Special Issue: Review Received 27 November 2012,
Revised 18 January 2013,
Accepted 29 January 2013
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3038
11
C-labeled and 18F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain†‡ Uta Funke,a,b* Danielle J. Vugts,b Bieneke Janssen,b Arnold Spaans,a,b Perry S. Kruijer,a Adriaan A. Lammertsma,b Lars R. Perk,a and Albert D. Windhorstb The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping and eating disorders, neurodegeneration, neuroinflammation, mood disorders, and pruritus. In the past 20 years, several ligands targeting the four different histamine receptor subtypes have been explored as potential radiotracers for positron emission tomography (PET). This contribution provides an overview of the developments of subtype-selective carbon-11-labeled and fluorine-18-labeled compounds for imaging in the brain. Using specific radioligands, the H1R expression in human brain could be examined in diseases such as schizophrenia, depression, and anorexia nervosa. In addition, the sedative effects of antihistamines could be investigated in terms of H1R occupancy. The H3R is of special interest because of its regulatory role in the release of various other neurotransmitters, and initial H3R PET imaging studies in humans have been reported. The H4R is the youngest member of the histamine receptor family and is involved in neuroinflammation and various sensory pathways. To date, two H4R-specific 11C-labeled ligands have been synthesized, and the imaging of the H4R in vivo is in the early stage. Keywords: histamine receptor; [11C]doxepin; [11C]pyrilamine; imidazole; [11C]methylation; [18F]fluoride
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Introduction
Radioligands for the histamine H1 receptor
Histamine (2-(1H-imidazol-4-yl)ethanamine) is an endogenous short-acting biogenic amine that plays a key role in various physiological processes. Apart from its peripheral functions, it acts as a neurotransmitter1,2 and regulator of cell proliferation and differentiation3 in the central nervous system (CNS). This action is exerted by binding to four specific histamine receptor subtypes, H1R, H2R, H3R, and H4R,4–6 all belonging to the superfamily of G protein-coupled receptors (GPCR). Alterations in cerebral histaminergic neurotransmission are involved in numerous pathologies of the CNS such as sleep, eating and moving disorders, dementia, epilepsy, addiction, depression, schizophrenia, pain, and neuroinflammation as well as neurodegeneration, for example in Alzheimer’s and Parkinson’s diseases.1,2,7 This has stimulated great interest in neuronal histamine receptors not only as a target for therapy5 but also for in vivo imaging and quantification, using positron emission tomography (PET). Although several former reviews have included8–10 or have even focused on histaminergic PET imaging,11–13 they are mainly limited to the imaging of the H1R. The purpose of the present review is to provide an overview of the current state in the development of PET tracers for the imaging of all histamine receptor subtypes.
In the human brain, the H1R is mainly expressed in neo-cortex, the limbic system, and hypothalamus, as shown by [3H]doxepin binding to human brain tissues.14 For in vivo imaging of the H1R, two carbon-11-labeled ligands have been reported: [11C]pyrilamine, also known as [11C]mepyramine (N1-(4-methoxybenzyl)-N2,N2-dimethylN1-(pyridin-2-yl)ethane-1,2-diamine; Scheme 1), and [11C]doxepin
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a
BV Cyclotron VU, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands
b
VU University Medical Center, Department of Radiology & Nuclear Medicine, Location Radionuclide Center, De Boelelaan 1085c, 1081 HV Amsterdam, The Netherlands *Correspondence to: Uta Funke, BV Cyclotron VU, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands. E-mail: [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 - CEA4 Place du Général Leclerc - F-91406 Orsay - France.
‡
This article was published online on 24 April 2013. Errors were subsequently identified. This notice is included in the online versions 16 August 2013 and corrected by an erratum in the next print version to indicate that the article has been corrected.
Copyright © 2013 John Wiley & Sons, Ltd.
U. Funke et al. Biography
Biography
Uta Funke was born in Leipzig, Germany, in 1978. After graduating 2005 with a German diploma, which is a master’s degree in chemistry at the Universität Leipzig, investigating the [18F]fluoro-arylation of carbonyl compounds by reductive bond formation, she obtained her PhD in 2011 with Prof. Jörg Steinbach on the development of indolylalkylamine-based
Arnold Spaans was born in Maassluis, the Netherlands, in 1978. He obtained his bachelor’s degree in organic chemistry in 2001. In 2002, he started at Altana Pharma as a preclinical research associate focusing on the development of new phosphodiesterase inhibitors for the treatment of chronic obstructive pulmonary disease. After 5 years, he became a research chemist at Mercachem BV, where he worked on various contract-based organic chemistry projects. In April 2009, he started as a radiochemist at BV Cyclotron VU and at the department of Radiology & Nuclear Medicine at the VU University Medical Center in Amsterdam. His work for BV Cyclotron VU is commercializing new 18F-labeled radiopharmaceuticals under good manufacturing practice (GMP) conditions, and within the INMiND project, he focuses on the identification of novel biological targets of neuroinflammation for both diagnostic and therapeutic purposes.
radiotracers for the serotonin transporter. In a cooperation project with the Universität Leipzig, since 2009, she worked with Prof. Peter Brust on the development of phosphodiesterase 10A selective PET ligands for the diagnosis and therapy monitoring of brain disorders. In May 2012, she started as a postdoc at the BV Cyclotron VU and the Radionuclide Center at the VU University Medical Center, Amsterdam. Within the framework of the INMiND project, her research focuses now on 11C- and 18 F-labeled radiopharmaceuticals directed against novel targets on activated microglia for diagnosis and therapy follow-up in neuroinflammation and neurodegeneration.
Perry S. Kruijer was born in Langedijk, the Netherlands. From 1985 to 1992, he obtained his (Higher Laboratory Education) HLO-certificate and a master’s degree in organic chemistry from the University of Amsterdam, both with parttime studies. From 1987 until 1991, he worked as an organic chemist for De Rover Chemie (now Katwijk Chemie). Afterward,
Biography Danielle J. Vugts was born in Tilburg, the Netherlands, in 1979. She studied organic chemistry, and after obtaining her PhD in 2006 with Prof. Dr. R.V.A. Orru at the VU University on Mureidomycine and Dihydropyrimidine Nucleosides, she started as a postdoc at the Department of Otolaryngology and Department of Nuclear Medicine & PET research of the VU University Medical Center on a project together with Philips on pretargeting with antibodies using the Staudinger ligation. After this, she continued as a postdoc in the field of immuno- PET. Since 2012, she holds a permanent position as a researcher at the same institute where she is responsible for the clinical preparation of immuno-PET products. Her research interests besides immunoPET are the development of basic radiolabeling strategies with 11 C and 18F and the application of these compounds in oncology and neurology.
