Comparison of Two Compartmental Models for Describing Receptor Ligand Kinetics and Receptor Availability in Multiple Injection PET Studies

1996 ◽  
Vol 16 (5) ◽  
pp. 841-853 ◽  
Author(s):  
Evan D. Morris ◽  
Nathaniel M. Alpert ◽  
Alan J. Fischman
Keyword(s):  
Specific Activity ◽  
Tissue Response ◽  
High Rate ◽  
Receptor Modeling ◽  
Model Parameters ◽  
Multiple Injection ◽  
Positron Emission ◽  
Receptor Sites ◽  
Tracer Kinetic

The goal of research with receptor ligands and PET is the characterization of an in vivo system that measures rates of association and dissociation of a ligand-receptor complex and the density of available binding sites. It has been suggested that multiple injection studies of radioactive ligand are more likely to identify model parameters than are single injection studies. Typically, at least one of the late injections is at a low specific activity (SA), so that part of the positron emission tomography (PET) curve reflects ligand dissociation. Low SA injections and the attendant reductions in receptor availability, however, may violate tracer kinetic assumptions, namely, tracer may no longer be in steady state with the total (labeled and unlabeled) ligand. Tissue response becomes critically dependent on the dose of total ligand, and an accurate description of the cold ligand in the tissue is needed to properly model the system. Two alternative models have been applied to the receptor modeling problem, which reduces to describing the time-varying number of available receptor sites. The first ( Huang et al., 1989 ) contains only compartments for the hot ligand, ‘hot only’ (HO), but indirectly accounts for the action of cold ligand at receptor sites via SA. The second stipulates separate compartments for the hot and cold ligands, ‘hot and cold’ (HC), thus explicitly calculating available number of receptors. We examined these models and contrasted their abilities to predict PET activity, receptor availability, and SA in each tissue compartment. For multiple injection studies, the models consistently predicted different PET activities—especially following the third injection. Only for very high rate constants were the models identical for multiple injections. In one case, simulated PET curves were quite similar, but discrepancies appeared in predictions of receptor availability. The HO model predicted nonphysiological changes in the availability of receptor sites and introduced errors of 30–60% into estimates of B′max for test data. We, therefore, strongly recommend the use of the HC model for all analyses of multiple injection PET studies.

scholarly journals The Quantitative Analysis of D2-Dopamine Receptors in Baboon Striatum in vivo with 3-N-[2'-18F]Fluoroethylspiperone Using Positron Emission Tomography

1990 ◽  
Vol 10 (5) ◽  
pp. 720-726 ◽  
Author(s):  
S. Jovkar ◽  
K. Wienhard ◽  
G. Pawlik ◽  
H. H. Coenen
Keyword(s):  
Positron Emission Tomography ◽  
Kinetic Model ◽  
Dopamine Receptors ◽  
Specific Activity ◽  
Emission Tomography ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Positron Emission ◽  
Model Configuration

We used the ligand 3- N-[2'-18F]fluoroethylspiperone (FESP), which binds to D2-dopamine receptors in the striatum, and positron emission tomography (PET) to quantify striatal D2-dopamine densities ( Bmax) and binding kinetics in baboon brain in vivo. Sequential PET scans were obtained for 4 h post injection. Various similar models based on a nonlinear kinetic four-compartment model that takes into account the effect of ligand specific activity were used. We investigated the effect of exact model configuration on the reliability of Bmax and other kinetic transfer coefficients. We found that with the ligand FESP and dynamic PET studies, the estimated values of Bmax and other model parameters are sensitive to the choice of model configuration, ligand specific activity, and data analysis technique. The limitations of the reliability of parameter estimates in a complex kinetic model for receptor ligands were studied in simulation calculations. Results showed that the accuracy of estimated values of Bmax is affected by both the ligand binding properties and the injected dose of ligand. The estimated average value of kinetic model parameters was as follows: ligand-receptor dissociation constant k4 = 0.0080 min−1; the product of ligand-receptor association constant and fraction of ligand available to bind to specific receptors f2 ka = 0.0052 (min n M)−1; and D2-dopamine receptor density Bmax = 37.5 pmol g−1.

scholarly journals Quantitation of Extrastriatal D2 Receptors Using a Very High-Affinity Ligand (FLB 457) and the Multi-Injection Approach

