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 [ 11 C]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 [ 11 C]VC-002 binding in lung and to examine the reliability using a test-retest paradigm. This work constituted a selfstanding 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 [ 11 C]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 (V T) values were obtained on a regional and voxel-by-voxel basis. Kinetic one-tissue and twotissue 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 V T estimates was evaluated by absolute variability (VAR) and intraclass correlation coefficients (ICCs). Results: The 1TCM was the statistically preferred model for description of [ 11 C]VC-002 binding in the lungs. Low VAR (< 10%) across analysis methods indicated good reliability of the PET measurements. The V T estimates were stable after 60 min.

Imaging in Asthma Management

“…116 Initial studies in humans suggest that this tracer has promise for developing new inhaled therapies for lung disease, which could ultimately impact the development of new asthma medications. 117 Ultimately, PET imaging has shown utility in identifying ventilation defects, airway inflammation, and drug delivery in patients with asthma. At the same time, this technique delivers ionizing radiation, and thus has more limitations on its widespread use than techniques such as hyperpolarized gas MRI or the more ubiquitous CT imaging.…”

Lung muscarinic receptor occupancy by tiotropium: translational PET studies in non-human primates and humans

“…ROIs for the lungs and the arch of the aorta were delineated automatically as described previously (Cselényi et al 2020). In short, the method relied on the co-registered CT images to identify voxels in the body with a density below water based on the CT Houns eld unit value.…”

“…The PET image was evaluated and, if possible, corrected for inter-frame subject movements as described previously (Cselényi et al 2020). In short, the reconstructed 4D PET image was frame-by-frame realigned to have a consistent subject position throughout.…”

“…[ 11 C]VC-002 binding to muscarinic receptors has very recently been further examined in a test-retest study in humans (Cselényi et al 2020). It was concluded that the kinetic behaviour and the binding characteristics of the radioligand appears suitable for applied studies on muscarinic receptor occupancy in the human lungs.…”

<p>Long-Acting Muscarinic Antagonists Under Investigational to Treat Chronic Obstructive Pulmonary Disease</p>

“…Discovery (now Pulmagen Therapeutics) with seven patent applications claiming multiple MABAs. 56 Five RCTs are registered as completed on clinicaltrial. gov, three phase I studies (NCT03097380, NCT01283984, NCT01445782) and two phase II studies (NCT01498081, NCT02109406).…”