Biography
he worked as an organic (radio)chemist for the Radionuclide Center of the VU University Medical Center, Amsterdam, until assuming a position at BV Cyclotron VU in 1998. His first project at BV Cyclotron VU was setting up the [18F]FDG-production facility and making it ready for commercially supplying [18F]FDG. Besides, much of his time was dedicated to improving production methods and improving the GMP-level at the company. Since 2006, he has been responsible for the general management. Biography Adriaan A. Lammertsma, PhD, is vicechair for research of the recently established Department of Radiology & Nuclear Medicine of the VU University Medical Center in Amsterdam. He has been active in PET research since 1979, when he joined the MRC Cyclotron Unit, Hammersmith Hospital, London, UK. Apart from a sabbatical year at UCLA, Los Angeles, he stayed in London until 1996, and then moved to Amsterdam. Over the years, his research focus has been the development and application of tracer kinetic models for quantitative PET studies. Initially, he worked on the oxygen-15 steady-state method for measuring regional tissue perfusion and oxygen utilization. Later, when scanners became faster, he moved to dynamic techniques and developed models for a series of novel tracers with applications in neurology, cardiology and oncology. Adriaan Lammertsma is co-author of more than 350 peer-reviewed papers with the most cited one presenting the simplified reference tissue model for PET receptor studies. In 2012, he was recipient of the Kuhl–Lassen Award, presented by the Brain Imaging Council of the Society of Nuclear Medicine, for significant contributions to the field of functional brain imaging.
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Bieneke Janssen was born in Groningen, the Netherlands, in 1987. She obtained her bachelor’s degree in chemistry in 2008 and her master’s degree in chemical sciences (master program Drug Innovation) in January 2012, both at Utrecht University. In March 2012, she started as a PhD student at the Department of Radiology and Nuclear Medicine of the VU University Medical Center in Amsterdam. Within the INMiND project, she is currently working on the synthesis and development of novel PET tracers for the visualization of microglial activation in neuroinflammation and neurodegeneration.
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Biography
U. Funke et al. Biography Lars R. Perk was born in Sneek, the Netherlands, and has been working at BV Cyclotron VU since 2008. He has been especially involved in the development of new PET tracers, together with the Department of Radiology & Nuclear Medicine at the VU University Medical Center in Amsterdam, as well as in process design, construction, and project management of pharmaceutical processes (implementation of GMP) and facilities (GMP hot-labs). Dr. Perk obtained his PhD degree in 2009, with the publication of his thesis ‘The long-lived positron emitters zirconium-89 and iodine-124 for imaging and quantification of tumor-seeking proteins and peptides by positron emission tomography’. He obtained his MSc degree in molecular sciences in 2002 at the Wageningen University, with a specialization in bio-organic chemistry.
Biography Albert D. Windhorst obtained his PhD in 1998 with Prof. Dr. H. Timmerman on the development of PET and single-photon emission computed tomography (SPECT) ligands for the histamine H3 receptor. In the same year, he started as a postdoc at the Radionuclide Center of the VU University Medical Center, Amsterdam, and in 2000, he was appointed as an assistant professor at the same institute. He currently holds a position as an associate professor in radiopharmaceutical chemistry at the VU University Medical Center, where he heads the radiopharmaceutical chemistry section of the Department of Radiology & Nuclear Medicine with in total 31 radiochemists: staff, postdocs, PhD students and research technicians. His main research interest is in the development and production of 11C and 18F radiolabeled compounds for clinical PET imaging, both research as for routine applications.
Scheme 1. Radiosynthesis of the H1R antagonist [11C]pyrilamine.
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Scheme 2. Radiosyntheses of the H1R antagonist [11C]doxepin.
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((E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1amine; Scheme 2). Both radioligands can be obtained by N-[11C]methylation of the corresponding desmethyl precursors. For [11C]pyrilamine, this was first performed in 1988, using [11C]methyl iodide and desmethylpyrilamine (Scheme 1).15,16 The radioligand was obtained 22 min after [11C]carbon dioxide production (end of bombardment, EOB), in a decay-corrected radiochemical yield (RCY) of 34%, in a radiochemical purity (RCP) >99%, and with a specific activity of 93 GBq/mmol. A semi-automated method offered more convenient conditions for reaction and formulation, and fulfilled the requirements for clinical application such as product sterility, although with a reduced RCY of [11C]pyrilamine (RCY ~20%, specific activity ~44 GBq/mmol).17 Analogous to the [11C]pyrilamine preparation, the radiosynthesis of [11C]doxepin was developed by the reaction of nordoxepin with [11C]CH3I (Scheme 2, condition A). At 18–20 min after EOB, the radioligand was obtained in 15% RCY (based on [11C]CH3I) with a specific activity of ~61 GBq/mmol.16,18 However, a minor content of precursor was observed in the product.18 To overcome the relative low radiochemical yields, attributed to the loss of volatile [11C]CH3I, an on-line method for radiomethylation of various substrates coated on a gas chromatography column was developed.19 By using this approach, the product yield could be increased to 82%. Nevertheless, this method remained uncommon for the synthesis of [11C]doxepin. Ten years later, with the progress of automated procedures, the radioligand could be synthesized in a combined loop-solid phase extraction (SPE), starting from [11C] methyl triflate (Scheme 2, condition B).20 Although the overall synthesis time increased to 40 min, an RCY of >40%, an RCP >99%, and specific activities of ~100 GBq/mmol could be achieved.21,22 Today, this is the most widely used method for [11C]doxepin preparation. However, more recently, a fully automated synthesis of [11C]doxepin starting from [11C]CH3I has been published.23 The described method with a total synthesis time of 37 min, achieving RCYs of ~47%, an RCP >97.5%, and specific activities of around 45 GBq/mmol, does not represent a radiosynthetic improvement but offers a convenient alternative for [11C]doxepin production in clinical routine. H1R binding has been extensively studied in vivo using both radioligands in mouse, beagle dog, baboon, and healthy human.15,24–33 [11C]Doxepin proved to be the more suitable ligand for PET investigations because of its lower metabolic degradation29,32 and higher contrast in brain images.25,32,34 For the quantification of H1R specific binding in the presence of nonspecific binding, compartmental models have been developed,21,35–37 also in combination with the use of an artificial neuronal network.38 Quantitative PET studies have been used successfully to correlate age with H1R densities,27,31 to show gender differences,39 and to demonstrate H1R alterations in disorders such as depression,40 schizophrenia,41,42 Alzheimer’s disease,43–45 and anorexia nervosa.22 No evidence was found for a role of H1R in attentive waking and circadian rhythm.46 Most [11C]doxepin studies were performed to investigate potential cognitive side effects of antihistamines, such as affected attention and psychomotor skills,47,48 based on their receptor occupancies (ROs).49 Various antihistamines were evaluated in blocking studies,39,50–59 also in combination with the investigation of sleepiness and cognitive performance.60–65 The results suggest a classification of antihistamines in sedative (H1R RO >50%), less sedative (RO of 20–50%), and nonsedative (RO 99% and a specific activity >95 GBq/mmol.80 A logD7.2 of 1.88, inhibition of the rat H3R with a Ki of 2.3 nM, and high selectivity of VUF 5000 over various other targets pointed to good imaging properties of the corresponding radioligand. In vivo, however, [18F]VUF 5000 showed very low brain uptake.81 The urea derivative [18F]VUF 5182 (Scheme 5, X¼O) was synthesized in a comparable way via an isocyanate building block for the amidation of the piperidine. The total synthesis time was 4 h, resulting in 12% RCY of the radioligand with an RCP >99.9%. Unfortunately, [18F]VUF 5182 also revealed low cerebral uptake.81 Another imidazole-based PET ligand investigated was [18F]fluoroproxyfan (Scheme 6). The multistep radiosynthesis started with the radiofluorination of benzaldehyde, followed by reduction with sodium borohydride, and conversion to
Scheme 3. Radiosynthesis of
18
F labeled FUB 272.
