Human brain imaging post-mortem - whole hemisphere technologies

Hall, Håkan; Hurd, Yasmin L.; Pauli, Stefan; Halldin, Christer; Sedvall, Göran

doi:10.1080/09540260020024141

Cited by 12 publications

(9 citation statements)

References 26 publications

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“…The sectioning of the brains and the autoradiography experiments were performed at the Department of Clinical Neuroscience, Karolinska Institutet. The cryosectioning took place on a Leica cryomacrocut system (San Marcos, CA, USA) [28,29]. Horizontal sections (100 μm thick, containing cerebral cortex, white matter, cerebellum, and pons) and coronal sections (100 μm thick, containing cerebral cortex, white matter, putamen, and caudate nucleus) were used.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

et al. 2012

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BackgroundDysfunction of the glycine transporter 1 (GlyT1) has been suggested to be involved in psychiatric disorders such as schizophrenia. GlyT1 inhibitors have therefore been considered to have antipsychotic therapeutic potential. Positron emission tomography (PET) imaging probes for GlyT1 are, consequently, expected to be useful for investigating the mechanism of such disease conditions and for measuring occupancy of GlyT1 inhibitors in vivo. The aim of this study was to assess the potential of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl] 3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET imaging agent for GlyT1.Methods[11 C]N-methyl-SSR504734 was synthesized by N-[11 C]methylation of SSR504734 via [11 C]CH3OTf. In vitro brain distribution of [11 C]N-methyl-SSR504734 was tested in whole-hemisphere autoradiography (ARG) on human brain slices. Initial PET studies were performed using a cynomolgus monkey at baseline and after pretreatment with 0.1 to 1.5 mg/kg of SSR504734. Then, PET studies using rhesus monkeys were performed with arterial blood sampling at baseline and after pretreatment with 1.5 to 4.5 mg/kg SSR504734. Distribution volumes (VT) were calculated with a two-tissue compartment model, and GlyT1 occupancy by SSR504734 was estimated using a Lassen plot approach.Results[11 C]N-methyl-SSR504734 was successfully synthesized in moderate radiochemical yield and high specific radioactivity. In the ARG experiments, [11 C]N-methyl-SSR504734 showed specific binding in the white matter and pons. In the initial PET experiments in a cynomolgus monkey, [11 C]N-methyl-SSR504734 showed high brain uptake and consistent distribution with previously reported GlyT1 expression in vivo (thalamus, brainstem > cerebellum > cortical regions). However, the brain uptake increased after pretreatment with SSR504734. Further PET studies in rhesus monkeys showed a similar increase of brain uptake after pretreatment with SSR504734. However, the VT of [11 C]N-methyl-SSR504734 was found to decrease after pretreatment of SSR504734 in a dose-dependent manner. GlyT1 occupancy was calculated to be 45% and 73% at 1.5 and 4.5 mg/kg of SSR504734, respectively.Conclusions[11 C]N-methyl-SSR504734 is demonstrated to be a promising PET radioligand for GlyT1 in nonhuman primates. The present results warrant further PET studies in human subjects.

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Section: Methodsmentioning

confidence: 99%

Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

et al. 2012

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“…Tissue was obtained from six male subjects with no documented history of neurological or psychiatric disorders (age 32–70 years, mean 51 years, postmortem time 5–48 h, mean 21 h, storage time in brain bank 2.5–20 years, mean 9 years). Whole hemispheres were removed, frozen and cryosectioned as described earlier (Hall et al ., 1994, 1998, 2001) using a heavy‐duty cryomicrotome (Leica Cryomacrocut CM3600, Leica, Nussloch, Germany). Briefly, 100‐µm‐thick horizontal cryosections were cut parallel to the Talairach anterior commissure–posterior commissure plane (Talairach & Tournoux, 1988).…”

Section: Methodsmentioning

confidence: 99%

Autoradiographic mapping of dopamine‐D₂/D₃ receptor stimulated [³⁵S]GTPγS binding in the human brain

Sóvágó

Makkai

Gulyás

et al. 2005

Eur J of Neuroscience

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Agonist stimulated [35S]guanosine 5'-gamma-thiotriphosphate ([35S]GTPgammaS) binding autoradiography was established for the examination of dopamine-D2/D2 receptors in human brain sections. The distribution of G proteins activated by dopamine-D2/D3 receptors was studied in whole hemisphere cryosections. Dopamine stimulated [35S]GTPgammaS binding in brain regions with high densities of dopamine D2-like receptors, i.e. putamen (23 +/- 2%, mean +/- SEM,% stimulation over basal binding), caudate (20 +/- 0%) and substantia nigra (22 +/- 2%), but also in regions with lower receptor densities such as amygdala (17 +/- 8%), hippocampus (16 +/- 6%), anterior cingulate (13 +/- 3%), and thalamus (12 +/- 2%). Dopamine stimulated [35S]GTPgammaS binding to significantly higher levels in the dorsal than in the ventral part of the striatum. Dopamine caused low or very low stimulation in all cortical areas. Raclopride, a selective D2/D3 receptor antagonist, potently inhibited dopamine stimulated [35S]GTPgammaS binding, whereas R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390), a selective D1 antagonist, did not block the [35S]GTPgammaS binding response stimulated by dopamine. Hence, the stimulatory effect of dopamine was primarily mediated by D2/D3 receptors. Quinpirole stimulated [35S]GTPgammaS binding in the same regions as dopamine. The maximal level of stimulation induced by dopamine and quinpirole was not significantly different. The present study demonstrates that agonist stimulated [35S]GTPgammaS binding autoradiography could be a suitable technique for the examination of dopamine-D2/D3 receptors in the human brain. This functional assay could provide useful new information about dopamine receptor/G protein coupling in the postmortem human brain, and reveal possible disease related alterations of the interaction between D2/D3 receptors and G proteins.

