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(Chest. 2005;128:3020-3027.)
© 2005 American College of Chest Physicians

Positron Emission Tomography Studies of Human Airways Using an Inhaled ß-Adrenoceptor Antagonist, S-11C-CGP 12388*

Aren van Waarde, PhD; Bram Maas, BSc; Petra Doze, PhD; Riemer H. Slart, MD; Henderik W. Frijlink, PhD; Willem Vaalburg, PhD and Philip H. Elsinga, PhD

* From the Department of Nuclear Medicine & Molecular Imaging (Drs. Van Waarde, Doze, Slart, Vaalburg, and Elsinga, and Mr. Maas), University Medical Center of Groningen, the Netherlands; and the Department of Pharmaceutical Technology and Biopharmacy (Dr. Frijlink), Groningen University Institute for Drug Exploration (GUIDE), Groningen, the Netherlands.

Correspondence to: Aren van Waarde, PhD, Groningen University Medical Center, PO Box 30001, 9700RB Groningen, the Netherlands; e-mail: a.van.waarde{at}pet.azg.nl


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: Positron emission tomography (PET) scanning may provide information on changes in the density and affinity of airway ß-adrenoceptors in lung diseases. However, the injection of a radiolabeled ß-blocker results in a pulmonary PET signal that reflects the binding of the ligand in the alveoli and not in the airways. Better discrimination between alveolar and airway ß-adrenoceptors may be possible with an inhaled radioligand.

Design: A nebulizer was used to administer the antagonist S-11C-CGP12388 in aerosol form. Eight volunteers inhaled the tracer twice, at baseline and after pretreatment with a ß-adrenergic drug. In both PET scan studies, a dynamic scan of the lungs was followed by a whole-body scan to assess the inhaled dose. Pulmonary uptake was quantified using a region-of-interest-based analysis.

Setting: University hospital.

Participants: Healthy volunteers.

Interventions: Pretreatment consisted either of inhaled salbutamol (400 µg, 20 min before the scan), or orally administered pindolol (3 x 5 mg during a period of 16 h before PET scanning).

Results: Drug pretreatment did not affect pulmonary deposition of the radioligand. The agonist salbutamol accelerated the monoexponential washout of 11C not only in the peripheral lung (mainly alveoli), but also in the central lung (mainly airways) and in the main bronchi. An even larger increase of the washout rate was induced by the antagonist pindolol.

Conclusion: The similar effects of pindolol and salbutamol on tracer kinetics suggest that accelerated washout is due to the blockade of ß-adrenoceptors. Thus, the interaction of drugs with airway ß-adrenoceptors can be visualized using PET scanning and an inhaled radioligand.

Key Words: ß-adrenoceptors • airways • lung • positron emission tomography • radioaerosol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Binding of the neurotransmitter norepinephrine to ß-adrenoceptors on airway smooth muscle results in muscle relaxation and airway widening.12 This function of norepinephrine may be altered in patients with pulmonary diseases such as asthma and COPD.34 Using the radiolabeled antagonist S-[11C]CGP12177 and positron emission tomography (PET) scanning, pulmonary ß-adrenoceptor densities have been determined in healthy volunteers and patients with asthma, before and after therapy with inhaled steroids and ß-agonists.56789 In these studies, the radioligand was administered by IV injection, resulting in the labeling of the complete pulmonary ß-adrenoceptor pool (ie, receptors on airway smooth muscle, alveolar walls, mucosal glands, and adrenergic neurons). Since 90% of all ß-adrenoceptors in the human lung are located in the alveoli,10 IV administration of a radioligand results in a PET signal that reflects the binding potential of alveolar receptors rather than airway ß-adrenoceptors.11

Binding sites for norepinephrine within the alveoli are not involved in the regulation of airway caliber, in contrast to those on smooth muscle cells. The subpopulations of ß-adrenoceptors within the airways and in the alveolar wall of the human lung may be differently regulated.12 A technique that visualizes airway ß-adrenoceptors rather than alveolar ß-adrenoceptors would therefore be useful to study the mechanisms of congestion and airway hyperreactivity in patients with pulmonary diseases.

The current study is the first attempt to visualize ß-adrenoceptors on the smooth muscle of human airways by inhalation of an aerosol containing a radiolabeled ß-blocker. By administering S-[11C]CGP12388 to healthy volunteers in aerosol form, we tried to answer the following two questions: (1) can ß-adrenoceptors in human airways be visualized with an inhaled radioligand?; and (2) can the interaction of ß-adrenergic drugs with airway receptors be assessed with PET scanning? The subjects were scanned at baseline and after pretreatment with either a ß-agonist (salbutamol) or a ß-adrenoceptor antagonist (pindolol). Both the agonist and the antagonist will compete with S-[11C]CGP12388 for binding to ß-adrenoceptors, resulting in a loss of (apparent) binding sites and the accelerated washout of the radioligand. However, the agonist and the antagonist will have different (ie, accelerating and retarding, respectively) effects on other pulmonary parameters like mucociliary clearance.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Participants
Two PET scans were made in eight healthy volunteers (mean [± SD] age, 29 ± 9 years; mean body length, 179 ± 11 cm; mean body weight, 70 ± 10 kg) [Table 1 ]. All volunteers were nonsmokers. They were medically examined and declared healthy after laboratory tests of blood samples had indicated normal kidney and liver function. Subjects with pulmonary diseases such as tuberculosis, asthma, hay fever, or COPD, individuals displaying any sneezing, wheezing, or shortness of breath, and subjects with infections of the upper respiratory tract within 2 weeks prior to the study were excluded from the study. The project was approved by the Medical Ethics Committee of the Groningen University Hospital. Each individual gave written informed consent.