Figure 1. [11C]Nizatidine.
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Scheme 4. Radiosynthesis of [11C]UCL 1829 via S-[11C]methylation of the free thiophenol.
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Figure 2. First reported PET ligand for the H3R.
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Scheme 5. Radiosyntheses of the fluorine-18-labeled thioperamide analog H3R antagonists [18F]VUF 5000 and [18F]VUF 5182.
Scheme 6. Radiosynthesis of the H3R antagonist [18F]fluoroproxyfan.
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[18F]fluorobenzyl bromide by means of triphenylphosphine dibromide, carried out on a C-18 cartridge. Subsequently, the bromide was used for the alkylation of the imidazolylpropanol moiety in a Williamson ether synthesis. After purification of the tritylated intermediate by SPE, the protecting group was removed under acidic conditions. In less than 100 min synthesis time, [18F] fluoroproxyfan was prepared in an RCY of ~10% with a specific activity ≥150 GBq/mmol.82,83 In vivo evaluation in rats showed a heterogeneous distribution of the radioligand with the highest ratio of hypothalamus to cerebellum of 1.9 at 60 min postinjection p.i.. This uptake could be blocked by the nonradioactive compound, resulting in a reduced hypothalamus to cerebellum ratio from 1.6 to 1.0 at 30 min p.i.. Metabolic stability of [18F]fluoroproxyfan appeared to be adequate with ~94% of the brain activity representing parent compound at 30 min p.i. However, cortex-to-cerebellum ratios did not change with increased injected dose of fluoroproxyfan, indicating interaction with binding sites unrelated to H3R. This is in accordance with the results of a SPECT study using the structurally related [123I]iodoproxyfan,84 of which binding was not inhibited by pretreatment with [R]-a-methylhistamine. As non-imidazole-based H3R antagonists seemed to be more promising clinical candidates as pharmaceuticals, because of higher target selectivity and less drug–drug interactions,74,85 the pharmacophores in the development of PET ligands changed as well. The first reported non-imidazole-based radioligand was derived from the benzylmorpholine JNJ-
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10181457, which demonstrated binding affinity to human H3R with a Ki of 0.8 nM and was shown to be a highly selective H3R antagonist. Its moderate lipophilicity with a logD7.4 = 1.54 pointed to a sufficient uptake via the BBB.86 Radiosynthesis of [11C]JNJ-10181457 was carried out in a one-pot procedure, starting with the [11C]carboxylation of an in situ generated phenyllithium precursor, followed by conversion of the benzoic acid into the benzoyl chloride by means of oxalyl chloride (Scheme 7). Finally, the benzoyl chloride was reacted with morpholine and the resulting amide reduced by means of lithium aluminum hydride to obtain [11C]JNJ-10181457. Despite the five preparative steps, radiolabeling could be performed in 67 min and provided the radioligand with an RCY of ≥20%, an RCP >99%, and a specific activity ≥30 GBq/mmol.86 Uptake of [11C]JNJ-10181457 in rat brain was sufficient with up to 1.7 %ID/g in cerebral cortex and 1.4 %ID/g in hippocampus. The lowest uptake was observed in cerebellum with 0.8 %ID/g at 30 min p.i., matching H3R expression levels in the mammalian brain. Unfortunately, radioligand binding could not be inhibited significantly, neither by preadministration of nonradioactive compound nor by the H3R antagonist JNJ-5207852 (10 mg/kg, i.p.). This was not due to uptake of radiolabeled metabolites, as in brain at 30 min p.i. more than 80% of radioactivity corresponded to parent compound. Furthermore, uptake of [11C]JNJ-10181457 was also high in H3R gene knockout mice with up to 13 %ID/g in cerebral cortex, indicating a high level of nonspecific binding. Most progress in H3R imaging has been made with the benzoazepane [11C]GSK189254. The H3R antagonist GSK189254
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Scheme 7. Radiosynthesis of the H3R antagonist [11C]JNJ-10181457.
showed high affinity for human H3R with a pKi value of 9.59 and a >10,000-fold selectivity over other histamine receptor subtypes.87 There are two ways to synthesize [11C]GSK189254 (Scheme 8). The first radiochemical approach proceeded via [11C]methylation of the free amide GSK185071B with [11C]methyl iodide (Scheme 8, condition A), to yield up to 80% of the radioligand (based on [11C]CH3I) with an RCP >99% and a specific activity of ~150 GBq/mmol in a total synthesis time of 35 min.88,89 Some simplifications and shortening of the synthesis time were possible by the use of an HPLC loop method for trapping and reacting [11C]CH3I90 to gain up to 20% uncorrected RCY in a total synthesis time of 27 min.91 The second approach by means of [11C]methyl triflate (Scheme 8, condition B) resulted in a maximum RCY of 60% (based on [11C]CO2) and a specific activity of up to 740 GBq/mmol at EOB in a total synthesis time of 40 min.92 A logD7.4 of 1.7489 and a logP of 2.2492 hint to good BBB permeability of [11C]GSK189254. In porcine experiments, a high uptake in the brain was observed with 9.0 %ID/L at 20 min p.i.89 and the highest accumulation in known H3R-rich regions such as striatum and cortex. Resulting striatum and frontal cortex over cerebellum ratios were 4.7 and 2.9 at 85 min p.i., respectively.88 In humans, [11C]GSK189254 showed high metabolic stability.91 Brain uptake was rapid and heterogeneous between the brain regions (Figure 3, top), with minor washout. Highest uptake was observed in caudate, which was reduced by ~80% with 50 mg of nonlabeled GSK189254 p.o. (Figure 3, middle; 4 h prior to radioligand). The effects of slow washout could be overcome by an alternative two-tissue compartment model.91,93 Further, in baboon brain, 90% of [11C]GSK189254 binding could be blocked by the orally administered H3R antagonist JNJ-39220675.94 Altogether, the results of these studies show the clinical applicability of [11C]GSK189254 PET and suggest to include it in the pharmacological characterization of H3R antagonistic drug candidates.
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Figure 3. Representative PET images of [11C]GSK189254 uptake in a healthy human subject before (top) and 4 h after (middle) a 50-mg oral dose of GSK189254.91 Mean standardized uptake value images (0–90 min) are shown together with structural magnetic resonance image (MRI, bottom) for the same subject. Reprinted by permission of the Society of Nuclear Medicine from: Ashworth S, Rabiner EA, Gunn RN, et al. Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med. 2010; 51(7): 1021–1029. Figure 1. This figure is available in colour online at wileyonlinelibrary.com/journal/jlcr
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Scheme 8. Radiosynthesis of the highly selective H3R antagonist [11C]GSK189254 via [11C]methylation with A: [11C]methyl iodide and B: [11C]methyl triflate.