1999 ◽  
Vol 19 (5) ◽  
pp. 533-546 ◽  
Author(s):  
Jacques Delforge ◽  
Michel Bottlaender ◽  
Christian Loc'h ◽  
Ilonka Guenther ◽  
Chantal Fuseau ◽  
...  
Keyword(s):  
D2 Receptor ◽  
Free Ligand ◽  
Brain Regions ◽  
Model Parameters ◽  
Tracer Injection ◽  
High Affinity ◽  
Precise Knowledge ◽  
Receptor Sites ◽  
Very High

The multi-injection approach has been used to study in baboon the in vivo interactions between the D2 receptor sites and FLB 457, a ligand with a very high affinity for these receptors. The model structure was composed of four compartments (plasma, free ligand, and specifically and unspecifically bound ligands) and seven parameters (including the D2 receptor site density). The arterial plasma concentration, after correction for metabolites, was used as the input function, The experimental protocol, which consisted of three injections of labeled and/or unlabeled ligand, allowed the evaluation of all model parameters from a single positron emission tomography experiment In particular, the concentration of receptor sites available for binding ( B'max) and the apparent in vivo FLB 457 affinity were estimated in seven brain regions, including the cerebellum and several cortex regions, in which these parameters are estimated in vivo for the first time ( B'max is estimated to be 4,0 ± 1.3 pmol/mL in the thalamus and from 0.32 to 1.90 pmol/mL in the cortex), A low receptor density was found in the cerebellum ( B'max = 0.39 ± 0.17 pmol/mL), whereas the cerebellum is usually used as a reference region assumed to be devoid of D2 receptor sites, In spite of this very small concentration (1 % of the striatal concentration), and because of the high affinity of the ligand, we demonstrated that after a tracer injection, most of the PET-measured radioactivity in the cerebellum results from the labeled ligand bound to receptor sites, The estimation of all the model parameters allowed simulations that led to a precise knowledge of the FLB 457 kinetics in all brain regions and gave the possibility of testing the equilibrium hypotheses and estimating the biases introduced by the usual simplified approaches.

scholarly journals Differentiation of Radioligand Delivery and Binding in the Brain: Validation of a Two-Compartment Model for [11C]Flumazenil

1991 ◽  
Vol 11 (5) ◽  
pp. 745-752 ◽  
Author(s):  
Vjera A. Holthoff ◽  
Robert A. Koeppe ◽  
Kirk A. Frey ◽  
Avram H. Paradise ◽  
David E. Kuhl
Keyword(s):  
Benzodiazepine Receptor ◽  
Occipital Cortex ◽  
Compartment Model ◽  
Stable Measure ◽  
Intravenous Injections ◽  
Audiovisual Stimulation ◽  
Positron Emission ◽  
Two Compartment Model ◽  
Tracer Kinetic

We recently developed a two-compartment, two-parameter tracer kinetic model to estimate the in vivo ligand transport rate ( K1) and distribution volume (DV) for the benzodiazepine antagonist [11C]flumazenil (FMZ) as measured by positron emission tomography (PET). The aim of the present study was to validate that this simplified model provides a stable measure of regional benzodiazepine receptor availability even when ligand delivery is altered. Six young normal volunteers underwent two PET studies subsequent to intravenous injections of [11C]FMZ. Each FMZ study was immediately preceded by measurements of CBF following injection of [15O]water. One set of scans (water/FMZ) was acquired under resting conditions and the other set during audiovisual stimulation. Six additional volunteers underwent two FMZ studies under identical resting conditions. Parametric images were analyzed and a comparison of test-retest studies in the stimulation group revealed a significant increase of CBF and K1 of FMZ in the occipital cortex evoked by visual activation, whereas no regional changes were noted for the DV of FMZ. No significant changes were noted for either K1 or DV of FMZ when comparing studies in the rest-rest setting. The results indicate that the use of a simple two-compartment model for the tracer kinetic analysis of [11C]FMZ makes it possible to separate high-affinity binding from altered radioligand delivery to the human brain.

scholarly journals Synthesis and Initial In Vivo Evaluation of [11C]AZ683 – a Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R)

2018 ◽  
Author(s):  
Sean S. Tanzey ◽  
Xia Shao ◽  
Jenelle Stauff ◽  
Janna Arteaga ◽  
Phillip Sherman ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Radiochemical Purity ◽  
Specific Activity ◽  
High Specific Activity ◽  
Colony Stimulating Factor ◽  
Positron Emission ◽  
New Strategy ◽  
Activity Yield ◽  
Stimulating Factor

