Quantification of [18F]diprenorphine kinetics in the human brain with compartmental and non-compartmental modeling approaches

doi:10.1016/j.neuroimage.2004.04.009

NeuroImage

Volume 22, Issue 4, August 2004, Pages 1523-1533

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Abstract

6-O-(2-[¹⁸F]fluoroethyl)-6-O-desmethyldiprenorphine ([¹⁸F]FDPN) is a nonselective opiate ligand that binds to postsynaptic μ, κ and δ opiate receptors. Due to the longer half-life of F-18, compared to C-11, labeling DPN with F-18 allows for alternative experimental protocols and potentially the evaluation of endogenous opioid release. The applicability of this compound to assorted experimental protocols motivated the evaluation of [¹⁸F]FDPN kinetics with compartmental and non-compartmental models. The results indicate that a two-tissue compartmental model best characterizes the data obtained following a bolus injection of [¹⁸F]FDPN (120-min scanning protocol). Estimates of distribution volume (DV) were robust, being highly correlated for the one-tissue compartmental model as well as the invasive Logan model and the basis function method. Furthermore, the DV estimates were also stable under a shortened protocol of 60 min, showing a significant correlation with the full protocol. The binding potential (BP) values showed more variability between methods and in some cases were more sensitive to protocol length. In conclusion, this evaluation of [¹⁸F]FDPN kinetics illustrates that DV values can be estimated robustly using compartmental modeling, the basis function method or the invasive Logan modeling approach on a volume of interest level. BP values were also found to correlate with DV values; however, these results should be interpreted with the understanding that specific binding in the reference region (occipital region) may exist.

Introduction

The radioligand, [¹¹C]diprenorphine ([¹¹C]DPN), is commonly used to assess the opiate receptor system in physiologic and pathophysiologic conditions Duncan, 1999, Jones et al., 1991, Mayberg et al., 1991, Sadzot et al., 1990, Weeks et al., 1997. However, applicability of this radioligand to long acquisition protocols can be limited due to the short half-life of ¹¹C (t_{1/2, C-11} = 20 min). Thus, efforts were made to synthesize 6-O-(2-[¹⁸F]fluoroethyl)-6-O-desmethyldiprenorphine ([¹⁸F]FDPN) (Wester et al., 2000), which has similar pharmacologic properties to [¹¹C]DPN, but a longer half-life (t_{1/2, F-18} = 109.7 min). [¹⁸F]FDPN is now applicable to alternative experimental designs, including single bolus protocols investigating endogenous ligand release Alpert et al., 2003, Pappata et al., 2002, Sprenger et al., 2003, which may serve as alternatives to the two scan or bolus plus constant infusion approaches. Furthermore, this compound can be used at centers without an on-site cyclotron, thereby increasing its usage in the assessment of the opiate receptor system as well as its use in routine clinical evaluations. Due to the longer half-life, this compound also shows improved signal intensity compared that of [¹¹C]DPN, which results in an improved signal to noise ratio (SNR) (Wester et al., 2000).

The potential application of [¹⁸F]FDPN within the scientific and medical community motivated the characterization of this compound's time-varying dynamics in a population of normal healthy subjects. Therefore, we have undertaken a kinetic study to compare the performance of various modeling approaches with the [¹⁸F]FDPN tracer. The invasive models assessed here include the standard one-tissue and two-tissue compartmental models, the Logan model and the basis function method. Additionally, three reference tissue models were examined, including the noninvasive Logan model, the simplified reference tissue model and the tissue ratio method. The performance of each model is evaluated and estimates of distribution volume (DV) and binding potential (BP) are compared. Lastly, the stability of the DV and BP parameters are also examined for a shortened protocol.

Section snippets

Data acquisition

Six healthy volunteers (mean age 42 years, range 30–59 years; two females, four males) underwent a [¹⁸F]FDPN PET-study as part of an existing protocol. All subjects gave informed written consent and the study protocol was approved by the ethics committee at the Technische Universität München and the radiation protection authorities. Images were acquired over 120 min with the following frame durations: 6 × 30 s; 7 × 1 min; 4 × 2.5 min; 2 × 5 min; 3 × 10 min; 5 × 2 min; 4 × 2.5 min; 2 × 5 min; 3

Compartmental model performance

Representative time activity curves from a single subject are shown in Fig. 1. Fig. 2 presents the model fits from the 2T and 1T analyses to data from the occipital and thalamus VOIs of this subject. In general, the 1T model tended to underestimate the kinetic behavior at early and late time points while overestimating the concentration in the middle portion of the curve. This was especially evident in the occipital and cerebellum VOIs, which were both fit optimally with a 2T model.

The

Discussion

In ligand binding studies, it is desired to determine the receptor density and the binding/release of a ligand under different physiologic conditions. Thus, in the analysis of PET radioligand experiments, kinetic models have been formulated that provide surrogate measures of ligand binding kinetics (e.g. B_max/K_d) (Mintun et al., 1984). In this regard, the macro-parameters of DV and BP have been established as standard outcome measures for ligand binding studies. These parameters are

Acknowledgements

We would like to acknowledge the work of our colleagues Brigitte Dzewas and Choletta Kruschke for their excellent technical assistance in data acquisition. This work was supported by grants from the KKF (8764153), the Deutsche Forschungsgesellschaft (SFB 391, TP C9), the German Network for Neuropathic Pain by BMBF and the Norwegian Research Council Project number 151445/432.

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Quantification of [18F]diprenorphine kinetics in the human brain with compartmental and non-compartmental modeling approaches

Abstract

Introduction

Section snippets

Data acquisition

Compartmental model performance

Discussion

Acknowledgements

NeuroImage

Nucl. Med. Biol.

J. Neurosci. Methods

Eur. Neuropsychopharmacol.

NeuroImage

Methods

Nucl. Med. Biol.

NeuroImage

Brain Res.

Nucl. Med. Biol.

Pain

A new look at the statistical model identification

IEEE Trans. Autom. Control

Definition of a reference region for PET/[11C]diprenorphine studies

J. Cereb. Blood Flow Metab.

Comparison of bolus and infusion methods for receptor quantitation: application to [18F]cyclofoxy and positron emission tomography

J. Cereb. Blood Flow Metab.

Positron emission tomography receptor studies in epilepsy

Rev. Neurol. (Paris)

Quantification of [¹⁸F]diprenorphine kinetics in the human brain with compartmental and non-compartmental modeling approaches

Definition of a reference region for PET/[¹¹C]diprenorphine studies

Comparison of bolus and infusion methods for receptor quantitation: application to [¹⁸F]cyclofoxy and positron emission tomography