scholarly journals Regional Heterogeneity of 5-HT1A Receptors in Human Cerebellum as Assessed by Positron Emission Tomography

2005 ◽  
Vol 25 (7) ◽  
pp. 785-793 ◽  
Author(s):  
Ramin V Parsey ◽  
Victoria Arango ◽  
Doreen M Olvet ◽  
Maria A Oquendo ◽  
Ronald L Van Heertum ◽  
...  
Keyword(s):  
White Matter ◽  
Arterial Input Function ◽  
Input Function ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Reference Region ◽  
Nonspecific Binding ◽  
Cerebellar White Matter ◽  
Way 100635

Two measures used in brain imaging are binding potential (BP) and the specific to nonspecific equilibrium partition coefficient ( V3“). V3” determined using the 5-HT1A ligand [11C]WAY-100635 is sensitive to changes in the free and nonspecific binding of the ligand in the reference region ( V2). Healthy female volunteers have higher 5-HT1A BP but not V3“ compared with men, because V2 is higher in women. While there could be several explanations for this observation, we hypothesized that women have more 5-HT1A receptors in the cerebellum. We explore the cerebellum to define a subregion that more accurately represents the free and nonspecific binding, potentially allowing the use of V3”. A quantitative autoradiogram in human brain using [3H]WAY-100635 identified a cerebellar subregion devoid of 5-HT1A receptors. In vivo 5-HT1A receptors were evaluated using [11C]WAY-100635 in 12 healthy women and 13 healthy men. Each subject had a metabolite-corrected arterial input function. The autoradiogram demonstrates the lowest concentration of 5-HT1A receptors in the cerebellar white matter (CW) and highest concentration in the cerebellar vermis (CV). The CW volume of distribution ( VT) is lower than CV. Cerebellar white matter is adequately modeled by a one-tissue compartmental model, while a two-tissue model is necessary to model CV or the total cerebellum (CT). Women have a higher CW VT compared with men, suggesting a difference in V2. Use of CW improves identifiability and time stability of BP in cortical regions. Cerebellar white matter might be a better reference region for use in future 5-HT1A studies using [11C]WAY-100635. With CW as a reference region, V3“ cannot be used to detect differences in 5-HT1A receptors between men and women, suggesting the need for arterial input functions to determine BP.

scholarly journals Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

2020 ◽  
Author(s):  
Naoyuki Obokata ◽  
Chie Seki ◽  
Takeshi Hirata ◽  
Jun Maeda ◽  
Hideki Ishii ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Inflammatory Diseases ◽  
Input Function ◽  
Binding Potential ◽  
Dependent Manner ◽  
Reference Tissue ◽  
Molar Activity ◽  
The Brain

AbstractPurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in-vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in-vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥ 99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In-vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in-vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

scholarly journals Quantitative Analysis for Estimating Binding Potential of the Brain Serotonin Transporter with [11C]McN5652

2002 ◽  
Vol 22 (4) ◽  
pp. 490-501 ◽  
Author(s):  
Yoko Ikoma ◽  
Tetsuya Suhara ◽  
Hinako Toyama ◽  
Tetsuya Ichimiya ◽  
Akihiro Takano ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Arterial Input Function ◽  
Volume Ratio ◽  
Least Square Method ◽  
Distribution Volume ◽  
Least Square ◽  
Binding Potential ◽  
Nonspecific Binding ◽  
Distribution Volume Ratio

[11C](+)McN5652 is a selective serotonin reuptake inhibitor with subnanomolar potency for the serotonin transporter, and is currently being used for positron emission tomography studies. However, quantification of the regional [11C](+)McN5652 binding potential in vivo is a controversial issue because of its complex characteristics. The authors examined the regional differences in nonspecific binding and proposed simple methods for estimating the binding potential of [11C](+)McN5652. The regional difference in nonspecific binding was evaluated by the activity ratio of the thalamus compared with the cerebellum for inactive-isomer [11C](−)McN5652 and [11C](+)McN5652 saturation studies. The distribution volume of the thalamus was approximately 1.16 times larger than that of the cerebellum. The thalamus-to-cerebellum distribution volume ratio was estimated by nonlinear least square and graphical methods, with and without arterial input function. The graphical method with k2′ without blood sampling was practical and most applicable for estimation of the distribution volume ratio because this method is more stable than the nonlinear least square method in the simulation study. Binding potential estimated with the distribution volume ratio of [11C](+)McN5652 and the correction with distribution volume ratio of [11C](−)McN5652 represent the most reliable parameters for the assessment of serotonin transporter binding.

