy subjects and patients in neurology or psychiatry. According to the International Union of Basic and Clinical
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L. Zimmer and D. Le Bars Pharmacology database, there are 14 currently known 5-HT receptors and more than a hundred of 5-HT ligands including molecules with therapeutic actions, that is, antipsychotics, antiemetic and antimigraine agents.2 Despite this large number of pharmacological ligands, it has to be kept in mind that many 5-HT receptor families do not have yet their own PET radiotracers and if they have, there is still a bottleneck between the available PET tracer candidates and the PET radiotracer usable in humans. As mentioned earlier, only five 5-HT receptors have their own PET radiotracer used in humans and eight 5-HT receptors are not yet investigable by PET in humans: 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5 and 5-HT7 receptors. Different situations can be described. The first is that the receptor has not yet a selective ligand, that is, a ligand targeting one specific 5-HT family with a higher affinity than for other 5-HT families or other targets. Indeed, if it is relatively easy to select a list of ligands with a high affinity for a dedicated receptor, not every molecule is selective for only one receptor: for example, the 5-HT1E receptors do not have yet selective ligands. The other situation is that the radioligand candidate was tested in animal models but failed at this stage because of the characteristics of its pharmacokinetics (rapid metabolism. . .), its pharmacodynamics (brain exclusion via efflux transporter. . .) or unknown reasons (low target-to-background ratio despite favourable characteristics. . .). Finally, it has to be highlighted that the transfer of a radiotracer used in animals to humans requires ever increasing and demanding radiopharmaceutical prerequisites. All these diverse situations explain the high attrition rate in the development of new PET radiopharmaceuticals for 5-HT brain imaging. Radiotracers for endogenous serotonin level measurement Another need for research into 5-HT radiotracers is the development and validation of radiotracers able to measure endogenous 5-HT fluctuations. Under certain circumstances indeed, PET can provide a dynamic measure of neurotransmission by measuring acute fluctuations in synaptic neurotransmitter concentrations in vivo. This function is based on the principle of competition between a particular radioligand and a neurotransmitter.105 Several reports demonstrate that PET, using a ligand with a relatively low affinity for the said receptor, might be able to evaluate the release of a neurotransmitter after a pharmacological challenge. This explains that the search for the ideal PET radiotracer designed to measure in vivo serotonin fluctuations is still ongoing. Numerous studies performed in animal models or in humans investigated the susceptibility of serotonin receptor radiotracers to manipulation of endogenous serotonin. The most studied radiotracers in humans were [18F]MPPF for the 5-HT1A receptors,106 [18F]altanserin for the 5-HT2A receptors,107 a single study with [11C]SB207145 for the 5-HT4 receptors100 and [11C] AZ10419369 for 5-HT1B receptors.60,108 However, as these results obtained with antagonists are contradictory, we suggest that agonist radiotracers, more sensitive to extracellular change in neurotransmitters, could open a perspective.
Conclusions This review presented the PET radiotracers currently injectable in humans for the exploration of 5-HT receptors. Validated radiotracers for imaging the 5-HT system exist for 5-HT1A, 5-HT1B, 5-HT2A, 5-HT4 and 5-HT6 receptors. Among these radiotracers, several are well validated and used in clinical research (i.e. [11C]WAY100635, [18F]MPPF, [18F]altanserin) and other are currently emerging with preliminary evaluations in humans (i.e. [11C]CUMI-101, [11C] AZ10419369, [11C]P943, and [11C]SB207145). Despite numerous characterizations of radiotracer-candidates, there are currently no PET radioligands for the exploration of 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5 and 5-HT7 receptor in humans. The availability of new selective antagonists and agonists for many of these receptors should facilitate the emergence of PET radiotracers for future studies of the 5-HT neurotransmission.
Conflict of Interest The authors did not report any conflict of interest.
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A large majority of PET radiotracers currently used for the 5-HT receptor exploration are antagonists (see Section 2: 12 out of 13 PET radiotracers used in humans). It is known that pharmacological properties distinguishing antagonist and agonist have possible consequences in PET imaging. The principle is that
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agonists preferentially bind to receptors that are coupled to G-proteins, whereas antagonists are believed to label receptors indiscriminately. Growing evidence suggests that G-protein receptor-coupling (corresponding to the functional receptors) may be involved in both the pathogenesis and treatment of mood disorders109 or in neurodegenerative disorders.110 Therefore, the comparison between a PET antagonist binding (thought to label a receptor family indiscriminately) and an agonist (thought to label G-protein coupled receptors of this family) could reflect the proportion of functional receptors, particularly in the field of 5-HT neurotransmission. Theoretically, 5-HT agonist radiotracers may be more sensitive to 5-HT extracellular levels because 5-HT binds preferentially to the high affinity state of the receptor and could fully displace a PET agonist bound to the same receptor population. Development of this concept comes, among others, from 5-HT1A agonists tested as radiopharmaceuticals in animal models and in healthy human subjects.53–55,58,59 However, the proof of concept of this promising approach has still to be provided.
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