Radiofluorinated histamine H3 receptor antagonist as a potential probe for in vivo PET imaging: Radiosynthesis and pharmacological evaluation (original) (raw)
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Journal of Medicinal Chemistry, 2012
A known chemotype of H 3 receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H 3) receptors in vivo with positron emission tomography (PET), namely non-imidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)methanone (9). Compound 9 was labeled with fluorine-18 (t 1/2 = 109.7 min) in high specific activity by treating the prepared nitro analog (12) with cyclotron-produced [ 18 F]fluoride ion. [ 18 F]9 was studied with PET in mouse and in monkey after intravenous injection. [ 18 F]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H 3 receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H 3 receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands.
Journal of Nuclear …, 2009
The histamine H(3) receptor is a G-protein-coupled presynaptic auto- and heteroreceptor whose activation leads to a decrease in the release of several neurotransmitters including histamine, acetycholine, noradrenaline, and dopamine. H(3) receptor antagonists such as 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) can increase the release of these neurotransmitters and thus may offer potential therapeutic benefits in diseases characterized by disturbances of neurotransmission. The aim of this study was to synthesize and evaluate (11)C-labeled GSK189254 ((11)C-GSK189254) for imaging the histamine H(3) receptor in vivo by PET. GSK189254 exhibits high affinity (0.26 nM) and selectivity for the human histamine H(3) receptor. Autoradiography experiments were performed using (3)H-GSK189254 to evaluate its in vitro binding in porcine brain tissues. GSK189254 was labeled by N-alkylation using (11)C-methyl iodide in good y...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
The histamine 3 (H3) receptor is a presynaptic autoreceptor in the central nervous system that regulates the synthesis and release of histamine and modulates the release of other major neurotransmitters. H3 receptor inverse agonists (IAs) may be efficacious in the treatment of various central nervous system disorders, including excessive daytime sleepiness, attention deficit hyperactivity disorder, Alzheimer disease, ethanol addiction, and obesity. Using PET and a novel high-affinity and selective radioligand (11)C-MK-8278, we studied the tracer biodistribution, quantification, and brain H3 receptor occupancy (RO) of MK-0249 and MK-3134, 2 potential IA drugs targeting cerebral H3 receptors, in 6 healthy male subjects (age, 19-40 y). The relationship among H3 IA dose, time on target, and peripheral pharmacokinetics was further investigated in 15 healthy male volunteers (age, 18-40 y) with up to 3 PET scans and 3 subjects per dose level. The mean effective dose for (11)C-MK-8278 was 5...
Bioorganic & Medicinal Chemistry Letters, 2012
a b s t r a c t GSK189254 and its corresponding precursor GSK185071B were synthesized from 3-methoxyphenylacetic acid with 6-chloropyridine-3-carbolic acid or 6-chloronicotinamide in 8 and 7 steps with either 6% or 7% and either 14% or 16% yield, respectively. [ 11 C]GSK189254 was prepared from GSK185071B with [ 11 C]CH 3 OTf through N-[ 11 C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 50-60% radiochemical yield based on [ 11 C]CO 2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/lmol specific activity at EOB.
[ 18 F]F15599, a novel 5-HT 1A receptor agonist, as a radioligand for PET neuroim
Eur J Nucl Med Mol Imaging, 2010
Purpose The serotonin-1A (5-HT 1A ) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT 1A receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high-and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT 1A receptors. Since all clinical PET 5-HT 1A radiopharmaceuticals are antagonists, it is of great interest to develop a 18 F labelled agonist. Methods F15599 (3-chloro-4-fluorophenyl-(4-fluoro-4{[(5methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1yl)-methanone) is a novel ligand with high affinity and selectivity for 5-HT 1A receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT 1A recep-tors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [ 18 F]MPPF, a validated 5-HT 1A antagonist radiopharmaceutical. Results The chemical and radiochemical purities of [ 18 F] F15599 were >98%. In vitro [ 18 F]F15599 binding was consistent with the known 5-HT 1A receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [ 18 F]F15599 binding, consistent with a specific binding to G proteincoupled receptors. In vitro binding of [ 18 F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT 1A antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain radioactive metabolites. Remarkably, in microPET studies, [ 18 F]F15599 notably displayed a pattern of brain labelling that did not correlate with in vitro observations. Thus, in cat, the highest binding was observed in dorsal raphe and cingulate cortex with little binding in other cortical regions and none in hippocampus. In vivo binding was abolished by WAY100635, indicating specific labelling of 5-HT 1A
[18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging
European Journal of Nuclear Medicine and Molecular Imaging, 2010
The serotonin-1A (5-HT(1A)) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT(1A) receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT(1A) receptors. Since all clinical PET 5-HT(1A) radiopharmaceuticals are antagonists, it is of great interest to develop a( 18)F labelled agonist. F15599 (3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone) is a novel ligand with high affinity and selectivity for 5-HT(1A) receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT(1A) receptors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [(18)F]MPPF, a validated 5-HT(1A) antagonist radiopharmaceutical. The chemical and radiochemical purities of [(18)F]F15599 were >98%. In vitro [(18)F]F15599 binding was consistent with the known 5-HT(1A) receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [(18)F]F15599 binding, consistent with a specific binding to G protein-coupled receptors. In vitro binding of [(18)F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT(1A) antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain radioactive metabolites. Remarkably, in microPET studies, [(18)F]F15599 notably displayed a pattern of brain labelling that did not correlate with in vitro observations. Thus, in cat, the highest binding was observed in dorsal raphe and cingulate cortex with little binding in other cortical regions and none in hippocampus. In vivo binding was abolished by WAY100635, indicating specific labelling of 5-HT(1A) receptors. [(18)F]F15599 is a radiofluorinated agonist presenting interesting characteristics for probing in vitro and in vivo the high-affinity states of the 5-HT(1A) receptors. Its differential labelling of 5-HT(1A) receptors in vitro and in vivo may result from its reported preferential interaction with receptors coupled to specific G-protein subtypes.
Nuclear Medicine and Biology, 1999
We have synthesized three 123 I-labeled histamine H 3 receptor ligands, i.e., [ 123 I]GR 190028, [ 123 I]FUB 271, and [ 123 I]iodoproxyfan, in moderate to good radiochemical yields via a Cu ؉ -assisted I-for-123 I exchange method. Biodistribution in the rat of these compounds revealed high hepatic and pulmonary uptake. Brain uptake was moderate, but for [ 123 I]iodoproxyfan, brain uptake was high enough for a pilot single photon emission computed tomography (SPECT) study in the rabbit.