In a series of H3R inverse agonists, two spiroisobenzofuranones occurred as highly potent inhibitors: a 5-methoxy (IC50 of 0.54 nM)95 and a 5-fluoromethoxy derivative (IC 50 of 0.90 nM). 96 Based on these compounds, 5-[11C] methoxy and 5-[18F]fluorodideuteromethoxy derivatives have been synthesized and evaluated in vivo96 (here and in 97 noted as [11C]Merck 1b and [18F]Merck 2b, respectively, Scheme 9). With a logD7.4 of 2.2 for [11C]Merck 1b and of 2.1 for [18F]Merck 2b, together with low P-glycoprotein affinity, it was expected that the radioligands were able to enter the brain sufficiently. Both radioligands were synthesized by alkylation of the corresponding phenolic precursor. The radiosynthesis of [11C]Merck 1b occurred by means of [11C]methyl iodide and of [18F]Merck 2b with [18F]fluoromethyl bromide-d2. The latter was prepared by radiofluorination of dibromomethane-d2.96 [11C]Merck 1b was obtained in a non-decay-corrected RCY of 34% with an RCP of more than 98% and a specific activity ≥92 GBq/mmol, whereas the non-decay-corrected RCY was
U. Funke et al. only ~4% for [18F]Merck 2b in an RCP >98% and a specific activity ≥36 GBq/mmol. Both radioligands entered the rhesus monkey brain with highest uptake in striatum and frontal cortex and a notably slow washout. Blocking studies with quinazolinone-based H3R inverse antagonists98 caused efficient inhibition, demonstrating low levels of nonspecific binding. Therefore, both [11C]Merck 1b and [18F]Merck 2b were considered to be useful tools for imaging H3R and to determine in vivo potencies of various H3R inverse antagonists. Another non-imidazole-based radioligand was the radiofluorinated 2-aminoethylbenzofuran [18F]XB-1 (Scheme 10). This antagonist/inverse agonist inhibited human H3R with a pKi of 9.57 99 and a Ki of 1.9 nM,97 and showed a >100-fold lower affinity for other histamine receptor subtypes as well as various other receptors and transporters. The radioligand was synthesized from the nitro precursor by substitution with [18F]fluoride using microwave heating.97,100 In a total synthesis time of about 110 min, [18F]XB-1 was obtained with an RCY of ~9%, a specific activity of ~49 GBq/mmol, and an RCP >99%. PET imaging in mice revealed fast uptake of the radioligand in brain. Pretreatment with XB-1 or the nitro precursor (1.0 mg/kg intravenously, 30 min prior to [18F]XB-1 injection) increased the initial uptake and caused reduction to about 50% of the baseline uptake at 90 min p.i. The high level of nonspecific binding was confirmed by pretreatment experiments with ciproxifan (2.0 mg/kg intravenously, 30 min prior to [18F]XB-1 injection) and by results of a PET study in rhesus monkeys.97 More recently, an 18F-labeled radioligand based on the H3R antagonist ST-889 was reported. This ligand possesses high affinity for human H3R with a Ki of 0.094 nM.101 For the radiosynthesis of [18F]ST-889, the mesyl group of the corresponding precursor was substituted by [18F]fluoride within 30 min (Scheme 11). In a total synthesis time of ~100 min, the radioligand could be obtained with an RCY of 8–20%, an RCP >99%, and a specific activity ≥65 GBq/mmol.102 PET imaging in
rats demonstrated only a remarkably high and persistent glandular accumulation of the radioligand. The negligible level of cortical uptake was slightly increased by co-administered H3R antagonists and showed that [18F]ST-889 is inappropriate for the imaging of H3R in the brain.
Radioligands for the histamine H4 receptor Apart from its localization on microglia,103 H4R has been shown to be functionally expressed in cerebral cortex, cerebellum, hippocampus, thalamus and caudate putamen of the mouse, and insular cortex of the human brain.104 For imaging of H4R using PET, two 11C-labeled analogs of the highly potent and subtype-selective H4R antagonists VUF10558 (pKi = 8.35, in humans)105 and JNJ7777120106 (pKi = 8.4, in humans) were developed and investigated in vivo.107 Both radioligands were synthesized by N-[11C]methylation of the piperazinyl moiety (Scheme 12) and resulted in an RCY of 40%, an RCP >99%, and specific activities of 20–40 GBq/mmol. Whereas [11C]VUF10558 showed no uptake in the brain, [11C]JNJ7777120 passed the BBB, which shows promise for further PET studies.
Conclusion Although the only two carbon-11-labeled H1R targeting ligands showed unfavorable properties, such as high nonspecific binding, PET imaging of H1R in the human brain has been established successfully. Especially [11C]doxepin has been used effectively in the evaluation of side effects of new therapeutics, in particular antihistamines, by quantification of their H1R occupancy in the brain. This application of H1R PET clearly showed the added value of quantitative molecular imaging as a tool in drug development. The H2R could not be visualized by PET yet, neither in CNS nor in peripheral tissues. The only reported H2R-selective ligand
Scheme 11. Radiosynthesis of the H3R antagonist [18F]ST-889.
Scheme 9. Radiosynthesis of H3R affinity inverse agonists.
11
C- and
18
F-labeled spiro-isobenzofuranones, high
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Scheme 10. Microwave-assisted radiosynthesis of the H3R antagonists/inverse agonist [18F]XB-1.
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Scheme 12. Radiosyntheses of the H 4 R antagonists [ 11 C]VUF10558 and [ 11 C]JNJ7777120.
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U. Funke et al. [11C]nizatidine accumulated in the mouse brain to a small extent. In contrast, numerous efforts have resulted in some useful radioligands for neuroimaging of the H3R. Two 11C- and 18 F-labeled spiro-isobenzofuranones where discovered that could be used to specifically image H3R in the brain of rhesus monkey. These radioligands are supposed to be suitable for clinical studies. With the benzoazepane [11C] GSK189254, H3R could already be quantified in the human brain, thereby providing the first H3R PET tracer to be ready for clinical studies and drug development. PET ligands for the H4R are hitherto rather limited. One carbon-11-labeled compound, [11C]JNJ7777120, is currently under investigation in vivo. Fortunately, a growing number of high-affinity H4R compounds provide leads for potential radioligands,108,109 both for carbon-11 and fluorine-18 labeling. Combined with increased clinical interest in the H4R, e.g. caused by probable involvement in neuroinflammation103,110,111 and sensory pathways,112,113 this will encourage new H4R PET tracer developments.
Acknowledgement The compilation of this literature review has been made possible by the funding from the European Union’s Seventh Framework Program (FP7/2007-2013) under grant agreement number HEALTH-F2-2011-278850 (INMiND).
Conflict of Interest The authors did not report any conflict of interest.
