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

2012 ◽  
Vol 32 (8) ◽  
pp. 1546-1558 ◽  
Author(s):  
Dustin W Wooten ◽  
Ansel T Hillmer ◽  
Jeffrey M Moirano ◽  
Elizabeth O Ahlers ◽  
Maxim Slesarev ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Specific Binding ◽  
Temporal Cortex ◽  
Compartmental Analysis ◽  
Input Function ◽  
Anterior Cingulate ◽  
Receptor Density ◽  
Binding Parameters ◽  
In Vivo Measurement

The goal of this work was to characterize the in-vivo behavior of [18F]mefway as a suitable positron emission tomography (PET) radiotracer for the assay of 5-hydroxytryptamine1A (5-HT1A) receptor density ( Bmax). Six rhesus monkeys were studied using a multiple-injection (M-I) protocol consisting of three sequential bolus injections of [18F]mefway. Injection times and amounts of unlabeled mefway were optimized for the precise measurement of Bmax and specific binding parameters koff and kon for estimation of apparent KD. 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 K1, k2, koff, Bmax, and KDapp 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 Bmax 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 KDapp of mefway for the 5-HT1A receptor sites was 4.3±1.3 nmol/L. In conclusion, these results show that M-I [18F]mefway PET experiments can be used for the in-vivo measurement of 5-HT1A receptor density.

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 Arterial Input Function Derived from Pairwise Correlations Between PET-image Voxels

2013 ◽  
Vol 33 (7) ◽  
pp. 1058-1065 ◽  
Author(s):  
Martin Schain ◽  
Simon Benjaminsson ◽  
Katarina Varnäs ◽  
Anton Forsberg ◽  
Christer Halldin ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Pearson Correlation ◽  
Invasive Procedure ◽  
Compartmental Analysis ◽  
Input Function ◽  
Time Activity ◽  
Pairwise Correlation ◽  
Positron Emission ◽  
Using Data ◽  
Suitable Reference

A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [ 11 C]flumazenil and [ 11 C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes ( VT) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in VT was good (~3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.

scholarly journals In Vivo Measurement of Receptor Density and Affinity: Comparison of the Routine Sequential Method with a Nonsequential Method in Studies of Dopamine D2 Receptors with [11C]Raclopride

2003 ◽  
Vol 23 (3) ◽  
pp. 280-284 ◽  
Author(s):  
Doris J. Doudet ◽  
Salma Jivan ◽  
James E. Holden
Keyword(s):  
D2 Receptors ◽  
Emission Tomography ◽  
Receptor Density ◽  
Sequential Method ◽  
In Vivo Measurement ◽  
Positron Emission ◽  
Stable Conditions ◽  
Radiotracer Injection ◽  
Sequential Studies

Positron emission tomography with the dopamine D2/3 receptor ligand raclopride was used to compare sequential (studies on 1 day) and nonsequential (different days) approaches to in vivo measurement of the density and affinity of receptors. The choice of temporal sequence of radiotracer injection over a range of specific activities might result in bias because of diverse factors. A strong concordance is reported between the outcomes of the sequential and nonsequential methods. This suggests that the characteristics of the dopamine D2/3 receptors are relatively stable within physiologic boundaries and can be reproducibly and reliably measured in stable conditions.

scholarly journals Multiinjection Approach for D2 Receptor Binding Quantification in Living Rats using [11C]Raclopride and the β-Microprobe: Crossvalidation with in Vitro Binding Data

2005 ◽  
Vol 25 (11) ◽  
pp. 1517-1527 ◽  
Author(s):  
Gweltas Mauger ◽  
Wadad Saba ◽  
Philippe Hantraye ◽  
Frédéric Dolle ◽  
Christine Coulon ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Specific Binding ◽  
D2 Receptor ◽  
Correlation Study ◽  
Kinetics Parameters ◽  
In Vitro Binding ◽  
Vitro Binding ◽  
Modelling Approach

