Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab

National Institute of Mental Health, Molecular Imaging Branch, Bethesda, Maryland, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 10/2007; 27(9):1533-9. DOI: 10.1038/sj.jcbfm.9600493
Source: PubMed


An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.

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Available from: James E Holden, Mar 10, 2014
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    • ") (Figure S1) and simplified reference tissue model (SRTM) (Gunn et al., 1997; Innis et al., 2007; Lammertsma and Hume, 1996) (Figure S2). Using the LoganREF model, the volume of distribution ratio (DVR) was estimated in each ROI using a MATLAB (Mathworks Inc., Natick, MA) implementation of these tracer kinetic methods as previously published (Logan et al., 1990). "
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    ABSTRACT: Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling. A PET tracer for PDE10A may serve as a tool to evaluate PDE10A expression in vivo in central nervous system disorders with striatal pathology. Here, we further characterized the binding properties of a previously reported radioligand we developed for PDE10A, [(11)C]TZ1964B, in rodents and nonhuman primates (NHPs). The tritiated counterpart [(3)H]TZ1964B was used for in vitro binding characterizations in rat striatum homogenates and in vitro autoradiographic studies in rat brain slices. The carbon-11 labeled [(11)C]TZ1964B was utilized in the ex vivo autoradiography studies for the brain of rats and microPET imaging studies for the brain of NHPs. MicroPET scans of [(11)C]TZ1964B in NHPs were conducted at baseline, as well as with using a selective PDE10A inhibitor MP-10 for either pretreatment or displacement. The in vivo regional target occupancy (Occ) was obtained by pretreating with different doses of MP-10 (0.05 - 2.00 mg/kg). Both in vitro binding assays and in vitro autoradiographic studies revealed a nanomolar binding affinity of [(3)H]TZ1964B to the rat striatum. The striatal binding of [(3)H]TZ1964B and [(11)C]TZ1964B was either displaced or blocked by MP-10 in rats and NHPs. Autoradiography and microPET imaging confirmed that the specific binding of the radioligand was found in the striatum but not in the cerebellum. Blocking studies also confirmed the suitability of the cerebellum as an appropriate reference region. The binding potentials (BPND) of [(11)C]TZ1964B in the NHP striatum that were calculated using either the Logan reference model (LoganREF, 3.96 ± 0.17) or the simplified reference tissue model (SRTM, 4.64 ± 0.47), with the cerebellum as the reference region, was high and had good reproducibility. The occupancy studies indicated a MP-10 dose of 0.31 ± 0.09 mg/kg (LoganREF) / 0.45 ± 0.17 mg/kg (SRTM) occupies 50% striatal PDE10A binding sites. Studies in rats and NHPs demonstrated radiolabelled TZ1964B has a high binding affinity and good specificity for PDE10A, as well as favorable in vivo pharmacokinetic properties and binding profiles. Our data suggests that [(11)C]TZ1964B is a promising radioligand for in vivo imaging PDE10A in the brain of living subject. Copyright © 2015. Published by Elsevier Inc.
    NeuroImage 11/2015; 121:253-262. DOI:10.1016/j.neuroimage.2015.07.049 · 6.36 Impact Factor
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    • "The [ 123 I]-beta-CIT uptake in each ROI was expressed as mean counts per pixel, and the specific uptake of [ 123 I]-beta-CIT was calculated as: BetaCIT uptake in the brainstem ROI À BetaCIT uptake in the occipital ROI Binding potential quantifies the equilibrium concentration of specific binding as a ratio to a reference concentration. As defined by Innis et al., BP ND refers to the ratio at equilibrium of specifically bound radioligand to that of non-displaceable radioligand in tissue (Innis et al., 2007). BP ND for 5-HTT was then defined as the ratio of specific uptake to uptake in the occipital reference region using the formula: "
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    ABSTRACT: Preclinical studies demonstrate that pro-inflammatory cytokines increase serotonin transporter availability and function, leading to depressive symptoms in rodent models. Herein we investigate associations between circulating inflammatory markers and brainstem serotonin transporter (5-HTT) availability in humans. We hypothesised that higher circulating inflammatory cytokine concentrations, particularly of tumour necrosis factor (TNF-α), would be associated with greater 5-HTT availability, and that TNF-α inhibition with etanercept (sTNFR:Fc) would in turn reduce 5-HTT availability. In 13 neurologically healthy adult women, plasma TNF-α correlated significantly with 5-HTT availability (rho=0.6; p=0.03) determined by [(123)I]-beta-CIT SPECT scanning. This association was replicated in an independent sample of 12 patients with psoriasis/psoriatic arthritis (rho=0.76; p=0.003). Indirect effects analysis, showed that there was a significant overlap in the variance explained by 5-HTT availability and TNF-α concentrations on BDI scores. Treatment with etanercept for 6-8weeks was associated with a significant reduction in 5-HTT availability (Z=2.09; p=0.03; r=0.6) consistent with a functional link. Our findings confirm an association between TNF-α and 5-HTT in both the basal physiological and pathological condition. Modulation of both TNF-α and 5-HTT by etanercept indicate the presence of a mechanistic pathway whereby circulating inflammatory cytokines are related to central nervous system substrates underlying major depression. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 08/2015; DOI:10.1016/j.bbi.2015.08.005 · 5.89 Impact Factor
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    • "The quantitative analysis of [ 11 C](R)-MeQAA were carried out by the simplified reference tissue model (SRTM) to calculate nondisplaceable binding potential (BP ND ) using the TAC in the cerebellum (Cere) as an indirect input function (Innis et al., 2007) and the compartment models of 1-tissue compartment (1-TC) and 2-TC (Mintun et al., 1984; Huang et al., 1986), all of which were performed using PMOD software (PMOD Technologies, Zurich, Switzerland). In 1-TC analysis, unmetabolized radioligand in the arterial plasma was passed through the blood–brain barrier (BBB), and then into the first tissue compartment (free 1 bound fraction compartment). "
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    ABSTRACT: The present study was aimed to assess the correlations among α7 nicotinic acetylcholine receptor (α7-nAChR) binding, amyloid-β (Aβ) deposition, and mitochondrial complex I (MC-I) activity in the brain of aged monkeys (Macaca mulatta). PET measurements with [(11) C](R)-MeQAA, [(11) C]PIB, and [(18) F]BCPP-EF were conducted in monkeys in a conscious condition. [(11) C](R)-MeQAA binding was analyzed by a simplified reference tissue model (SRTM) to calculate non-displaceable binding potential (BPND ), [(11) C]PIB uptake was calculated by standard uptake value ratio (SUVR), and [(18) F]BCPP-EF binding was determined by Logan graphical analysis to calculate total distribution volume (VT ) with arterial blood sampling. Higher brain uptake was determined in the thalamus, hippocampus, striatum, and cortical regions for [(11) C](R)-MeQAA, while being lower in the cerebellum. Significant age-related reduction of [(11) C](R)-MeQAA binding to α7-nAChR was determined only in the occipital cortex. The plot of Vt of [(18) F]BCPP-EF against BPND of [(11) C](R)-MeQAA indicated a significant negative correlation in the hippocampus and cortical regions in aged animals. Plotting of SUVR of [(11) C]PIB against BPND of [(11) C](R)-MeQAA showed a positive correlation. The in vivo binding of [(11) C](R)-MeQAA could reflect the upregulation of α7-nAChR induced by neurodegenerative damage determined by Aβ deposition as well as impaired MC-I activity in living brain. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Synapse 08/2015; 69(10). DOI:10.1002/syn.21842 · 2.13 Impact Factor
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