Characterization of bromine-76-labelled 5-bromo-6-nitroquipazine for PET studies of the serotonin transporter

Lundkvist, Camilla; Loc’h, Christian; Halldin, Christer; Bottlaender, Michel; Ottaviani, M.; Coulon, Christine; Fuseau, Chantal; Mathis, Chester A.; Farde, Lars; Mazièré, B.

doi:10.1016/s0969-8051(99)00019-0

Cited by 23 publications

(9 citation statements)

References 21 publications

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“…The ratio between specific and nonspecific binding is only 1.3-1.7:1, depending on the brain region. [ 76 Br]5-bromo-6-nitroquipazine has high affinity for SERT and is displaceable with citalopram [69]. It reaches equilibrium very slowly, but the long half-life of 76 Br (16.2 h) enables imaging even one day after administration.…”

Section: Serotonin Transportermentioning

confidence: 99%

PET Studies of Brain Monoamine Transporters

Laakso

Hietala²

2000

CPD

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Monoamine transporters are proteins mainly located on nerve terminals of dopaminergic, noradrenergic and serotonergic neurons. They are members of a larger sodium dependent transporter family and represent a major mechanism terminating the action of released neurotransmitter in the synaptic cleft. In addition to being important target molecules for many antidepressive drugs and substances of abuse, transporter proteins are good markers for the integrity of monoaminergic innervation. Therefore, there is a growing interest for in vivo imaging studies using positron emission tomography (PET) or single photon emission computed tomography (SPECT) and ligands selective for monoamine transporters. In this review, the use of monoamine transporter ligands (or tracers) for imaging studies of cocaine dependence, neurodegenerative diseases and mechanism of antidepressant drug action is discussed, with special focus on the use of PET for evaluating possible new pharmacological innovations.

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Section: Serotonin Transportermentioning

confidence: 99%

PET Studies of Brain Monoamine Transporters

Laakso

Hietala²

2000

CPD

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“…The quipazines, and especially the radiohalogenated analogs of 6-nitroquipazine, is a third chemical family explored for imaging of 5-HTT (Mathis et al, 1994). However, [ 11 C]5-methyl-6-nitroquipazine (Sandell et al, 2002), [ 123 I]5-iodo-6-nitroquipazine, and [ 76 Br]5-bromo-6-nitroquipazine (Jagust et al, 1993;Lundkvist et al, 1999) all have too high nonspecific binding and too slow binding kinetics in order to be optimal.…”

Section: Introductionmentioning

confidence: 99%

[11C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET

Halldin

Lundberg

Sóvágó

et al. 2005

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The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.

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“…High SERT density is observed at the level of the midbrain nuclei, reflecting the presence of SERT on both the 5-HT cell body (raphe nuclei) and on terminals of the dense 5-HT innervation of the adjacent structures (substantia nigra, nucleus interpeduncularis, locus ceruleus, nucleus nervi Br]5-bromo-6-nitroquipazine have been evaluated as potential PET or SPECT radiotracers and found to be unsuitable due to high lipophilicity and/or high nonspecific binding (Hashimoto et al, 1987;Lasne et al, 1989;Dannals et al, 1990;Hume et al, 1991;Nelson et al, 1991;Livni et al, 1994;Scheffel et al, 1994;Jagust et al, 1996;Bergstrom et al, 1997;Smith et al, 1997;Zea-Ponce et al, 1997;Lundkvist et al, 1999).…”

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Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [¹¹C]McN 5652, [¹¹C]ADAM, [¹¹C]DASB, [¹¹C]DAPA, and [¹¹C]AFM

Huang

Hwang

Narendran

et al. 2002

J Cereb Blood Flow Metab

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The recent introduction of a number of new radiotracers suitable for imaging the serotonin transporters (SERT) has radically changed the field of SERT imaging. Whereas, until recently, only one selective SERT radiotracer was available ([11C]McN 5652) for SERT imaging with positron emission tomography (PET), several new C-11-labeled radiotracers of the N,N-dimethyl-2-(arylthio)benzylamine class have been described as appropriate imaging agents for the SERT. The aim of this study was to conduct a comparative evaluation of four of the most promising agents in this class ([11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM) with the reference tracer [11C]McN 5652 under standardized experimental conditions. This evaluation included in vitro measurements of affinity and lipophilicity, and in vivo PET imaging experiments in baboons. In vitro, DASB displayed significantly lower affinity for SERT than the other four tracers. In the blood, [11C]DASB and [11C]AFM display faster clearance and higher free fractions. Brain uptake was analyzed with kinetic modeling using a one-tissue compartment model and the metabolite-corrected arterial input function. The kinetic uptake of [11C]DASB was significantly faster compared with the other compounds, and the scan duration required to derive time-independent estimates of regional distribution volumes was shorter. [11C]DAPA exhibited the slowest brain kinetic. Regional-specific-to-nonspecific equilibrium partition coefficient (V3“) was the highest for [11C]AFM, followed by [11C]DASB and [11C]DAPA, which in turn provided higher V3” values than [11C]ADAM and [11C]McN 5652. From these experiments, two ligands emerged as superior radiotracers that provide a significant improvement over [11C]McN 5652 for PET imaging of SERT: [11C]DASB, because it enables the measurement of SERT availability in a shorter scanning time, and [11C]AFM, because its higher signal-to-noise ratios provide a more reliable measurement of SERT availability in brain regions with relatively low density of SERT, such as in the limbic system.

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Characterization of bromine-76-labelled 5-bromo-6-nitroquipazine for PET studies of the serotonin transporter

Cited by 23 publications

References 21 publications

PET Studies of Brain Monoamine Transporters

PET Studies of Brain Monoamine Transporters

[11C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET

Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [¹¹C]McN 5652, [¹¹C]ADAM, [¹¹C]DASB, [¹¹C]DAPA, and [¹¹C]AFM

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Characterization of bromine-76-labelled 5-bromo-6-nitroquipazine for PET studies of the serotonin transporter

Cited by 23 publications

References 21 publications

PET Studies of Brain Monoamine Transporters

PET Studies of Brain Monoamine Transporters

[11C]MADAM, a new serotonin transporter radioligand characterized in the monkey brain by PET

Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM

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Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [¹¹C]McN 5652, [¹¹C]ADAM, [¹¹C]DASB, [¹¹C]DAPA, and [¹¹C]AFM