Matches in SemOpenAlex for { <https://semopenalex.org/work/W1591525184> ?p ?o ?g. }
- W1591525184 abstract "The molecular imaging technique positron emission tomography (PET) allows for non-invasive examination of biochemical markers in the living brain. For over three decades PET studies have provided important insight into the relationship of monoaminergic neurotransmitter systems to brain functioning and psychiatric disorders. A more recent application of PET is the study of endogenous neurotransmitter release in vivo. Clinical relevance of such methods is found in studies demonstrating enhanced amphetamine-induced dopamine release in schizophrenia patients, whereas PET studies in non-human primates provide a translational model for evaluation of the pharmacological mechanisms before initiation of studies in man. The first aim of this thesis was to develop improved methods for measurement of endogenous dopamine levels. In study I the potent D2/D3 receptors agonist (R)-(-)-2methoxy-N-n-propyl-norapomorphine (MNPA) was radiolabeled with carbon-11 and found suitable for in vivo characterization of the high affinity state. In study II, amphetamine-induced displacement of [ 11 C]MNPA binding by dopamine was ~1.8 fold higher at four different doses than for the antagonist [ 11 C]raclopride and demonstrated that an agonist radioligand has improved sensitivity to endogenous neurotransmitter level. Study III aimed to further obtain in vivo support for the existence of two affinity states for the D2/D3 receptors. Receptor occupancy of the exogenous agonist apomorphine was determined with [ 11 C]MNPA and [ 11 C]raclopride. Binding of [ 11 C]MNPA and [ 11 C]raclopride was inhibited monophasic and approached full saturation. ID50 and Ki values of apomorphine were indistinguishable when measured with the agonist or antagonist radioligand. Study III did not support the existence of two affinity states and a possible explanation could be that all D2/D3 receptors are in the high affinity state in vivo. In study IV, the new D1/D5 receptors partial agonist radioligand (S)-[ 11 C]N-methyl-NNC 01-0259 was found insensitive to dopamine levels, and receptor binding was inferior to previously developed antagonist radioligands. Moreover, a COMT formed radiometabolite was found to enter the brain but the formation could be prevented with the use of a COMT inhibitor. COMT inhibition provides a methodology enabling quantitative PET measurements with (S)-[ 11 C]Nmethyl-NNC 01-0259. The second aim of this thesis was to evaluate the sensitivity of the new 5-HT1B receptor radioligand [ 11 C]AZ10419369 to alterations in endogenous serotonin concentration. Previous serotonergic PET radioligands have ambiguously shown sensitivity to serotonin level. In study V the effective serotonin releaser fenfluramine decreased the binding of [ 11 C]AZ10419369 in a dose-dependent manner. In study VI the effect of fenfluramine on [ 11 C]AZ10419369 binding was confirmed using an equilibrium approach with a bolus infusion protocol. The further developed methodology is suitable for exploring the sensitivity limit to serotonin levels as measured using [ 11 C]AZ10419369 and PET. In conclusion, the present thesis demonstrates that the D2/D3 receptors agonist radioligand [ 11 C]MNPA is an improvement for measurement of dopamine release, when compared to previously used antagonist radioligands. Moreover, a novel methodology, using the 5-HT1B receptor antagonist [ 11 C]AZ10419369 and PET, was developed for measurement of serotonin release in the living brain. These newly developed methodologies may help to further understand the treatment and pathophysiology of several major neurological and psychiatric disorders. “Zing, vecht, huil, bid, lach, werk en bewonder” [Sing, fight, cry, pray, laugh, work and admire] Ramses Shaffy, 1933-2009 LIST OF PUBLICATIONS This thesis is based on six studies performed at the Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. The studies are presented in the following papers and will be referred to in the text by their roman numerals: I. Finnema SJ, Seneca N, Farde L, Shchukin E, Sovago J, Gulyas B, Wikstrom HV, Innis RB, Neumeyer JL and Halldin C. (2005) A preliminary PET evaluation of the new dopamine D2 receptor agonist [ 11 C]MNPA in cynomolgus monkey. Nuclear Medicine and Biology 32:353-360. II. Seneca N, Finnema SJ, Farde L, Gulyas B, Wikstrom HV, Halldin C * and Innis RB * . (2006) Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand [ 11 C]MNPA and antagonist [ 11 C]raclopride. Synapse 59:260-269. III. Finnema SJ, Halldin C, Bang-Andersen B, Gulyas B, Bundgaard C, Wikstrom HV and Farde L. (2009) Dopamine D2/3 receptor occupancy of apomorphine in the nonhuman primate brain – a comparative PET study with [ 11 C]raclopride and [ 11 C]MNPA. Synapse 63:378-389. IV. Finnema SJ, Bang-Andersen B, Jorgensen M, Gulyas B, Wikstrom HV, Farde L and Halldin C. Inhibition of catechol-O-methyltransferase enhances visualization of (S)-[ 11 C]N-methyl-NNC 01-0259 binding to dopamine D1-like receptors in monkey brain. Manuscript. V. Finnema SJ, Varrone A, Hwang TJ, Gulyas B, Pierson ME, Halldin C * and Farde L * . (2010) Fenfluramine-induced serotonin release decreases [ 11 C]AZ10419369 binding to 5-HT1B-receptors in the primate brain. Synapse 64:573-577. VI. Finnema SJ, Varrone A, Hwang TJ, Halldin C * and Farde L * . Confirmation of fenfluramine effect on 5-HT1B receptor binding of [ 11 C]AZ10419369 using an equilibrium approach. Manuscript. *Authors contributed equally to this work." @default.
