Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Rice, Onarae V.

doi:10.1016/s0893-133x(01)00287-1

Cited by 23 publications

(17 citation statements)

References 44 publications

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“…This is confirmed by the SB where no change is seen. These findings are in agreement with other studies that have reported no change or a small decline in the binding of WAY100635 (Hume et al, 2001; Maeda et al, 2001; Rice et al, 2001) or MPPF (Udo De Haes et al, 2005; Zimmer et al, 2002).…”

Section: Discussionsupporting

confidence: 92%

Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI‐101 in awake rats

Palner

Underwood

Kumar

et al. 2011

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[³H]CUMI-101 is a 5-HT(1A) partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [³H]CUMI-101 ex vivo in awake rats and determine if [³H]CUMI-101 can measure changes in synaptic levels of serotonin after different challenge paradigms. [³H]CUMI-101 shows good uptake and good specific binding ratio (SBR) in frontal cortex 5.18 and in hippocampus 3.18. Binding was inhibited in a one-binding-site fashion by WAY100635 and unlabeled CUMI-101. The ex vivo B(max) of [³H]CUMI-101 in frontal cortex (98.7 fmol/mg) and hippocampus (131 fmol/kg) agree with the ex vivo B(max) of [³H]MPPF in frontal cortex (147.1 fmol/mg) and hippocampus (72.1 fmol/mg) and with in vitro values reported with 8-OH-DPAT. Challenges with citalopram, a selective serotonin reuptake inhibitor, fenfluramine, a serotonin releaser, and 4-chloro-DL-phenylalanine, a serotonin synthesis inhibitor, did not show any effect on the standardized uptake values (SUVs) in any region. Citalopram did alter SBR, but this was due to changes in cerebellar SUVs. Our results indicate that [³H]CUMI-101 is a good radioligand for imaging 5-HT(1A) high-density regions in rats; however, the results from pharmacological challenges remain inconclusive.

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Section: Discussionsupporting

confidence: 92%

Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI‐101 in awake rats

Palner

Underwood

Kumar

et al. 2011

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“…Using Parsey et al (1999) found paradoxical increases in [ 11 C]WAY-100635 binding in baboons (using both 2.5 mg/ kg fenfluramine and 1.5 mg/kg amphetamine). In studies in which 5-HT levels have been depleted, neither Maeda et al (2001) using reserpine in rats, nor Rice et al (2001) using p-chlorophenylalanine in mice, identified any changes in radiolabeled WAY-100635 binding. However, Zimmer et al (2003b), using a b þ probe in rats, have recently reported a significant increase in [ 18 F]MPPF specific binding in the hippocampus after 5-HT depletion using p-ethynylphenylalanine (p-EPA).…”

Section: Discussionmentioning

confidence: 92%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Neuropsychopharmacol

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Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.

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“…Similar studies with PET ligands have been performed for the dopamine system to closely examine the effects of endogenous neurotransmitter on radioligand binding (Delforge et al, 2001). Without these experiments, we are left to speculate that the effects of competing 5-HT will induce only small changes in these results based on the similarities in in-vivo behavior between [ 18 F]mefway with [ 11 C]WAY-100635 (Wooten et al, 2011a,b (Maeda et al, 2001;Rice et al, 2001). Further, our previous invitro work revealed that inhibition by 5-HT was similar for mefway (Saigal et al, 2006) and WAY-100635 (Khawaja et al, 1995).…”

Section: Bp Nd As An Index For B Maxmentioning

confidence: 92%

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

Hillmer

Moirano

Ahlers

et al. 2012

J Cereb Blood Flow Metab

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The goal of this work was to characterize the in-vivo behavior of [ 18 F]mefway as a suitable positron emission tomography (PET) radiotracer for the assay of 5-hydroxytryptamine 1A (5-HT 1A ) receptor density (B max ). Six rhesus monkeys were studied using a multiple-injection (M-I) protocol consisting of three sequential bolus injections of [ 18 F]mefway. Injection times and amounts of unlabeled mefway were optimized for the precise measurement of B max and specific binding parameters k off and k on for estimation of apparent K D . The PET time series were acquired for 180 minutes with arterial sampling performed throughout. Compartmental analysis using the arterial input function was performed to obtain estimates for K 1 , k 2 , k off , B max , and K Dapp in the cerebral cortex and raphe nuclei (RN) using a model that accounted for nontracer doses of mefway. Averaged over subjects, highest binding was seen in the mesial temporal and dorsal anterior cingulate cortices with B max values of 42 ± 8 and 36 ± 8 pmol/mL, respectively, and lower values in the superior temporal cortex, RN, and parietal cortex of 24 ± 4, 19 ± 4, and 13 ± 2 pmol/mL, respectively. The K Dapp of mefway for the 5-HT 1A receptor sites was 4.3 ± 1.3 nmol/L. In conclusion, these results show that M-I [ 18 F]mefway PET experiments can be used for the in-vivo measurement of 5-HT 1A receptor density.

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Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Cited by 23 publications

References 44 publications

Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI‐101 in awake rats

Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI‐101 in awake rats

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate

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Effects of Endogenous Neurotransmitters on the in vivo Binding of Dopamine and 5-HT Radiotracers in Mice

Cited by 23 publications

References 44 publications

Ex vivo evaluation of the serotonin 1A receptor partial agonist [3H]CUMI‐101 in awake rats

Ex vivo evaluation of the serotonin 1A receptor partial agonist [3H]CUMI‐101 in awake rats

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Measurement of 5-HT1A Receptor Density and in-vivo Binding Parameters of [18F]mefway in the Nonhuman Primate

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Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI‐101 in awake rats

Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI‐101 in awake rats

Measurement of 5-HT_1A Receptor Density and in-vivo Binding Parameters of [¹⁸F]mefway in the Nonhuman Primate