References
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J. Label Compd. Radiopharm 2013, 56 120–129
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Revised 18 January 2013,
Accepted 29 January 2013
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3038
11
C-labeled and 18F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain†‡ Uta Funke,a,b* Danielle J. Vugts,b Bieneke Janssen,b Arnold Spaans,a,b Perry S. Kruijer,a Adriaan A. Lammertsma,b Lars R. Perk,a and Albert D. Windhorstb The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping and eating disorders, neurodegeneration, neuroinflammation, mood disorders, and pruritus. In the past 20 years, several ligands targeting the four different histamine receptor subtypes have been explored as potential radiotracers for positron emission tomography (PET). This contribution provides an overview of the developments of subtype-selective carbon-11-labeled and fluorine-18-labeled compounds for imaging in the brain. Using specific radioligands, the H1R expression in human brain could be examined in diseases such as schizophrenia, depression, and anorexia nervosa. In addition, the sedative effects of antihistamines could be investigated in terms of H1R occupancy. The H3R is of special interest because of its regulatory role in the release of various other neurotransmitters, and initial H3R PET imaging studies in humans have been reported. The H4R is the youngest member of the histamine receptor family and is involved in neuroinflammation and various sensory pathways. To date, two H4R-specific 11C-labeled ligands have been synthesized, and the imaging of the H4R in vivo is in the early stage. Keywords: histamine receptor; [11C]doxepin; [11C]pyrilamine; imidazole; [11C]methylation; [18F]fluoride
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Introduction
Radioligands for the histamine H1 receptor
Histamine (2-(1H-imidazol-4-yl)ethanamine) is an endogenous short-acting biogenic amine that plays a key role in various physiological processes. Apart from its peripheral functions, it acts as a neurotransmitter1,2 and regulator of cell proliferation and differentiation3 in the central nervous system (CNS). This action is exerted by binding to four specific histamine receptor subtypes, H1R, H2R, H3R, and H4R,4–6 all belonging to the superfamily of G protein-coupled receptors (GPCR). Alterations in cerebral histaminergic neurotransmission are involved in numerous pathologies of the CNS such as sleep, eating and moving disorders, dementia, epilepsy, addiction, depression, schizophrenia, pain, and neuroinflammation as well as neurodegeneration, for example in Alzheimer’s and Parkinson’s diseases.1,2,7 This has stimulated great interest in neuronal histamine receptors not only as a target for therapy5 but also for in vivo imaging and quantification, using positron emission tomography (PET). Although several former reviews have included8–10 or have even focused on histaminergic PET imaging,11–13 they are mainly limited to the imaging of the H1R. The purpose of the present review is to provide an overview of the current state in the development of PET tracers for the imaging of all histamine receptor subtypes.
In the human brain, the H1R is mainly expressed in neo-cortex, the limbic system, and hypothalamus, as shown by [3H]doxepin binding to human brain tissues.14 For in vivo imaging of the H1R, two carbon-11-labeled ligands have been reported: [11C]pyrilamine, also known as [11C]mepyramine (N1-(4-methoxybenzyl)-N2,N2-dimethylN1-(pyridin-2-yl)ethane-1,2-diamine; Scheme 1), and [11C]doxepin
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a
BV Cyclotron VU, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands
b
VU University Medical Center, Department of Radiology & Nuclear Medicine, Location Radionuclide Center, De Boelelaan 1085c, 1081 HV Amsterdam, The Netherlands *Correspondence to: Uta Funke, BV Cyclotron VU, De Boelelaan 1081, 1081 HV Amsterdam, The Netherlands. E-mail: [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 - CEA4 Place du Général Leclerc - F-91406 Orsay - France.
‡
This article was published online on 24 April 2013. Errors were subsequently identified. This notice is included in the online versions 16 August 2013 and corrected by an erratum in the next print version to indicate that the article has been corrected.
Copyright © 2013 John Wiley & Sons, Ltd.
U. Funke et al. Biography
Biography
Uta Funke was born in Leipzig, Germany, in 1978. After graduating 2005 with a German diploma, which is a master’s degree in chemistry at the Universität Leipzig, investigating the [18F]fluoro-arylation of carbonyl compounds by reductive bond formation, she obtained her PhD in 2011 with Prof. Jörg Steinbach on the development of indolylalkylamine-based
Arnold Spaans was born in Maassluis, the Netherlands, in 1978. He obtained his bachelor’s degree in organic chemistry in 2001. In 2002, he started at Altana Pharma as a preclinical research associate focusing on the development of new phosphodiesterase inhibitors for the treatment of chronic obstructive pulmonary disease. After 5 years, he became a research chemist at Mercachem BV, where he worked on various contract-based organic chemistry projects. In April 2009, he started as a radiochemist at BV Cyclotron VU and at the department of Radiology & Nuclear Medicine at the VU University Medical Center in Amsterdam. His work for BV Cyclotron VU is commercializing new 18F-labeled radiopharmaceuticals under good manufacturing practice (GMP) conditions, and within the INMiND project, he focuses on the identification of novel biological targets of neuroinflammation for both diagnostic and therapeutic purposes.
radiotracers for the serotonin transporter. In a cooperation project with the Universität Leipzig, since 2009, she worked with Prof. Peter Brust on the development of phosphodiesterase 10A selective PET ligands for the diagnosis and therapy monitoring of brain disorders. In May 2012, she started as a postdoc at the BV Cyclotron VU and the Radionuclide Center at the VU University Medical Center, Amsterdam. Within the framework of the INMiND project, her research focuses now on 11C- and 18 F-labeled radiopharmaceuticals directed against novel targets on activated microglia for diagnosis and therapy follow-up in neuroinflammation and neurodegeneration.
Perry S. Kruijer was born in Langedijk, the Netherlands. From 1985 to 1992, he obtained his (Higher Laboratory Education) HLO-certificate and a master’s degree in organic chemistry from the University of Amsterdam, both with parttime studies. From 1987 until 1991, he worked as an organic chemist for De Rover Chemie (now Katwijk Chemie). Afterward,
Biography Danielle J. Vugts was born in Tilburg, the Netherlands, in 1979. She studied organic chemistry, and after obtaining her PhD in 2006 with Prof. Dr. R.V.A. Orru at the VU University on Mureidomycine and Dihydropyrimidine Nucleosides, she started as a postdoc at the Department of Otolaryngology and Department of Nuclear Medicine & PET research of the VU University Medical Center on a project together with Philips on pretargeting with antibodies using the Staudinger ligation. After this, she continued as a postdoc in the field of immuno- PET. Since 2012, she holds a permanent position as a researcher at the same institute where she is responsible for the clinical preparation of immuno-PET products. Her research interests besides immunoPET are the development of basic radiolabeling strategies with 11 C and 18F and the application of these compounds in oncology and neurology.
