Quantification and reliability of [11C]VC - 002 binding to muscarinic acetylcholine receptors in the human lung - a test-retest PET study in control subjects

Abstract

Background: The radioligand [11C]VC-002 was introduced in a small initial study long ago for imaging of muscarinic acetylcholine receptors (mAChRs) in human lungs using positron emission tomography (PET). The objectives of the present study in control subjects were to advance the methodology for quantification of [11C]VC-002 binding in lung and to examine the reliability using a test-retest paradigm. This work constituted a self-standing preparatory step in a larger clinical trial aiming at estimating mAChR occupancy in the human lungs following inhalation of mAChR antagonists.

Methods: PET measurements using [11C]VC-002 and the GE Discovery 710 PET/CT system were performed in seven control subjects at two separate occasions, 2-19 days apart. One subject discontinued the study after the first measurement. Radioligand binding to mAChRs in lung was quantified using an image-derived arterial input function. The total distribution volume (VT) values were obtained on a regional and voxel-by-voxel basis. Kinetic one-tissue and two-tissue compartment models (1TCM, 2TCM), analysis based on linearization of the compartment models (multilinear Logan) and image analysis by data-driven estimation of parametric images based on compartmental theory (DEPICT) were applied. The test-retest repeatability of VT estimates was evaluated by absolute variability (VAR) and intraclass correlation coefficients (ICCs).

Results: The 1TCM was the statistically preferred model for description of [11C]VC-002 binding in the lungs. Low VAR (< 10%) across analysis methods indicated good reliability of the PET measurements. The VT estimates were stable after 60 min.

Conclusions: The kinetic behaviour and good repeatability of [11C]VC-002 as well as the novel lung image analysis methodology support its application in applied studies on drug-induced mAChR receptor occupancy and the pathophysiology of pulmonary disorders.

Trial registration: ClinicalTrials.gov identifier: NCT03097380, registered: 31 March 2017.

Keywords: Lungs; Muscarinic acetylcholine receptors; Positron emission tomography; Test-retest; [11C]VC-002.

Conflict of interest statement

ZC, AJ, PJ, MS, LF, KG, PE, CK and UGE are employees of AstraZeneca and may own stock or stock options. The other authors have no disclosures to report.

Figures

Fig. 1

Coronal and axial summation PET images (0–93 min) in thorax after intravenous injection of the radioligand [11C]VC-002 in healthy subject #1. Coloured PET images in standardized uptake value units (SUV) are overlaid on structural CT images in grey scale

Fig. 2

a Time-radioactivity curves (TACs, mean ± SD) in standardized uptake value units (SUV) for the lung after i.v. injection of [11C]VC-002. b TACs in lung, corrected for radioactivity in pulmonary blood volume. c TACs in plasma. d Lung-to-plasma ratio of TACs

Fig. 3

a Radiochromatogram from gradient HPLC analysis of human plasma at 30 min after I.V. injection of [11C]VC-002 in subject #1. The larger peak to the right represents unchanged [11C]VC-002, whereas the left peak represents a radioactively labelled metabolite that is more polar than [11C]VC-002. b Time course for the fraction (%) of radioactivity in plasma representing unchanged [11C]VC-002 (mean fitted curves with SD indicated using error bars). An empirical model using the Richards equation [25] was fitted to the measured parent fraction

Fig. 4

a Radioactivity in lung tissue vs time (not corrected for blood volume) after I.V. injection of [11C]VC-002 in subject #1 and 1TCM, 2TCM fits. b Illustration of Logan’s linear graphical analysis for subject #1 (1st PET). c Regression of VT parameter estimates from MLLogan vs. 1TCM

Fig. 5

Representative parametric lung images obtained from DEPICT analysis of [11C]VC-002 binding in subject #1. Note that the heart and liver were not included in the generation of parametric images. a Fractional blood volume (Vb). b Kinetic rate constant K1, showing the radioligand influx rate from blood to tissue that is proportional to blood flow and the radioligand extraction coefficient. c Total distribution volume (VT), which is the main outcome parameter of the analysis. d Compartmental model order (MO), showing the estimated number of pharmacokinetic compartments in tissue that is sufficient to adequately describe the data

Fig. 6

Time stability of VT measurements for [11C]VC-002. The effect of progressive truncation of measurement time on: a the lung VT mean estimates, and b their repeatability (absolute variability, VAR). Comparison of time stability between one-tissue compartment model (1TCM) and multi-linear Logan graphical analysis (MLLogan)