Robust experiment design for estimating myocardial adrenergic receptor concentration using PET

Abstract

Myocardial beta adrenergic receptor (beta-AR) concentration can substantially decrease in congestive heart failure and significantly increase in chronic volume overload, such as in severe aortic valve regurgitation. Positron emission tomography (PET) with an appropriate ligand-receptor model can be used for noninvasive estimation of myocardial beta-AR concentration in vivo. An optimal design of the experiment protocol, however, is needed for sufficiently precise estimates of beta-AR concentration in a heterogeneous population. Standard methods of optimal design do not account for a heterogeneous population with a wide range of beta-AR concentrations and other physiological parameters and consequently are inadequate. To address this, we have developed a methodology to design a robust two-injection protocol that provides reliable estimates of myocardial beta-AR concentration in normal and pathologic states. A two-injection protocol of the high affinity beta-AR antagonist [18F]-(S)-fluorocarazolol was designed based on a computer-generated (or synthetic) population incorporating a wide range of beta-AR concentrations. Timing and dosage of the ligand injections were optimally designed with minimax criterion to provide the least bad beta-AR estimates for the worst case in the synthetic population. This robust experiment design for PET was applied to experiments with pigs before and after beta-AR upregulation by chemical sympathectomy. Estimates of beta-AR concentration were found by minimizing the difference between the model-predicted and experimental PET data. With this robust protocol, estimates of beta-AR concentration showed high precision in both normal and pathologic states. The increase in beta-AR concentration after sympathectomy predicted noninvasively with PET is consistent with the increase shown by in vitro assays in pig myocardium. A robust experiment protocol was designed for PET that yields reliable estimates of beta-AR concentration in a population with normal and pathologic states. This methodology is applicable in general to optimal estimation of parameters in heterogeneous populations.

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

“…Experimental designs were investigated for 2-and 3-injection studies to select the amount of unlabeled mefway and the injection time for each administration. The experimental design was selected using the D-optimal criterion, which minimizes the correlation between the kinetic parameters (described in Salinas et al, 2007). The inverse determinant of the reduced Hessian (det(H R ) À1 ) is proportional to the volume of the indifference region for the parameter estimates.…”

“…The requirement was enforced that the first injection of each study consist of high specific activity [ 18 F]mefway and 90 minutes of scanning. It has been shown that for other applications, it is possible to measure B max with a 2-injection protocol with partial saturating doses of the ligand for the first injection (Salinas et al, 2007). Such a design foregoes the ability to measure BP ND for comparison with radiotracer-only scans and was therefore not investigated for this work.…”

“…The M-I method provides a measure of receptor density that is independent of the characteristics of the radioligand, unlike the 'binding potential' metric obtained with tracer-only PET studies, which represent a composite function of B max and ligand-receptor affinity (Innis et al, 2007). The M-I methods have also been used for the measurement of B max in the peripheral benzodiazepine (Delforge et al, 1996), badrenergic (Muzic et al, 2000;Salinas et al, 2007), dopamine transporter (Morris et al, 1996;Poyot et al, 2001), dopamine D2 (Delforge et al, 1999;Christian et al, 2004;Mauger et al, 2005;Vandehey et al, 2010), and nicotinic acetylcholine (Gallezot et al, 2008) receptor systems.…”

Measuring α4β2∗Nicotinic Acetylcholine Receptor Densityin Vivowith [18F]nifene PET in the Nonhuman Primate

“…The D-optimal criterion, described in detail by Salinas and co-workers, 15 was used to maximize the identification and precision of the kinetic parameters B max , k on , and k off to select the optimal MI experimental design. Optimization of MI experiments focused on the thalamic regions of the brain.…”

Kinetic Analysis of Drug–Target Interactions with PET for Characterization of Pharmacological Hysteresis

“…2 For example multiple injection (MI) protocols using different specific activities (SA) were first proposed by Delforge et al 3 and subsequently used to estimate the affinity of labeled compounds, for example, CFT, 4 fallypride, 5 and fluorocarazolol. 6 Further, if a reference region devoid of specific target sites exists, the pseudoequilibrium method or multiple ligand concentration receptor assay can be applied using different SA injections, allowing for estimation of the affinity in an analogous manner to the in vitro Scatchard approach. 7,8 These methods work by achieving different levels of target occupancy via homologous competition with the radiolabeled compound, allowing separate estimates of target density and radioligand affinity.…”