Biography
he worked as an organic (radio)chemist for the Radionuclide Center of the VU University Medical Center, Amsterdam, until assuming a position at BV Cyclotron VU in 1998. His first project at BV Cyclotron VU was setting up the [18F]FDG-production facility and making it ready for commercially supplying [18F]FDG. Besides, much of his time was dedicated to improving production methods and improving the GMP-level at the company. Since 2006, he has been responsible for the general management. Biography Adriaan A. Lammertsma, PhD, is vicechair for research of the recently established Department of Radiology & Nuclear Medicine of the VU University Medical Center in Amsterdam. He has been active in PET research since 1979, when he joined the MRC Cyclotron Unit, Hammersmith Hospital, London, UK. Apart from a sabbatical year at UCLA, Los Angeles, he stayed in London until 1996, and then moved to Amsterdam. Over the years, his research focus has been the development and application of tracer kinetic models for quantitative PET studies. Initially, he worked on the oxygen-15 steady-state method for measuring regional tissue perfusion and oxygen utilization. Later, when scanners became faster, he moved to dynamic techniques and developed models for a series of novel tracers with applications in neurology, cardiology and oncology. Adriaan Lammertsma is co-author of more than 350 peer-reviewed papers with the most cited one presenting the simplified reference tissue model for PET receptor studies. In 2012, he was recipient of the Kuhl–Lassen Award, presented by the Brain Imaging Council of the Society of Nuclear Medicine, for significant contributions to the field of functional brain imaging.
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Bieneke Janssen was born in Groningen, the Netherlands, in 1987. She obtained her bachelor’s degree in chemistry in 2008 and her master’s degree in chemical sciences (master program Drug Innovation) in January 2012, both at Utrecht University. In March 2012, she started as a PhD student at the Department of Radiology and Nuclear Medicine of the VU University Medical Center in Amsterdam. Within the INMiND project, she is currently working on the synthesis and development of novel PET tracers for the visualization of microglial activation in neuroinflammation and neurodegeneration.
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Biography
U. Funke et al. Biography Lars R. Perk was born in Sneek, the Netherlands, and has been working at BV Cyclotron VU since 2008. He has been especially involved in the development of new PET tracers, together with the Department of Radiology & Nuclear Medicine at the VU University Medical Center in Amsterdam, as well as in process design, construction, and project management of pharmaceutical processes (implementation of GMP) and facilities (GMP hot-labs). Dr. Perk obtained his PhD degree in 2009, with the publication of his thesis ‘The long-lived positron emitters zirconium-89 and iodine-124 for imaging and quantification of tumor-seeking proteins and peptides by positron emission tomography’. He obtained his MSc degree in molecular sciences in 2002 at the Wageningen University, with a specialization in bio-organic chemistry.
Biography Albert D. Windhorst obtained his PhD in 1998 with Prof. Dr. H. Timmerman on the development of PET and single-photon emission computed tomography (SPECT) ligands for the histamine H3 receptor. In the same year, he started as a postdoc at the Radionuclide Center of the VU University Medical Center, Amsterdam, and in 2000, he was appointed as an assistant professor at the same institute. He currently holds a position as an associate professor in radiopharmaceutical chemistry at the VU University Medical Center, where he heads the radiopharmaceutical chemistry section of the Department of Radiology & Nuclear Medicine with in total 31 radiochemists: staff, postdocs, PhD students and research technicians. His main research interest is in the development and production of 11C and 18F radiolabeled compounds for clinical PET imaging, both research as for routine applications.
Scheme 1. Radiosynthesis of the H1R antagonist [11C]pyrilamine.
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Scheme 2. Radiosyntheses of the H1R antagonist [11C]doxepin.
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((E/Z)-3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-dimethylpropan-1amine; Scheme 2). Both radioligands can be obtained by N-[11C]methylation of the corresponding desmethyl precursors. For [11C]pyrilamine, this was first performed in 1988, using [11C]methyl iodide and desmethylpyrilamine (Scheme 1).15,16 The radioligand was obtained 22 min after [11C]carbon dioxide production (end of bombardment, EOB), in a decay-corrected radiochemical yield (RCY) of 34%, in a radiochemical purity (RCP) >99%, and with a specific activity of 93 GBq/mmol. A semi-automated method offered more convenient conditions for reaction and formulation, and fulfilled the requirements for clinical application such as product sterility, although with a reduced RCY of [11C]pyrilamine (RCY ~20%, specific activity ~44 GBq/mmol).17 Analogous to the [11C]pyrilamine preparation, the radiosynthesis of [11C]doxepin was developed by the reaction of nordoxepin with [11C]CH3I (Scheme 2, condition A). At 18–20 min after EOB, the radioligand was obtained in 15% RCY (based on [11C]CH3I) with a specific activity of ~61 GBq/mmol.16,18 However, a minor content of precursor was observed in the product.18 To overcome the relative low radiochemical yields, attributed to the loss of volatile [11C]CH3I, an on-line method for radiomethylation of various substrates coated on a gas chromatography column was developed.19 By using this approach, the product yield could be increased to 82%. Nevertheless, this method remained uncommon for the synthesis of [11C]doxepin. Ten years later, with the progress of automated procedures, the radioligand could be synthesized in a combined loop-solid phase extraction (SPE), starting from [11C] methyl triflate (Scheme 2, condition B).20 Although the overall synthesis time increased to 40 min, an RCY of >40%, an RCP >99%, and specific activities of ~100 GBq/mmol could be achieved.21,22 Today, this is the most widely used method for [11C]doxepin preparation. However, more recently, a fully automated synthesis of [11C]doxepin starting from [11C]CH3I has been published.23 The described method with a total synthesis time of 37 min, achieving RCYs of ~47%, an RCP >97.5%, and specific activities of around 45 GBq/mmol, does not represent a radiosynthetic improvement but offers a convenient alternative for [11C]doxepin production in clinical routine. H1R binding has been extensively studied in vivo using both radioligands in mouse, beagle dog, baboon, and healthy human.15,24–33 [11C]Doxepin proved to be the more suitable ligand for PET investigations because of its lower metabolic degradation29,32 and higher contrast in brain images.25,32,34 For the quantification of H1R specific binding in the presence of nonspecific binding, compartmental models have been developed,21,35–37 also in combination with the use of an artificial neuronal network.38 Quantitative PET studies have been used successfully to correlate age with H1R densities,27,31 to show gender differences,39 and to demonstrate H1R alterations in disorders such as depression,40 schizophrenia,41,42 Alzheimer’s disease,43–45 and anorexia nervosa.22 No evidence was found for a role of H1R in attentive waking and circadian rhythm.46 Most [11C]doxepin studies were performed to investigate potential cognitive side effects of antihistamines, such as affected attention and psychomotor skills,47,48 based on their receptor occupancies (ROs).49 Various antihistamines were evaluated in blocking studies,39,50–59 also in combination with the investigation of sleepiness and cognitive performance.60–65 The results suggest a classification of antihistamines in sedative (H1R RO >50%), less sedative (RO of 20–50%), and nonsedative (RO 99% and a specific activity >95 GBq/mmol.80 A logD7.2 of 1.88, inhibition of the rat H3R with a Ki of 2.3 nM, and high selectivity of VUF 5000 over various other targets pointed to good imaging properties of the corresponding radioligand. In vivo, however, [18F]VUF 5000 showed very low brain uptake.81 The urea derivative [18F]VUF 5182 (Scheme 5, X¼O) was synthesized in a comparable way via an isocyanate building block for the amidation of the piperidine. The total synthesis time was 4 h, resulting in 12% RCY of the radioligand with an RCP >99.9%. Unfortunately, [18F]VUF 5182 also revealed low cerebral uptake.81 Another imidazole-based PET ligand investigated was [18F]fluoroproxyfan (Scheme 6). The multistep radiosynthesis started with the radiofluorination of benzaldehyde, followed by reduction with sodium borohydride, and conversion to
Scheme 3. Radiosynthesis of
18
F labeled FUB 272.
