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Detection of muscarinic receptors in the human lung using PET
T J Visser1, A van Waarde, T W van der Mark
1PET Center, Department of Pulmonary Diseases, Groningen University Hospital, The Netherlands.
Unlabelled:
The characterization of pulmonary muscarinic receptors with PET is still in its infancy. Because approximately 70% of the lungs consists of air and pulmonary muscarinic receptor densities are low, ligands with high receptor affinity are required to obtain reasonable signal-to-noise ratios on PET images. Therefore, the potent 11C-labeled muscarinic antagonist N-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide ([R]-VC-002) was developed. We administered this radioligand to four healthy human volunteers to examine its suitability for studying pulmonary muscarinic receptors in vivo.
Methods:
[11C]VC-002 (185 MBq, specific activity > 7.4 TBq/mmol) was intravenously injected on 2 separate days, with an interval of at least 1 wk. On the first day the volunteers were not pretreated, but on the second day they received the anticholinergic glycopyrronium bromide (Robinul; 2 x 0.1 mg intravenous) 25 and 30 min before the injection of the radiopharmaceutical. C[15O]O scans (approximately 740 MBq [20 mCi] by inhalation) were acquired before the receptor scan to calculate pulmonary blood volume.
Results:
On PET images of the thorax, the lungs were clearly visible. After the volunteer was pretreated with glycopyrronium bromide, pulmonary uptake of the radioligand was reduced to 32%+/-12% of the control value at 60 min postinjection and the lungs could no longer be seen. (R)-[11C]-VC-002 was rapidly cleared from plasma and was slowly metabolized during the time course (60 min) of the PET scan. The fraction of radioligand representing parent compound decreased from 99.9% at the time of injection to 82% at 40-60 min postinjection, both in the presence and absence of Robinul. Pulmonary tissue-to-plasma ratios, calculated on a count-per-minute-per-gram basis, reached a plateau value of 17.8+/-1.2 at 40-50 min postinjection.
Conclusion:
[11C]VC-002 appears to be suitable for in vivo studies of pulmonary cholinoceptors.
Insights
This study developed a novel PET radioligand, [R]-VC-002, for imaging pulmonary muscarinic receptors. The potent antagonist demonstrated suitability for in vivo characterization of these receptors in healthy volunteers.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Pulmonary pharmacology
Background:
- Pulmonary muscarinic receptor characterization using Positron Emission Tomography (PET) is an emerging field.
- Low receptor densities and high air content in lungs necessitate high-affinity ligands for PET imaging.
- Development of potent radioligands is crucial for achieving adequate signal-to-noise ratios.
Purpose of the Study:
- To develop and evaluate a potent radioligand for in vivo imaging of pulmonary muscarinic receptors.
- To assess the suitability of [R]-VC-002 for PET studies of the lungs.
- To examine the in vivo behavior of the radioligand in healthy human subjects.
Main Methods:
- Synthesis and administration of the novel 11C-labeled muscarinic antagonist, [R]-VC-002, to four healthy volunteers.
- PET scans were performed with and without pretreatment with the anticholinergic glycopyrronium bromide to assess specific binding.
- Pulmonary blood volume was calculated using C[15O]O inhalation scans.
Main Results:
- The lungs were clearly visualized on PET images with [R]-VC-002.
- Pretreatment with glycopyrronium bromide significantly reduced pulmonary radioligand uptake, indicating specific binding.
- [R]-VC-002 showed rapid plasma clearance and slow metabolism, with a stable tissue-to-plasma ratio.
Conclusions:
- The radioligand [R]-VC-002 is suitable for in vivo imaging of pulmonary cholinoceptors.
- This development advances the potential for PET-based research into lung diseases involving muscarinic receptors.
- Further studies can utilize [R]-VC-002 to investigate pulmonary cholinergic pathways.