- W1591525184 created "2016-06-24" @default.
- W1591525184 creator A5074768115 @default.
- W1591525184 date "2011-01-12" @default.
- W1591525184 modified "2023-09-23" @default.
- W1591525184 title "Assessment of Dopamine and Serotonin Release in the Non-Human Primate Brain using PET" @default.
- W1591525184 cites W1484727384 @default.
- W1591525184 cites W1484816836 @default.
- W1591525184 cites W1489775551 @default.
- W1591525184 cites W1502799818 @default.
- W1591525184 cites W1510579205 @default.
- W1591525184 cites W1527701604 @default.
- W1591525184 cites W1539659185 @default.
- W1591525184 cites W1546116904 @default.
- W1591525184 cites W1576430329 @default.
- W1591525184 cites W1589353809 @default.
- W1591525184 cites W1618289512 @default.
- W1591525184 cites W1658290039 @default.
- W1591525184 cites W1748945120 @default.
- W1591525184 cites W1785950437 @default.
- W1591525184 cites W180263596 @default.
- W1591525184 cites W1821065636 @default.
- W1591525184 cites W189146960 @default.
- W1591525184 cites W189999283 @default.
- W1591525184 cites W1936296662 @default.
- W1591525184 cites W1964030516 @default.
- W1591525184 cites W1964503514 @default.
- W1591525184 cites W1964793333 @default.
- W1591525184 cites W1964887266 @default.
- W1591525184 cites W1965264984 @default.
- W1591525184 cites W1966006747 @default.
- W1591525184 cites W1966533161 @default.
- W1591525184 cites W1966623267 @default.
- W1591525184 cites W1966740216 @default.
- W1591525184 cites W1966815742 @default.
- W1591525184 cites W1967139897 @default.
- W1591525184 cites W1967881177 @default.
- W1591525184 cites W1967966887 @default.
- W1591525184 cites W1968176029 @default.
- W1591525184 cites W1969866636 @default.
- W1591525184 cites W1969928171 @default.
- W1591525184 cites W1970047073 @default.
- W1591525184 cites W1970207337 @default.
- W1591525184 cites W1970328639 @default.
- W1591525184 cites W1970736649 @default.
- W1591525184 cites W1970926776 @default.
- W1591525184 cites W1972816542 @default.
- W1591525184 cites W1973611024 @default.
- W1591525184 cites W1974311568 @default.
- W1591525184 cites W1975860867 @default.
- W1591525184 cites W1975863542 @default.
- W1591525184 cites W1976132069 @default.
- W1591525184 cites W1976630512 @default.
- W1591525184 cites W1976968057 @default.
- W1591525184 cites W1977869470 @default.
- W1591525184 cites W1978301891 @default.
- W1591525184 cites W1979792701 @default.
- W1591525184 cites W1981420707 @default.
- W1591525184 cites W1982235280 @default.
- W1591525184 cites W1983200793 @default.
- W1591525184 cites W1983804154 @default.
- W1591525184 cites W1984201943 @default.
- W1591525184 cites W1984229889 @default.
- W1591525184 cites W1984596181 @default.
- W1591525184 cites W1985013294 @default.
- W1591525184 cites W1985050254 @default.
- W1591525184 cites W1986885544 @default.
- W1591525184 cites W1987587883 @default.
- W1591525184 cites W1988097700 @default.
- W1591525184 cites W1988885965 @default.
- W1591525184 cites W1989389872 @default.
- W1591525184 cites W1990121388 @default.
- W1591525184 cites W1990318285 @default.
- W1591525184 cites W1991080312 @default.
- W1591525184 cites W1991152368 @default.
- W1591525184 cites W1991263244 @default.
- W1591525184 cites W1991970216 @default.
- W1591525184 cites W1992991774 @default.
- W1591525184 cites W1993647063 @default.
- W1591525184 cites W1993675061 @default.
- W1591525184 cites W1993930054 @default.
- W1591525184 cites W1994863571 @default.
- W1591525184 cites W1996065499 @default.
- W1591525184 cites W1996187894 @default.
- W1591525184 cites W1996327177 @default.
- W1591525184 cites W1996724431 @default.
- W1591525184 cites W1997460720 @default.
- W1591525184 cites W1998454579 @default.
- W1591525184 cites W1998564307 @default.
- W1591525184 cites W2000164766 @default.
- W1591525184 cites W2001859804 @default.
- W1591525184 cites W2002713242 @default.
- W1591525184 cites W2003709517 @default.
- W1591525184 cites W2004485148 @default.
- W1591525184 cites W2005456488 @default.
- W1591525184 cites W2005820090 @default.
- W1591525184 cites W2005890911 @default.
- W1591525184 cites W2006180376 @default.
- W1591525184 cites W2006783519 @default.
- W1591525184 cites W2009456013 @default.