Development of positron emission tomography radioligands for the dopaminergic and serotonergic neurotransmission systems
Author: Lundkvist, Camilla
Date: 1998-09-04
Location: Institutionen för klinisk neurovetenskap, Karolinska Institutet, sektionen för psykiatri
Time: 9.00
Department: Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
Abstract
The dopaminergic and serotonergic neurotransmission systems are of
central interest in relation to several neuropsychiatric disorders. The
main objectives were to develop new suitable radioligands for positron
emission tomography (PET) examinations of the dopamine transporter (DAT)
as well as the serotonin 5-HT1A and 5-HT2A-receptors.
Radiolabelling was performed with any of the positron emitting
radionuclides carbon-11, fluorine-18 or bromine-76. Carbon-11 methylation
was achieved by alkylation of a phenol group or by esterification using [11C]methyl
iodide or [11C] C]methyl triflate. The latter improved the labelling
results giving higher radiochemical yields and higher specific
radioactivity. Another carbon-11 labelling route was acylation of an
amine group with [11C]acid chloride. Fluorine-18 labelling was achieved
by nucleophilic substitution and alkylation of a secondary amine with [18F]fluoropropyl
bromide. Labellings with bromine-76 were performed by regioselective
bromodestannylation. The in vivo distribution of radioactivity was
measured in the cynomolgus monkey brain. Particular attention was given
to the time course 'and identification of labelled metabolites that
appears in plasma and were measured with various HPLC methods.
Two phenyltropane analogues were evaluated as radioligands for the DAT.
[O-Methyl-11C]ßCIT-FE did readily reach equilibrium conditions in the
striatum within the time frame of a PET measurement, and should
accordingly be suitable for quantitation in applied studies. [O-Methyl-11C]ß-CIT-FP
bound specifically to the DAT as demonstrated with autoradiography and
PET. Radioligand binding approached equilibrium conditions at the end of
the PET measurement. Due to the longer half-life of the radioinuclide [18F]ß-CIT-FP
could more reliably be used to measure equilibrium conditions. A
lipophilic labelled metabolite was detected in monkey plasma after i.v.
injection of [O-methyl-11C]ß-CIT-FP and [O-methyl-11C]ß-CIT-FE.
Importantly, no lipophilic labelled metabolite was detected after i.v.
injection of [18F]ß-CIT-FP which further substantiate the advantage of
using [[18F]ß-CIT-FP for quantitation of the DAT.
In search for a serotonin transporter radioligand specific binding of [76Br]5-bromo-6
nitroquipazine was shown in ex vivo rat studies. A subsequent PET study
in a baboon demonstrated uptake in the thalamus and pons indicating that
[76Br]5-bromo-6-nitroquipazine might have potential as a PET radioligand
for the serotonin transporter.
Specific binding of the selective 5-HT1A antagonist WAY-100635 was
characterized with autoradiography and found to be high in 5-HT1A
receptor rich areas. Metabolite studies of [O methyl-11C]WAY-100635
revealed a significant fraction of the labelled metabolite [O-methyl-11C]WAY-
100634 which passes the blood-brain-barrier and add to the non-specific
binding in brain. [Carbonyl-11C]WAY-100635 was accordingly superior to
[O-methyl-11C]WAY-100635 for in vivo PET studies due to the absence of
labelled WAY-100634.
Specific binding to the 5-HT2A receptor in the neocortex was demonstrated
in a cynomolgus monkey with the highly selective 5-HT2A antagonist [11C]MDL
100907. The neocortex to cerebellum ratio was about four at time of
transient equilibrium and this radioligand has subsequently been used for
human PET studies.
Issue date: 1998-08-14
Publication year: 1998
ISBN: 91-628-3089-9
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