Elsevier

NeuroImage

Volume 39, Issue 2, 15 January 2008, Pages 717-727
NeuroImage

Quantification of nicotinic acetylcholine receptors in the human brain with PET: Bolus plus infusion administration of 2-[18F]F-A85380

https://doi.org/10.1016/j.neuroimage.2007.09.015Get rights and content

Abstract

Quantitative analysis of most positron emission tomography (PET) data requires arterial blood sampling and dynamic scanning when the radioligand is administered as a bolus injection. Less invasive studies can be accomplished if the radioligand is administered as a bolus plus constant infusion (B/I). The purpose of the current study was to evaluate a B/I paradigm for quantifying high affinity nicotinic acetylcholine receptors (nAChRs) with PET and 2-[18F]F-A85380 (2FA). Seven volunteers underwent a study in which 2FA was administered as a bolus injection and another study in which the 2FA was administered by B/I (Kbolus = 500 min). We evaluated the feasibility of using scans of a 2 h duration starting 6 h after the start of the 2FA administration and data from venous blood. Radioactivity in the brain and in arterial and venous plasma reached steady state by 6 h. Volumes of distribution (VT) calculated from the ratio of radioactivity in the brain areas of interest to the radioactivity corresponding to unbound, unmetabolized 2FA in venous plasma at steady state in the B/I studies were very similar to those calculated from time activity curves of unbound, unmetabolized 2FA in arterial plasma and regional brain radioactivity from 8-h dynamic scans after bolus administration of 2FA. The results of repeated PET studies with 2FA showed a high reproducibility of VT measurements. We conclude that B/I methodology will be useful for clinical and research studies of brain nAChRs.

Introduction

The α4β2* subtype of high affinity nicotinic acetylcholine receptors (nAChRs) is the most abundant nAChRs in the mammalian brain (Lindstrom et al., 1995). These receptors are involved in many neuropathological states including tobacco dependence, as well as in modulating neurotransmission under physiological conditions (Mihailescu and Drucker-Colin, 2000). Therefore, the ability to quantify nAChRs in vivo may be useful for elucidating their role in these processes. The first PET radioligand that allows visualization and quantification of nAChRs in humans is 2-[18F]F-A-85380 (2FA). PET studies in humans and non-human primates acquired following a bolus administration of 2FA have been particularly successful in imaging and quantifying nAChRs in vivo (Chefer et al., 2003, Gallezot et al., 2005, Herzog et al., 2006, Kendziorra et al., 2006, Kimes et al., 2003, Kimes et al., 2006, Meyer et al., 2006a, Meyer et al., 2006b, Mitkovski et al., 2005, Picard et al., 2006). Reliably quantifying these receptors in human brain requires arterial blood sampling, and long scan times are necessary to quantify them in brain regions that contain high densities (e.g., thalamus). Avoiding arterial blood sampling would be feasible if there were a suitable reference region for analysis. However, even the use of the corpus callosum, which has a very low density of nicotinic receptors, is problematic in smokers either because specific binding in this region or spillover from other brain regions is not trivial in smokers (Brody et al., 2006).

Theoretically, accurate quantification of nicotinic receptors in human brain with 2FA requires arterial blood sampling for the entire scanning period. One way to avoid the need for arterial blood and/or a reference region is to use a bolus plus constant infusion (B/I) method of radioligand administration and venous blood instead of arterial blood.

The use of B/I methodology has been validated for in vivo studies of various neuroreceptors with a number of PET and SPECT radioligands (e.g., cyclofoxy (Carson et al., 1993), raclopride (Ito et al., 1998), iomazenil (Abi-Dargham et al., 1994), altanserin (Pinborg et al., 2003)). Quantifying nAChRs with PET and 2FA by the B/I method has been validated in rats (Vaupel et al., 2007). Although this methodology has been used for PET studies with 2FA in humans (Brody et al., 2006), it remains to be validated for this purpose.

In theory, there are several advantages to using B/I administration of 2FA instead of a single bolus injection for quantifying brain nAChRs in humans. Major benefits of the B/I method are a shorter scanning period because acquiring data from the beginning of the radioligand administration period is unnecessary and the ability to replace continuous arterial blood sampling with the collection of a few venous blood samples obtained 6–8 h after the start of 2FA administration. Additional advantages of B/I administration are: (1) a greater concentration of unmetabolized radioligand in the blood and brain during the last hours of scanning compared to bolus administration for doses that produce equivalent radiation exposure to the volunteer; (2) data analysis is independent of the compartmental organization of brain regions; (3) modeling is unnecessary as a simple ratio of concentration in the tissue to that in venous plasma at equilibrium yields total volume of distribution (VT). Finally, this method offers a simple and very sensitive tool for studying dynamic changes in receptor occupancy (Brody et al., 2006).

