Research articleRadiosynthesis and biodistribution of a histamine H3 receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[11C]benzyl]-morpholine: evaluation of a potential PET ligand
Introduction
Histamine acts as a neurotransmitter in the central nervous system (CNS), regulating its own release and synthesis via a G-protein-coupled H3 autoreceptor [1], [2], [3], [4]. The H3 receptor also acts as a heteroreceptor, regulating the release of several other neurotransmitters, including dopamine [5], serotonin [6], noradrenaline [7], [8], glutamate [9], GABA and acetylcholine [10], [11]. In the mammalian brain, the highest H3 receptor densities have been found in the cerebral cortex, nucleus accumbens, striatum, olfactory bulb, substantia nigra and tuberomamillary nucleus [12], [13], [14]. Since the cloning of the H3 receptor [15], several H3 receptor isoforms have been discovered, displaying distinct regional CNS distribution and showing some differences in pharmacology and signaling [16], [17], [18], [19]. In addition, H3 receptors have shown significant differences in pharmacology between species [20], [21].
The abundance and localization of H3 receptors in the brain suggest that they may play a role in integrative nervous system functions and behaviors, such as in arousal mechanisms, regulation of food intake, and cognition and memory processes [22], [23], [24]. Thus, H3 receptor antagonists may have therapeutic potential in the treatment of sleep disorders and obesity [25], [26], and attention deficit hyperactivity disorder and Alzheimer's disease [27], [28].
Positron emission tomography (PET) is a noninvasive imaging method that can be used for studying CNS disorders [29], [30]. To further study the role of H3 receptors in the CNS and to evaluate the H3 receptor occupancy of potent H3-receptor-binding pharmaceuticals, a suitable H3 receptor PET radioligand would be highly beneficial [31], [32], [33]. Although a large number of selective H3 compounds have been discovered, no ligand suitable for PET imaging has been reported [34], [35], [36], [37], [38].
In selecting a proper H3 PET ligand, we considered the following requirements for the selection of our target compound: high selectivity and affinity for H3 receptor with fast on and off kinetics to the receptor and low nonspecific binding to tissues. In addition, the ligand should be sufficiently lipophilic to penetrate the blood–brain barrier, and it should be possible to rapidly synthesize it with high specific radioactivity [39]. 4-[3-(4-Piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine [JNJ-10181457 (1)] is an H3 receptor antagonist, which has high selectivity and nanomolar affinity for its target, and has a benzylic carbon available for labeling (Fig. 1). In this paper, we report the radiosynthesis of [11C]1 and the evaluation of its potential as a radioligand for H3 receptor PET imaging.
Section snippets
Materials
1-[4-(3-Bromophenyl)-but-3-ynyl]-piperidine (3) was synthesized at Johnson & Johnson Pharmaceutical Research and Development LLC (San Diego, CA; unpublished data). All reagents used for radiosynthesis were purchased from Aldrich Chemicals. Anhydrous tetrahydrofuran was prepared by distillation over LiAlH4. High-performance liquid chromatography (HPLC) solvents were purchased from J.T. Baker (HPLC grade). 11CO2 was produced in an IBA 18/9 Cyclone cyclotron [40].
The semipreparative HPLC system
Radiosynthesis
Labeled compound [11C]1 was prepared from the starting material Compound (3) via a five-step synthesis route (Scheme 1), starting with Br–Li exchange reaction and carboxylation with 11CO2, followed by quenching with HCl [45]. Acid (3-(4-(piperidin-1-yl)but-1-ynyl)benzoic acid, 5) was treated with oxalyl chloride, after which the reaction mixture was evaporated to dryness. Amide (morpholine(3-(4-(piperidin-l-yl)but-l-ynyl)phenyl)methanone, 7) was prepared by adding morpholine to the residue,
Discussion
[11C]1 was prepared in a one-pot synthetic procedure in 28±8% (decay-corrected) yield, affording 1543±394 MBq of formulated product at the end of synthesis with high specific radioactivity (56±26 GBq/μmol), within a total synthesis time of 67±4 min.
The brain uptake of [11C]1 was evaluated in vitro, through autoradiography of coronal rat brain sections, and in vivo, through biodistribution studies in rats, Balb/c mice and C57BL/6-H3(−/−) mice. Two different H3 receptor antagonists, Compound (2)
Acknowledgments
We thank Dr. Eva de Rijke for mass spectral measurements, Dr. X. Langlois for preparing the brain sections for autoradiography and Ms. Marijke Stigter-van Walsum for her invaluable assistance in mice studies. We also thank Peter van Leuffen and the operators of BV Cyclotron VU for providing [11C]CO2.
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Current address: Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, S-17176 Stockholm, Sweden.