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia. AZ683 has high affinity for CSF1R (Ki = 8 nM; IC50 = 6 nM) and >250-fold selectivity over 95 other kinases and, in this paper, we report the radiosynthesis of [11C]AZ683 and initial evaluation of its use in CSF1R PET. [11C]AZ683 was synthesized by 11C-methylation of the desmethyl precursor with [11C]MeOTf in 3.0% non-corrected activity yield (based upon [11C]MeOTf), >99% radiochemical purity and high specific activity. Preliminary PET imaging with [11C]AZ683 revealed no brain uptake in rodents and nonhuman primates suggesting that [11C]AZ683 is a poor candidate for imaging neuroinflammation, but that it could still be useful for peripheral imaging of inflammation.

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.

scholarly journals Erratum

1992 ◽  
Vol 12 (5) ◽  
pp. 885-885 ◽  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Specific Activity ◽  
Opiate Receptor ◽  
Emission Tomography ◽  
Parameter Estimates ◽  
Positron Emission ◽  
Receptor Concentration ◽  
Tracer Kinetic

Quantification of Human Opiate Receptor Concentration and Affinity Using High and Low Specific Activity [11C]Diprenorphine and Positron Emission Tomography Bernard Sadzot, Julie C. Price, Helen S. Mayberg, Kenneth H. Douglass, Robert F. Dannals, John R. Lever, Hayden T. Ravert, Alan A. Wilson, Henry N. Wagner, Jr., Marc A. Feldman, and J. James Frost [originally published in Journal of Cerebral Blood Flow and Metabolism 1991;11(2):204–219] Due to errors in the PET calibration factors, the published values of some of the parameter estimates are inaccurate. The correct values of Bmax and KD are 1.4 times and 0.4 times the published value, respectively. The correct values of Kl and Ktfk2 are 3.2 times the published value. Accordingly, the values of konf2 and f2 are 0.7 and 0.3 times the published value, respectively. The values of k2′ k3′ and k4 are correct. These quantitative errors in the parameter estimates do not affect the overall strategy for the application of tracer kinetic modeling nor the identification of the optimal fitting strategy. The authors regret these errors.

scholarly journals Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney

2016 ◽  
Vol 310 (8) ◽  
pp. F717-F725 ◽  
Author(s):  
Takashi Hato ◽  
Allon N. Friedman ◽  
Henry Mang ◽  
Zoya Plotkin ◽  
Shataakshi Dube ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Imaging Techniques ◽  
Multiphoton Microscopy ◽  
Tracer Uptake ◽  
Mitochondrial Potential ◽  
Pharmacological Inhibition ◽  
Positron Emission ◽  
Tracer Kinetic ◽  
Preclinical And Clinical Studies

The metabolic status of the kidney is a determinant of injury susceptibility and a measure of progression for many disease processes; however, noninvasive modalities to assess kidney metabolism are lacking. In this study, we employed positron emission tomography (PET) and intravital multiphoton microscopy (MPM) to assess cortical and proximal tubule glucose tracer uptake, respectively, following experimental perturbations of kidney metabolism. Applying dynamic image acquisition PET with 2-18fluoro-2-deoxyglucose (18F-FDG) and tracer kinetic modeling, we found that an intracellular compartment in the cortex of the kidney could be distinguished from the blood and urine compartments in animals. Given emerging literature that the tumor suppressor protein p53 is an important regulator of cellular metabolism, we demonstrated that PET imaging was able to discern a threefold increase in cortical 18F-FDG uptake following the pharmacological inhibition of p53 in animals. Intravital MPM with the fluorescent glucose analog 2-[ N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) provided increased resolution and corroborated these findings at the level of the proximal tubule. Extending our observation of p53 inhibition on proximal tubule glucose tracer uptake, we demonstrated by intravital MPM that pharmacological inhibition of p53 diminishes mitochondrial potential difference. We provide additional evidence that inhibition of p53 alters key metabolic enzymes regulating glycolysis and increases intermediates of glycolysis. In summary, we provide evidence that PET is a valuable tool for examining kidney metabolism in preclinical and clinical studies, intravital MPM is a powerful adjunct to PET in preclinical studies of metabolism, and p53 inhibition alters basal kidney metabolism.