The purpose of this study was to quantify D2 receptors density and affinity in living rats using [11C]raclopride and to validate the multiinjection modelling approach. To this aim, we used an intracerebral β+-sensitive probe as a highly sensitive system to quantify the radioligand activity using a single three-injection experimental paradigm. The study was divided into three main parts: (i) [11C]raclopride catabolism evaluation without and with cimetidine pretreatment (cytochrome P450 inhibitor); (ii) quantification of kinetics parameters in the striatum, enthorinal cortex, and cerebellum of living rats using a three-compartment model with an arterial input function; (iii) correlation study of in vivo and in vitro binding density and affinity values in the same striatal tissues. (i) raclopride catabolism was very reproducible between individuals; cimetidine pre-treatment resulted in a 30% reduction of raclopride metabolites. (ii) D2 striatal B'max and Kd Vr estimates obtained by compartmental modelling were 19.87 ± 6.45 and 6.2 ± 3.3 nmol/L, respectively. Cerebellum is the best candidate as a reference region with no specific binding detectable in vivo. (iii) When comparing density ( Bmax/ B'max) and affinity ( Kd/ Kd Vr) values in vivo and in vitro for each striatum, a high strict correlation was found ( r2 = 0.90 and 0.72, for density and affinity, respectively). These results validate the multi-injection modelling approach coupled to β-microprobe acquisitions as a mean to provide accurate and separate estimates of dopamine D2-receptor density and affinity, in the living rodent striatum.

In vivo occupancy of striatal and temporal cortical D2/D3 dopamine receptors by typical antipsychotic drugs

1999 ◽  
Vol 175 (3) ◽  
pp. 231-238 ◽  
Author(s):  
Valeria Bigliani ◽  
Rachel S. Mulligan ◽  
Paul D. Acton ◽  
Dimitris Visvikis ◽  
Peter J. Ell ◽  
...  
Keyword(s):  
Dopamine Receptors ◽  
Antipsychotic Drugs ◽  
Specific Binding ◽  
Temporal Cortex ◽  
Receptor Occupancy ◽  
Typical Antipsychotic ◽  
Dopamine Hypothesis ◽  
Antipsychotic Drug Treatment ◽  
The Relationship

BackgroundThe dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.AimTo evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.Method[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 age-matched healthy controls. [123I]-epidepride specific binding to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined.ResultsMean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively.ConclusionsTypical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.

scholarly journals Image-derived arterial input function for quantitative fluorescence imaging of receptor-drug binding in vivo

2015 ◽  
Vol 9 (3) ◽  
pp. 282-295 ◽  
Author(s):  
Jonathan T. Elliott ◽  
Kimberley S. Samkoe ◽  
Scott C. Davis ◽  
Jason R. Gunn ◽  
Keith D. Paulsen ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Arterial Input Function ◽  
Input Function ◽  
Drug Binding ◽  
Quantitative Fluorescence

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 Measuring the in Vivo Binding Parameters of [18F]-Fallypride in Monkeys Using a PET Multiple-Injection Protocol

2004 ◽  
Vol 24 (3) ◽  
pp. 309-322 ◽  
Author(s):  
Bradley T Christian ◽  
Tanjore Narayanan ◽  
Bing Shi ◽  
Evan D Morris ◽  
Joseph Mantil ◽  
...  
Keyword(s):  
Clinical Research ◽  
Ventral Striatum ◽  
Model Parameters ◽  
D3 Receptor ◽  
Receptor Density ◽  
Multiple Injection ◽  
Binding Parameters ◽  
Optimal Criterion ◽  
Experimental Protocols

The goal of this work was to quantify the in vivo transport and binding parameters of [F-18]fallypride and the D2/D3 receptor density (B′max) in both the striatal (putamen, caudate, ventral striatum) and extrastriatal regions (thalamus, amygdala, cerebellum, temporal and frontal cortices) of the rhesus monkey brain. Multiple-injection PET experimental protocols with injections of radiolabeled and unlabeled doses of fallypride were used to estimate the K1, k2, kon/VR, koff and B′max kinetic parameters. The experimental design was chosen using the D-optimal criterion to maximize the precision of the estimated binding parameters for the various brain regions. There was a significant range in B′max for the putamen (27pmol/mL), caudate (23pmol/mL), ventral striatum (14pmol/mL), thalamus (1.8pmol/mL) and amygdala (0.9pmol/mL). Significant receptor binding was also found in the cortical regions. Knowledge of these in vivo rate constants serves as a necessary step in using [F-18]fallypride PET to measure D2/D3 receptor density and drug occupancy in clinical research applications. We believe the precise parameter estimates derived from these complicated experimental protocols are necessary for proper application of drug occupancy and clinical research studies with [F-18]fallypride, which often rely on the validity of assumptions regarding the model parameters.

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