scholarly journals In vivo Serotonin-Sensitive Binding of [11C]CUMI-101: A Serotonin 1A Receptor Agonist Positron Emission Tomography Radiotracer

2010 ◽  
Vol 31 (1) ◽  
pp. 243-249 ◽  
Author(s):  
Matthew S Milak ◽  
Alin J Severance ◽  
Jaya Prabhakaran ◽  
JS Dileep Kumar ◽  
Vattoly J Majo ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Arterial Input Function ◽  
Input Function ◽  
Emission Tomography ◽  
Binding Potential ◽  
Papio Anubis ◽  
Positron Emission ◽  
Future Work ◽  
G Protein Coupled

Positron emission tomography studies of 5-hydroxytryptamine (5-HT)1A receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT1A agonist radiotracer [11C]CUMI-101. This study evaluates the sensitivity of [11C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [11C]CUMI-101 intravenous bolus of 4.5±1.5 mCi. Binding potential (BPF= Bavail/ KD) was measured before ( n=10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n=3; 4 mg/kg, n=3) and fenfluramine (2.5 mg/kg, n=3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BPF ( P=0.031, P=0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [11C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BPF may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges.

scholarly journals Reference Region Approaches in PET: a Comparative Study on Multiple Radioligands

2013 ◽  
Vol 33 (6) ◽  
pp. 888-897 ◽  
Author(s):  
Francesca Zanderigo ◽  
R Todd Ogden ◽  
Ramin V Parsey
Keyword(s):  
Rate Constant ◽  
Transfer Rate ◽  
Arterial Input Function ◽  
Likelihood Estimation ◽  
Input Function ◽  
Graphical Analysis ◽  
Binding Potential ◽  
Reference Region ◽  
Data Set ◽  
Transfer Rate Constant

Reference region (RR) approaches (RRAs) for positron emission tomography (PET) brain studies aim to obtain full quantification without arterial input function (IF) sampling, an invasive and costly procedure. Although they need a reliable RR and are only able to estimate the nondisplaceable binding potential (BPND), RRAs are widely used. If quantitatively reliable, then RRAs can greatly benefit PET investigations, but their suitability can vary widely from radioligand to radioligand. This study compares estimates of BPND both using IF data and several common RRAs on an extensive data set for each of several radioligands. In addition, two new methods, likelihood estimation in graphical analysis with RR and a bootstrapping algorithm for estimating precision, are presented here for the first time. Although many factors contribute to the performance of each RRA, our results suggest that the kinetics in the RR have a role. In particular, RRAs tend to be good when (1) the RR distribution volume is high; (2) the transfer rate constant from plasma to free compartment in the RR is high; and (3) the transfer rate constant from free to plasma compartment in the RR is low.

scholarly journals A Graphical Method to Compare the in vivo Binding Potential of PET Radioligands in the Absence of a Reference Region: Application to [11C]PBR28 and [18F]PBR111 for TSPO Imaging

2014 ◽  
Vol 34 (7) ◽  
pp. 1162-1168 ◽  
Author(s):  
Qi Guo ◽  
David R Owen ◽  
Eugenii A Rabiner ◽  
Federico E Turkheimer ◽  
Roger N Gunn
Keyword(s):  
Outcome Measure ◽  
Graphical Method ◽  
Volume Of Distribution ◽  
Translocator Protein ◽  
Binding Potential ◽  
Reference Region ◽  
Positron Emission ◽  
Tspo Imaging

Positron emission tomography (PET) radioligands for a reversible central nervous system (CNS) demand a high specific to nonspecific signal characterized by the binding potential ( BPND). The quantification of BPND requires the determination of the nondisplaceable binding usually derived from a reference region devoid of the target of interest. However, for many CNS targets, there is no valid reference region available. In such cases, the total volume of distribution ( VT) is often used as the outcome measure, which includes both the specific and nonspecific binding signals. Here we present a graphical method that allows for direct comparison of the binding potential of ligands using the regional VT data alone via linear regression. The method was first validated using literature data for five serotonin transporter ligands, for which a reference region exists, and then applied to two second generation 18 kDa translocator protein radioligands, namely [ 11 C]PBR28 and [ 18 F]PBR111. The analysis determined that [ 11 C]PBR28 had a higher BPND than [ 18 F]PBR111.