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“…The human brain used was obtained from clinical autopsy at the National Institute of Forensic Medicine (Karolinska Institutet, Stockholm, Sweden) and handled as previously described (Hall et al, 1998(Hall et al, , 2001). The study was approved by the Ethics Committee at Karolinska Institutet and the Swedish Board of Social Welfare.…”

Section: In Vitro Autoradiographic Studies On Human Post-mortem Brainmentioning

confidence: 99%

“…The study was approved by the Ethics Committee at Karolinska Institutet and the Swedish Board of Social Welfare. Cryosectioning on whole hemisphere sections was performed as previously described (Hall et al, 1998(Hall et al, , 2001). Experiments were performed on 100-m horizontal sections.…”

Section: In Vitro Autoradiographic Studies On Human Post-mortem Brainmentioning

confidence: 99%

Pharmacological Characterization of (E)-N-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter

Chalon¹,

Hall²,

Saba³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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In the aim to develop an efficient fluorinated probe for positron emission tomography (PET) exploration of the dopamine transporter (DAT), we studied several in vitro and in vivo characteristics of the phenyltropane derivative (E)-N-(4-fluorobut-2-enyl)-2␤-carbomethoxy-3␤-(4Ј-tolyl)nortropane (LBT-999). In vitro on rat striatal membrane, [3 H]LBT-999 bound to a single site with a K d of 9 nM, B max of 17 pmol/mg protein, and a very high selectivity for the DAT [IC 50 for 1-{2-[bis-(4-fluorophenyl)-methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909) and (E)-N-(3-iodoprop-2-enyl)-2␤-carbomethoxy-3␤-(4Ј-methylphenyl)nortropane (PE2I): 2.4 and 18 nM, respectively; IC 50 for paroxetine, citalopram, N,N-dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine, nisoxetine, and desipramine Ͼ1 M]. In vitro on post-mortem human brain sections, LBT-999 bound with high intensity to the caudate-putamen, weakly to the thalamus, and not in the neocortex and cerebellum. This binding was totally abolished in the presence of PE2I. Ex vivo cerebral biodistribution of [11 C]LBT-999 in rats showed striatum/ cerebellum radioactivity ratios of 18 and 25 at 30 and 60 min postinjection, respectively. This accumulation was strongly prevented by preinjection of GBR 12909, whereas paroxetine and nisoxetine had no effect. An in vivo kinetic PET study in three baboons showed a fast and very high uptake in the striatum, with a plateau at 30 min postinjection and a maximal putamen/ cerebellum ratio of 30. Taken together, these findings demonstrate that LBT-999 is a highly promising agent for in vivo exploration of the DAT. This probe is currently labeled with 18 F for further characterizations.As the membrane dopamine transporter (DAT) is very involved in a number of brain functions, in vivo exploration of this molecular target could become a relevant tool for the knowledge of pathophysiological mechanisms and diagnosis and follow-up of several neurological and psychiatric conditions. In this field, scintigraphic exploration of the DAT could be very useful for the early diagnosis and follow-up of Parkinson's disease. Most of these studies have been performed using single photon emission computerized tomography with radioligands chemically derived from the cocaine structure and labeled with 123 I such as 2␤-carbomethoxy-3␤-(4-iodophenyl)tropane (Innis et al., 1993;Seibyl et al., 1998; Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.105.096792.ABBREVIATIONS: DAT, dopamine transporter; FPCIT,

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Human brain imaging post-mortem - whole hemisphere technologies

Cited by 12 publications

References 26 publications

Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

Autoradiographic mapping of dopamine‐D₂/D₃ receptor stimulated [³⁵S]GTPγS binding in the human brain

Pharmacological Characterization of (E)-N-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter

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Human brain imaging post-mortem - whole hemisphere technologies

Cited by 12 publications

References 26 publications

Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

Synthesis and evaluation of 2-chloro N-[(S)-{(S)-1-[11 C]methylpiperidin-2-yl} (phenyl)methyl]3-trifluoromethyl-benzamide ([11 C]N-methyl-SSR504734) as a PET radioligand for glycine transporter 1

Autoradiographic mapping of dopamine‐D2/D3 receptor stimulated [35S]GTPγS binding in the human brain

Pharmacological Characterization of (E)-N-(4-Fluorobut-2-enyl)-2β-carbomethoxy-3β-(4′-tolyl)nortropane (LBT-999) as a Highly Promising Fluorinated Ligand for the Dopamine Transporter

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Autoradiographic mapping of dopamine‐D₂/D₃ receptor stimulated [³⁵S]GTPγS binding in the human brain