Detection of muscarinic receptors in the human lung using PET

The characterization of pulmonary muscarinic receptors with PET is still in its infancy. Because approximately 70% of the lungs consists of air and pu lmonary muscarinic receptor densities are low, ligands with high receptor a ffinity are required to obtain reasonable signal-to-noise ratios on PET ima ges. Therefore, the potent C-11-labeled muscarinic antagonist N-methyl-pipe ridin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide ([R]-VC-002) w as developed. We administered this radioligand to four healthy human volunt eers to examine its suitability for studying pulmonary muscarinic receptors in vivo. Methods: [C-11]VC-002 (185 MBq, specific activity > 7.4 TBq/mmol) was intravenously injected on 2 separate days, with an interval of at leas t 1 wk. On the first day the volunteers were not pretreated, but on the sec ond day they received the anticholinergic glycopyrronium bromide (Robinul; 2 x 0.1 mg intravenous) 25 and 30 min before the injection of the radiophar maceutical. C[O-15]O scans (approximately 740 MBq [20 mCi] by inhalation) w ere 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 m in postinjection and the lungs could no longer be seen. (R)-[C-11]-VC-002 w as rapidly cleared from plasma and was slowly metabolized during the time c ourse (60 min) of the PET scan. The fraction of radioligand representing pa rent 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, r eached a plateau value of 17.8 +/- 1.2 at 40-50 min postinjection. Conclusi on: [C-11]VC-002 appears to be suitable for in vivo studies of pulmonary ch olinoceptors.