The advantages of the B/I method are realized most if the appropriate ratio of the dose administered as a bolus injection to that administered as continuous infusion is used. Conversely, the use of an inappropriate dose ratio and data collection only over a predetermined time interval could lead to serious errors in VT measurements.

Kbolus, a frequently used parameter, characterizes the ratio of the bolus dose to the infusion dose. Kbolus is defined as the time required to infuse an amount of radioligand equal to that administered as a bolus. The dependence of the time to approach the steady-state concentration of radioligand in the blood or brain area (T*) on the value of Kbolus is described by a U-shaped function. The coordinates of the minimum values for T* could differ for different brain regions and could be distinct from that of blood. In general, the coordinates for these minima for the blood and brain regions depend on the rate of elimination of the radioligand from the blood. In addition, the coordinates of the minima for each brain region depend on the clearance of radioactivity from the specific region as well. Therefore, a goal in developing B/I protocols is to determine a single Kbolus that could be useful for the entire set of brain regions to be analyzed and for most, if not all, individuals being tested.

The goal of the current study was to evaluate B/I administration of 2FA for nAChR quantification with PET in human volunteers. The bolus to infusion dose ratio (Kbolus) was chosen to approach steady-state conditions between the plasma and tissue compartments as quickly as possible for diverse VT values. As a potential future application of a B/I protocol for 2FA is the investigation of brain nicotinic receptors in nonsmokers and in smokers, participants from both groups were included in this study. We expected that smokers would exhibit higher VT values than nonsmokers and could possibly show different 2FA pharmacokinetics as well. Therefore, we evaluated the applicability of this calculated Kbolus by determining its utility in multiple brain regions regardless of their VT and in human volunteers who had potential variations in pharmacokinetics or maximum VT. We performed two PET studies, one with bolus administration of 2FA and the other with B/I administration of 2FA, in seven volunteers, four of whom were smokers and compared VT values obtained by these methods. We determined the time required for the radioligand to reach a steady state in arterial blood and brain after B/I administration of 2FA. Finally, we obtained a preliminary estimate of test/retest variability of the B/I method of 2FA administration in three volunteers.

Section snippets

Methods

The Institutional Review Board of National Institute on Drug Abuse (NIDA) Intramural Research Program approved the design of this study. Administration of the radioligand to the human volunteers was performed under an Investigational New Drug (IND) application to the Food and Drug Administration (FDA).

Time course of concentration of radioactivity in brain regions and plasma after bolus and bolus/infusion 2FA administration

For the bolus administration studies, radioactivity in the plasma peaked immediately after the 2FA injection and declined steadily for the remainder of the study as expected (Fig. 1A). The TACs for the radioactivity in the various VOIs peaked between 1 and 3 h and declined steadily thereafter (Fig. 1A). Fig. 1B shows the curves predicted for the brain regions and plasma if the 2FA had been administered by B/I using a Kbolus of 500 min. The curves in Fig. 1C are based on actual data from the B/I

Discussion

In this study, we showed that the VT of 2FA, which interacts with nAChRs, can be reliably determined with PET using B/I methodology and the concentration of unbound, unmetabolized radioligand in venous blood. As mentioned in the Introduction section, the B/I method provides several advantages over the bolus administration of the respective radioligand both in terms of comfort for the research participant and invasiveness and simplicity of the methods. Furthermore, once steady state is reached,

Conclusion

We conclude that 2FA administration via B/I (Kbolus = 500 min) with venous blood sampling and scanning from 6 to 8 h after the start of the 2FA infusion is a reliable method for quantifying nAChRs in the human brain. Because of its minimal invasiveness and shorter scanning duration, this procedure will be particularly useful in many clinical and experimental investigations (e.g., % receptor occupancy by nicotine or measuring VT and nondisplaceable volume distribution in the same study on the same

Acknowledgments

The authors would like to acknowledge Peter Willis, Ph.D., Andrew Hall, B.S., Andrew Horti, Ph.D., and Larry Koenig, A.A. for the radiosynthesis of the radioligand; Varughese Kurian, M.H.S. and Amy Kunce, C.N.M.T., A.R.R.T.(N) for maintaining the PET camera and acquiring the PET scans; Dean Shumway, B.S. for analyzing the blood samples; Betty Jo Salmeron, M.D. for her medical expertise; and Joyce Lutz, R.N. B.S., Kathy Demuth, R.N., B.S., and the rest of the NIDA nursing staff for their medical

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