Figure 1. [11C]Nizatidine.
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Scheme 4. Radiosynthesis of [11C]UCL 1829 via S-[11C]methylation of the free thiophenol.
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Figure 2. First reported PET ligand for the H3R.
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Scheme 5. Radiosyntheses of the fluorine-18-labeled thioperamide analog H3R antagonists [18F]VUF 5000 and [18F]VUF 5182.
Scheme 6. Radiosynthesis of the H3R antagonist [18F]fluoroproxyfan.
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[18F]fluorobenzyl bromide by means of triphenylphosphine dibromide, carried out on a C-18 cartridge. Subsequently, the bromide was used for the alkylation of the imidazolylpropanol moiety in a Williamson ether synthesis. After purification of the tritylated intermediate by SPE, the protecting group was removed under acidic conditions. In less than 100 min synthesis time, [18F] fluoroproxyfan was prepared in an RCY of ~10% with a specific activity ≥150 GBq/mmol.82,83 In vivo evaluation in rats showed a heterogeneous distribution of the radioligand with the highest ratio of hypothalamus to cerebellum of 1.9 at 60 min postinjection p.i.. This uptake could be blocked by the nonradioactive compound, resulting in a reduced hypothalamus to cerebellum ratio from 1.6 to 1.0 at 30 min p.i.. Metabolic stability of [18F]fluoroproxyfan appeared to be adequate with ~94% of the brain activity representing parent compound at 30 min p.i. However, cortex-to-cerebellum ratios did not change with increased injected dose of fluoroproxyfan, indicating interaction with binding sites unrelated to H3R. This is in accordance with the results of a SPECT study using the structurally related [123I]iodoproxyfan,84 of which binding was not inhibited by pretreatment with [R]-a-methylhistamine. As non-imidazole-based H3R antagonists seemed to be more promising clinical candidates as pharmaceuticals, because of higher target selectivity and less drug–drug interactions,74,85 the pharmacophores in the development of PET ligands changed as well. The first reported non-imidazole-based radioligand was derived from the benzylmorpholine JNJ-
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10181457, which demonstrated binding affinity to human H3R with a Ki of 0.8 nM and was shown to be a highly selective H3R antagonist. Its moderate lipophilicity with a logD7.4 = 1.54 pointed to a sufficient uptake via the BBB.86 Radiosynthesis of [11C]JNJ-10181457 was carried out in a one-pot procedure, starting with the [11C]carboxylation of an in situ generated phenyllithium precursor, followed by conversion of the benzoic acid into the benzoyl chloride by means of oxalyl chloride (Scheme 7). Finally, the benzoyl chloride was reacted with morpholine and the resulting amide reduced by means of lithium aluminum hydride to obtain [11C]JNJ-10181457. Despite the five preparative steps, radiolabeling could be performed in 67 min and provided the radioligand with an RCY of ≥20%, an RCP >99%, and a specific activity ≥30 GBq/mmol.86 Uptake of [11C]JNJ-10181457 in rat brain was sufficient with up to 1.7 %ID/g in cerebral cortex and 1.4 %ID/g in hippocampus. The lowest uptake was observed in cerebellum with 0.8 %ID/g at 30 min p.i., matching H3R expression levels in the mammalian brain. Unfortunately, radioligand binding could not be inhibited significantly, neither by preadministration of nonradioactive compound nor by the H3R antagonist JNJ-5207852 (10 mg/kg, i.p.). This was not due to uptake of radiolabeled metabolites, as in brain at 30 min p.i. more than 80% of radioactivity corresponded to parent compound. Furthermore, uptake of [11C]JNJ-10181457 was also high in H3R gene knockout mice with up to 13 %ID/g in cerebral cortex, indicating a high level of nonspecific binding. Most progress in H3R imaging has been made with the benzoazepane [11C]GSK189254. The H3R antagonist GSK189254
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Scheme 7. Radiosynthesis of the H3R antagonist [11C]JNJ-10181457.
showed high affinity for human H3R with a pKi value of 9.59 and a >10,000-fold selectivity over other histamine receptor subtypes.87 There are two ways to synthesize [11C]GSK189254 (Scheme 8). The first radiochemical approach proceeded via [11C]methylation of the free amide GSK185071B with [11C]methyl iodide (Scheme 8, condition A), to yield up to 80% of the radioligand (based on [11C]CH3I) with an RCP >99% and a specific activity of ~150 GBq/mmol in a total synthesis time of 35 min.88,89 Some simplifications and shortening of the synthesis time were possible by the use of an HPLC loop method for trapping and reacting [11C]CH3I90 to gain up to 20% uncorrected RCY in a total synthesis time of 27 min.91 The second approach by means of [11C]methyl triflate (Scheme 8, condition B) resulted in a maximum RCY of 60% (based on [11C]CO2) and a specific activity of up to 740 GBq/mmol at EOB in a total synthesis time of 40 min.92 A logD7.4 of 1.7489 and a logP of 2.2492 hint to good BBB permeability of [11C]GSK189254. In porcine experiments, a high uptake in the brain was observed with 9.0 %ID/L at 20 min p.i.89 and the highest accumulation in known H3R-rich regions such as striatum and cortex. Resulting striatum and frontal cortex over cerebellum ratios were 4.7 and 2.9 at 85 min p.i., respectively.88 In humans, [11C]GSK189254 showed high metabolic stability.91 Brain uptake was rapid and heterogeneous between the brain regions (Figure 3, top), with minor washout. Highest uptake was observed in caudate, which was reduced by ~80% with 50 mg of nonlabeled GSK189254 p.o. (Figure 3, middle; 4 h prior to radioligand). The effects of slow washout could be overcome by an alternative two-tissue compartment model.91,93 Further, in baboon brain, 90% of [11C]GSK189254 binding could be blocked by the orally administered H3R antagonist JNJ-39220675.94 Altogether, the results of these studies show the clinical applicability of [11C]GSK189254 PET and suggest to include it in the pharmacological characterization of H3R antagonistic drug candidates.
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Figure 3. Representative PET images of [11C]GSK189254 uptake in a healthy human subject before (top) and 4 h after (middle) a 50-mg oral dose of GSK189254.91 Mean standardized uptake value images (0–90 min) are shown together with structural magnetic resonance image (MRI, bottom) for the same subject. Reprinted by permission of the Society of Nuclear Medicine from: Ashworth S, Rabiner EA, Gunn RN, et al. Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med. 2010; 51(7): 1021–1029. Figure 1. This figure is available in colour online at wileyonlinelibrary.com/journal/jlcr
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Scheme 8. Radiosynthesis of the highly selective H3R antagonist [11C]GSK189254 via [11C]methylation with A: [11C]methyl iodide and B: [11C]methyl triflate.