High non-specific binding of the β1-selective radioligand 2-125I-ICI-H

2003 ◽  
Vol 42 (04) ◽  
pp. 173-180 ◽  
Author(s):  
M. P. Law ◽  
K. Kopka ◽  
St. Wagner ◽  
S. Luthra ◽  
V. W. Pike ◽  
...  
Keyword(s):  
Specific Activity ◽  
Single Photon ◽  
Specific Binding ◽  
Photon Emission ◽  
Radiochemical Yield ◽  
Emission Computed Tomography ◽  
Biodistribution Studies ◽  
Positron Emission

Summary: Aim: As results of cardiac biopsies suggest, myocardial β1-adrenoceptor density is reduced in patients with chronic heart failure. However, changes in cardiac β2-adrenoceptors vary. With suitable radiopharmaceuticals single photon emission computed tomography (SPECT) and positron emission tomography (PET) offer the opportunity to assess β-adrenoceptors non-invasively. Among the novel racemic analogues of the established β1-selective adrenoceptor antagonist ICI 89.406 the iodinated 2-I-ICI-H showed high affinity and selectivity to β1-adrenoceptors in murine ventricular membranes. The aim of this study was its evaluation as a putative sub-type selective β1-adrenergic radioligand in cardiac imaging. Methods: Competition studies in vitro and in vivo were used to investigate the kinetics of 2-I-ICI-H binding to cardiac β-adrenoceptors in mice and rats. In addition, the radiosynthesis of 2-125I-ICI-H from the silylated precursor 2-SiMe3-ICI-H was established. The specific activity was 80 GBq/µmol, the radiochemical yield ranged from 70 to 80%. Results: The unlabelled compound 2-I-ICI-H showed high β1-selectivity and -affinity in the in vitro competition studies. In vivo biodistribution studies apparently showed low affinity to cardiac β-adrenoceptors. The radiolabelled counterpart 2-125I-ICI-H showed a high degree of non-specific binding in vitro and no specific binding to cardiac β1-adrenoceptors in vivo. Conclusion: Because of its high non-specific binding 2-125I-ICI-H is no suitable radiotracer for imaging in vivo.

PROLACTIN TURNOVER IN RAT ADENOHYPOPHYSES IN VIVO: ITS EVALUATION AS A METHOD FOR ESTIMATING SECRETION RATES

1972 ◽  
Vol 53 (1) ◽  
pp. 1-15 ◽  
Author(s):  
KAREN C. SWEARINGEN ◽  
C. S. NICOLL
Keyword(s):  
Rate Constant ◽  
Specific Activity ◽  
Slow Component ◽  
Average Rate ◽  
High Rate ◽  
Female Rat ◽  
Double Exponential ◽  
Secretion Rates ◽  
Gland Content

SUMMARY The kinetics of prolactin turnover were investigated in female rat adenohypophyses in vivo. The animals received an intravenous injection of [3H]leucine and groups were killed at various times thereafter. The prolactin in their adenohypophyses was separated and measured by disc electrophoresis and densitometry. The hormone band was cut from the gel columns and counted by liquid scintillation procedures. The specific activity data (c.p.m./μg) were fitted to single or double exponential functions by the method of least squares, using a computer program. The slow component of the double exponential, or the single component of the single exponential were assumed to represent secretion and their rate constants were multiplied by the hormone content of the gland to obtain an estimate of secretion rate. The assumptions involved in this method of estimating secretion rates are discussed and evaluated. The rate constant for prolactin in oestrogen + reserpine-treated females (0·10–0·08 h−1) was higher than that obtained in rats treated with oestrogen alone (0·05–0·06), and approximately three times that in rats treated with reserpine only (0·03). The prolactin concentration in the adenohypophysis was highest in reserpine-treated rats (8·2 μg/mg) while in glands from oestrogen-treated (4·1–6·0 μg/mg) and oestrogen + reserpine-treated animals (5·0–6·2 μg/mg) it was similar. The average prolactin secretion rates in oestrogen-treated (0·26 μg/mg/h) and reserpine-treated (0·25 μg/mg/h rats were similar, while the average rate in reserpine + oestrogen-treated rats (0·54 μg/mg/h) was twice as high. The results with reserpine-treated animals (low rate constant, high gland content), with oestrogen + reserpine-treated animals (high rate constant), and of those previously obtained by us in ectopic adenohypophysial transplants (high rate constant, low gland content) are discussed in terms of possible involvement of a prolactin stimulating factor. It is concluded that this method provides useful estimates of secretion rates as well as information on the intrapituitary turnover of prolactin.

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