scholarly journals Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

2021 ◽  
Author(s):  
Naoyuki Obokata ◽  
Chie Seki ◽  
Takeshi Hirata ◽  
Jun Maeda ◽  
Hideki Ishii ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Inflammatory Diseases ◽  
Input Function ◽  
Binding Potential ◽  
Dependent Manner ◽  
Reference Tissue ◽  
Molar Activity ◽  
The Brain

Abstract Purpose Phosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7. Methods [11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND. Results [11C]MTP38 was synthesized with radiochemical purity ≥99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function. Conclusion We have provided the first successful preclinical demonstration of in vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

scholarly journals Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

2011 ◽  
Vol 32 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Federico E Turkheimer ◽  
Sudhakar Selvaraj ◽  
Rainer Hinz ◽  
Venkatesha Murthy ◽  
Zubin Bhagwagar ◽  
...  
Keyword(s):  
Specific Binding ◽  
Normal Subjects ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Accurate Estimation ◽  
Data Sets ◽  
Reference Region ◽  
Reference Tissue ◽  
Positron Emission ◽  
Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

scholarly journals In vitro and In vivo Assessment of Suitable Reference Region and Kinetic Modelling for the mGluR1 Radioligand [11C]ITDM in Mice

2019 ◽  
Vol 22 (4) ◽  
pp. 854-863 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Špela Korat ◽  
Alan Miranda ◽  
Leonie wyffels ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Pet Imaging ◽  
Metabotropic Glutamate Receptor ◽  
Kinetic Modelling ◽  
Input Function ◽  
Dependent Manner ◽  
Reference Region ◽  
Suitable Reference

Abstract Purpose This study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [11C]ITDM in mice. Procedures We performed in vivo blocking as well as displacement of [11C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [3H]ITDM at two different doses of YM-202074. As an alternative to reference region models, we validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function measured with an invasive arteriovenous (AV) shunt using a population-based curve for radiometabolite correction and characterized the pharmacokinetic modelling of [11C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches. Results In vivo blocking with YM-202074 resulted in a decreased [11C]ITDM binding, ranging from − 35.8 ± 8.0 % in pons to − 65.8 ± 3.0 % in thalamus. Displacement was also markedly observed in all tested regions. In addition, in vitro [3H]ITDM binding could be blocked in a dose-dependent manner. The volume of distribution (VT) based on the noninvasive IDIF (VT (IDIF)) showed excellent agreement with the VT values based on the metabolite-corrected plasma input function regardless of the metabolite correction (r2 > 0.943, p < 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r2 > 0.960, p < 0.0001). A minimum scan duration of 80 min was required for proper parameter estimation. SUV was not reliable (r2 = 0.379, p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach. Conclusions No suitable reference region could be identified for [11C]ITDM as strongly supported by in vivo and in vitro evidence of specific binding in all brain regions. However, by applying appropriate kinetic models, [11C]ITDM PET imaging represents a promising tool to visualize mGluR1 in the mouse brain.

scholarly journals In vivo evidence for dysregulation of mGluR5 as a biomarker of suicidal ideation

2019 ◽  
Vol 116 (23) ◽  
pp. 11490-11495 ◽  
Author(s):  
Margaret T. Davis ◽  
Ansel Hillmer ◽  
Sophie E. Holmes ◽  
Robert H. Pietrzak ◽  
Nicole DellaGioia ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Suicide Risk ◽  
Potential Role ◽  
Input Function ◽  
Brain Regions ◽  
Volume Of Distribution ◽  
Regions Of Interest ◽  
Emission Tomography ◽  
Positron Emission

Recent evidence implicates dysregulation of metabotropic glutamatergic receptor 5 (mGluR5) in pathophysiology of PTSD and suicidality. Using positron emission tomography and [18F]FPEB, we quantified mGluR5 availability in vivo in individuals with PTSD (n = 29) and MDD (n = 29) as a function of suicidal ideation (SI) to compare with that of healthy comparison controls (HC; n = 29). Volume of distribution was computed using a venous input function in the five key frontal and limbic brain regions. We observed significantly higher mGluR5 availability in PTSD compared with HC individuals in all regions of interest (P’s = 0.001–0.01) and compared with MDD individuals in three regions (P’s = 0.007). mGluR5 availability was not significantly different between MDD and HC individuals (P = 0.17). Importantly, we observed an up-regulation in mGluR5 availability in the PTSD-SI group (P’s = 0.001–0.007) compared with PTSD individuals without SI. Findings point to the potential role for mGluR5 as a target for intervention and, potentially, suicide risk management in PTSD.

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