In a series of H3R inverse agonists, two spiroisobenzofuranones occurred as highly potent inhibitors: a 5-methoxy (IC50 of 0.54 nM)95 and a 5-fluoromethoxy derivative (IC 50 of 0.90 nM). 96 Based on these compounds, 5-[11C] methoxy and 5-[18F]fluorodideuteromethoxy derivatives have been synthesized and evaluated in vivo96 (here and in 97 noted as [11C]Merck 1b and [18F]Merck 2b, respectively, Scheme 9). With a logD7.4 of 2.2 for [11C]Merck 1b and of 2.1 for [18F]Merck 2b, together with low P-glycoprotein affinity, it was expected that the radioligands were able to enter the brain sufficiently. Both radioligands were synthesized by alkylation of the corresponding phenolic precursor. The radiosynthesis of [11C]Merck 1b occurred by means of [11C]methyl iodide and of [18F]Merck 2b with [18F]fluoromethyl bromide-d2. The latter was prepared by radiofluorination of dibromomethane-d2.96 [11C]Merck 1b was obtained in a non-decay-corrected RCY of 34% with an RCP of more than 98% and a specific activity ≥92 GBq/mmol, whereas the non-decay-corrected RCY was
U. Funke et al. only ~4% for [18F]Merck 2b in an RCP >98% and a specific activity ≥36 GBq/mmol. Both radioligands entered the rhesus monkey brain with highest uptake in striatum and frontal cortex and a notably slow washout. Blocking studies with quinazolinone-based H3R inverse antagonists98 caused efficient inhibition, demonstrating low levels of nonspecific binding. Therefore, both [11C]Merck 1b and [18F]Merck 2b were considered to be useful tools for imaging H3R and to determine in vivo potencies of various H3R inverse antagonists. Another non-imidazole-based radioligand was the radiofluorinated 2-aminoethylbenzofuran [18F]XB-1 (Scheme 10). This antagonist/inverse agonist inhibited human H3R with a pKi of 9.57 99 and a Ki of 1.9 nM,97 and showed a >100-fold lower affinity for other histamine receptor subtypes as well as various other receptors and transporters. The radioligand was synthesized from the nitro precursor by substitution with [18F]fluoride using microwave heating.97,100 In a total synthesis time of about 110 min, [18F]XB-1 was obtained with an RCY of ~9%, a specific activity of ~49 GBq/mmol, and an RCP >99%. PET imaging in mice revealed fast uptake of the radioligand in brain. Pretreatment with XB-1 or the nitro precursor (1.0 mg/kg intravenously, 30 min prior to [18F]XB-1 injection) increased the initial uptake and caused reduction to about 50% of the baseline uptake at 90 min p.i. The high level of nonspecific binding was confirmed by pretreatment experiments with ciproxifan (2.0 mg/kg intravenously, 30 min prior to [18F]XB-1 injection) and by results of a PET study in rhesus monkeys.97 More recently, an 18F-labeled radioligand based on the H3R antagonist ST-889 was reported. This ligand possesses high affinity for human H3R with a Ki of 0.094 nM.101 For the radiosynthesis of [18F]ST-889, the mesyl group of the corresponding precursor was substituted by [18F]fluoride within 30 min (Scheme 11). In a total synthesis time of ~100 min, the radioligand could be obtained with an RCY of 8–20%, an RCP >99%, and a specific activity ≥65 GBq/mmol.102 PET imaging in
rats demonstrated only a remarkably high and persistent glandular accumulation of the radioligand. The negligible level of cortical uptake was slightly increased by co-administered H3R antagonists and showed that [18F]ST-889 is inappropriate for the imaging of H3R in the brain.
Radioligands for the histamine H4 receptor Apart from its localization on microglia,103 H4R has been shown to be functionally expressed in cerebral cortex, cerebellum, hippocampus, thalamus and caudate putamen of the mouse, and insular cortex of the human brain.104 For imaging of H4R using PET, two 11C-labeled analogs of the highly potent and subtype-selective H4R antagonists VUF10558 (pKi = 8.35, in humans)105 and JNJ7777120106 (pKi = 8.4, in humans) were developed and investigated in vivo.107 Both radioligands were synthesized by N-[11C]methylation of the piperazinyl moiety (Scheme 12) and resulted in an RCY of 40%, an RCP >99%, and specific activities of 20–40 GBq/mmol. Whereas [11C]VUF10558 showed no uptake in the brain, [11C]JNJ7777120 passed the BBB, which shows promise for further PET studies.
Conclusion Although the only two carbon-11-labeled H1R targeting ligands showed unfavorable properties, such as high nonspecific binding, PET imaging of H1R in the human brain has been established successfully. Especially [11C]doxepin has been used effectively in the evaluation of side effects of new therapeutics, in particular antihistamines, by quantification of their H1R occupancy in the brain. This application of H1R PET clearly showed the added value of quantitative molecular imaging as a tool in drug development. The H2R could not be visualized by PET yet, neither in CNS nor in peripheral tissues. The only reported H2R-selective ligand
Scheme 11. Radiosynthesis of the H3R antagonist [18F]ST-889.
Scheme 9. Radiosynthesis of H3R affinity inverse agonists.
11
C- and
18
F-labeled spiro-isobenzofuranones, high
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Scheme 10. Microwave-assisted radiosynthesis of the H3R antagonists/inverse agonist [18F]XB-1.
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Scheme 12. Radiosyntheses of the H 4 R antagonists [ 11 C]VUF10558 and [ 11 C]JNJ7777120.
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U. Funke et al. [11C]nizatidine accumulated in the mouse brain to a small extent. In contrast, numerous efforts have resulted in some useful radioligands for neuroimaging of the H3R. Two 11C- and 18 F-labeled spiro-isobenzofuranones where discovered that could be used to specifically image H3R in the brain of rhesus monkey. These radioligands are supposed to be suitable for clinical studies. With the benzoazepane [11C] GSK189254, H3R could already be quantified in the human brain, thereby providing the first H3R PET tracer to be ready for clinical studies and drug development. PET ligands for the H4R are hitherto rather limited. One carbon-11-labeled compound, [11C]JNJ7777120, is currently under investigation in vivo. Fortunately, a growing number of high-affinity H4R compounds provide leads for potential radioligands,108,109 both for carbon-11 and fluorine-18 labeling. Combined with increased clinical interest in the H4R, e.g. caused by probable involvement in neuroinflammation103,110,111 and sensory pathways,112,113 this will encourage new H4R PET tracer developments.
Acknowledgement The compilation of this literature review has been made possible by the funding from the European Union’s Seventh Framework Program (FP7/2007-2013) under grant agreement number HEALTH-F2-2011-278850 (INMiND).
Conflict of Interest The authors did not report any conflict of interest.
References
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