5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice

Gao, Yongjun; Ravert, Hayden T.; Valentine, Heather; Scheffel, Ursula; Finley, Paige; Wong, Dean F.; Dannals, Robert F.; Horti, Andrew G.

doi:10.1016/j.bmc.2012.04.056

Cited by 8 publications

(7 citation statements)

References 21 publications

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“…Over the past decade, considerable effort has been expended toward the development of α7-nAChR ligands and more than 20 compounds have been radiolabeled for PET and SPECT, but previous efforts by several research groups (see for review (9–11)), including our own (12–14), to develop a clinically viable α7-nAChR tracer for PET or SPECT have proved unsuccessful. None of these radioligands manifested sufficiently high specific binding at α7-nAChRs in vivo.…”

Section: Introductionmentioning

confidence: 99%

¹⁸F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

Horti¹,

Gao²,

Kuwabara³

et al. 2014

J Nucl Med

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The α7-nicotinic cholinergic receptor (α7-nAChR) is a key mediator of brain communication and has been implicated in a wide variety of central nervous system disorders. None of the currently available PET radioligands for α7-nAChR are suitable for quantitative PET imaging, mostly due to insufficient specific binding. The goal of this study was to evaluate the potential of [18F]ASEM ([18F]JHU82132) as an α7-nAChR radioligand for PET. Methods Inhibition binding assay and receptor functional properties of ASEM were assessed in vitro. The brain regional distribution of [18F]ASEM in baseline and blockade were evaluated in DISC1 mice (dissection) and baboons (PET). Results ASEM is an antagonist for the α7-nAChR with high binding affinity (Ki = 0.3 nM). [18F]ASEM readily entered the baboon brain and specifically labeled α7-nAChR. The in vivo specific binding of [18F]ASEM in the brain regions enriched with α7-nAChRs was 80–90%. SSR180711, an α7-nAChR selective partial agonist, blocked [18F]ASEM binding in the baboon brain in a dose-dependent manner, suggesting that the binding of [18F]ASEM was mediated by α7-nAChRs and the radioligand was suitable for drug evaluation studies. In the baboon baseline studies, the brain regional volume of distribution (VT) values for [18F]ASEM were 23 (thalamus), 22 (insula), 18 (hippocampus) and 14 (cerebellum), whereas in the binding selectivity (blockade) scan, all regional VT values were reduced to less than 4. The range of regional binding potential (BPND) values in the baboon brain was from 3.9 to 6.6. In vivo cerebral binding of [18F]ASEM and α7-nAChR expression in mutant DISC1 mice, a rodent model of schizophrenia, was significantly lower than in control animals, which is in agreement with previous post-mortem human data. Conclusion [18F]ASEM holds promise as a radiotracer with suitable imaging properties for quantification of α7-nAChR in the human brain.

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Section: Introductionmentioning

confidence: 99%

¹⁸F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

Horti¹,

Gao²,

Kuwabara³

et al. 2014

J Nucl Med

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“…Gamma counters are also widely used in conjunction with positron emission tomography (PET), typically in the research setting. PET applications include metabolite analysis [ 3 ], tracer kinetic studies [ 4 ], and pre-clinical biodistribution studies [ 5 ]. While quantitative accuracy is important in any setting, PET applications typically have slightly different quantitative requirements than clinical in vitro studies.…”

Section: Introductionmentioning

confidence: 99%

Performance assessment of a NaI(Tl) gamma counter for PET applications with methods for improved quantitative accuracy and greater standardization

et al. 2015

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Background Although NaI(Tl) gamma counters play an important role in many quantitative positron emission tomography (PET) protocols, their calibration for positron-emitting samples has not been standardized across imaging sites. In this study, we characterized the operational range of a gamma counter specifically for positron-emitting radionuclides, and we assessed the role of traceable 68Ge/68Ga sources for standardizing system calibration. Methods A NaI(Tl) gamma counter was characterized with respect to count rate performance, adequacy of detector shielding, system stability, and sample volume effects using positron-emitting radionuclides (409- to 613-keV energy window). System efficiency was measured using 18F and compared with corresponding data obtained using a long-lived 68Ge/68Ga source that was implicitly traceable to a national standard. Results One percent count loss was measured at 450 × 103 counts per minute. Penetration of the detector shielding by 511-keV photons gave rise to a negligible background count rate. System stability tests showed a coefficient of variation of 0.13% over 100 days. For a sample volume of 4 mL, the efficiencies relative to those at 0.1 mL were 0.96, 0.94, 0.91, 0.78, and 0.72 for 11C, 18F, 125I, 99mTc, and 51Cr, respectively. The efficiency of a traceable 68Ge/68Ga source was 30.1% ± 0.07% and was found to be in close agreement with the efficiency for 18F after consideration of the different positron fractions. Conclusions Long-lived 68Ge/68Ga reference sources, implicitly traceable to a national metrology institute, can aid standardization of gamma counter calibration for 18F. A characteristic feature of positron emitters meant that accurate calibration could be maintained over a wide range of sample volumes by using a narrow energy window centered on the 511-keV peak.

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“…65 Another α7 nAChR radioligand, 5-(5-(6-[ 11 C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole ( Figure 2 , compound l; [ 11 C]rac-(1)) was also recently developed by the same group. 71 The compound showed promising initial selectivity for the α7 receptor subtype in an ex vivo biodistribution study in rodents. Horti et al .…”

Section: Nicotinic Acetylcholine Receptormentioning

confidence: 95%

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

Kassenbrock¹,

Vasdev²,

Liang

2016

CTMC

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Positron emission tomography (PET) neuroimaging of ion channel linked receptors is a developing area of preclinical and clinical research. The present review focuses on recent advances with radiochemistry, preclinical and clinical PET imaging studies of three receptors that are actively pursued in neuropsychiatric drug discovery: namely the γ-aminobutyric acid-benzodiazapine (GABA) receptor, nicotinic acetylcholine receptor (nAChR), and N-methyl-d-aspartate (NMDA) receptor. Recent efforts to develop new PET radioligands for these targets with improved brain uptake, selectivity, stability and pharmacokinetics are highlighted.

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5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice

Cited by 8 publications

References 21 publications

¹⁸F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

¹⁸F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

Performance assessment of a NaI(Tl) gamma counter for PET applications with methods for improved quantitative accuracy and greater standardization

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

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5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice

Cited by 8 publications

References 21 publications

18F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

18F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

Performance assessment of a NaI(Tl) gamma counter for PET applications with methods for improved quantitative accuracy and greater standardization

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

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¹⁸F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET

¹⁸F-ASEM, a Radiolabeled Antagonist for Imaging the α7-Nicotinic Acetylcholine Receptor with PET