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  		Table 1.. Characteristics of Volunteers

 
Radiopharmaceutical
S-[11C]CGP12388, the isopropyl analog of the well-known ß-adrenoceptor ligand S-[11C]CGP12177,1314 is currently employed for the visualization and quantification of ß-adrenoceptors in the human heart, using a multiinjection protocol.15 Specific binding of (IV-administered) S-[11C]CGP12388 is also visible in human lung and spleen.16 S-[11C]CGP12388 is hydrophilic (logD, –2.01 at pH 7.4) and binds to the surface but not to intracellular ß-adrenoceptors. The tracer has been validated in experimental animals and has been shown to bind to ß-adrenoceptors in vivo.14

Administration of Radiopharmaceutical
Before the first PET scan, the volunteers were instructed and trained in the use of the jet nebulizer (Pari Boy Pari LC Plus; Huisman; Tiel, the Netherlands). A mean dose of 552 ± 124 MBq of (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxy-propoxy)-2H-benzimidazol-2-one [S-11C-CGP12388] in 6 mL of saline solution (containing 9% ethanol; specific radioactivity of ligand, 22 to 30 TBq/mmol) was placed in the chamber of the nebulizer. The membrane pump of the device ensured the delivery of 1.76 mL of radioligand solution in aerosol form (mean x50 droplet size, 3.7 ± 0.2 µm) during a period of 2 min, corresponding to a mean decline of radioactivity within the nebulizer of 162 ± 53 MBq. The calculated radiation dose (both PET studies combined) that subjects received was < 3.0 mSv. Inhalation of the radioligand was performed with the subject seated on the bed of the PET camera (ECAT Exact HR+; Siemens; Munich, Germany) and a clamp on the nose of the subject to force inhalation through the mouth. Before the administration of the radioligand, the volunteer was properly positioned using the mid-clavicular line, jugulum, and xiphoid. This ensured that the carina was at the top of the field of view when the volunteer lay down after inhalation. When inhalation was completed, the subject immediately moved to the supine position. Data acquisition was started 2 min after the end of inhalation.

Each subject was examined twice, with an interval of at least 1 week between the two PET studies. The first study was performed under baseline conditions. Before the second study, subjects were treated with a ß-adrenergic drug. Pretreatment consisted either of inhaled salbutamol (400 µg from a commercial pressurized nebulizer, 20 min before the inhalation of S-[11C]CGP-12388), or orally administered pindolol (3 x 5 mg, at intervals of 16, 6, and 1 h before PET scanning).

Camera Protocol
The data acquisition protocol consisted of:

  1. Dynamic acquisition (with the carina at the top of the field of view). The following frames were defined: 10 x 30 s; 3 x 5 min; and 3 x 10 min. The total duration of the dynamic scan was 50 min (in volunteers 1 to 4). In the second series of PET studies (in volunteers 5 to 8), dynamic acquisition was performed over 40 min rather than over 50 min since subjects had complained about the long duration of the scan.
  2. Transmission scanning, using the internal 68Ge/68Ga sources of the camera (carina at top of field of view).
  3. Whole-body scan of seven positions, from the crown to the lower part of the abdomen, to assess the inhaled dose and the distribution of radioactivity in the time frame of 70 to 140 min after inhalation. Before undergoing the whole-body scan, the volunteers were allowed to leave the camera for a short interval to visit the toilet and to have a little bit of exercise.

Computation of Lung Clearance Rate and Pulmonary Deposition
Decay-corrected time-activity curves were derived from regions of interest (ROIs) drawn in the transaxial images. Three different regions (central, peripheral, and tracheobronchial) were examined as explained above (Fig 1 ). To improve the counting statistics, data from at least six consecutive planes were summed. In central and peripheral ROIs, there was no difference between a monoexponential half-life calculated from data from the initial 5 to 10 min and that calculated from the whole data set of the dynamic study. Thus, the half-life of the whole curve was used to describe the central and peripheral tracer clearance of each subject. In tracheobronchial ROIs, tracer clearance during the initial 5 to 10 min was more rapid than that in the subsequent period. Here, data from the last frames (10 to 50 min) were used to calculate washout, a common procedure the method for which was taken from the literature.17



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  		Figure 1.. Transaxial PET scan image of volunteer 5, with ROIs drawn on the peripheral lung (A), the central lung (B), and the tracheobronchial region (C). the pulmonary outline is determined from the transmission scan.

 
Pulmonary deposition of the S-[11C]CGP12388 radioaerosol was calculated from the scatter-corrected whole-body images, corrected for decay. The amount of radioactivity in the pulmonary planes was summed and divided by the amount of radioactivity within the entire body. This allowed us to express the pulmonary deposition as a percentage of the inhaled dose.

Statistical Analysis
The statistical significance of the differences between the mean values in control subjects and drug-treated subjects was determined using one-way analysis of variance. A p value of < 0.05 was considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Data on the deposition of S-11C-CGP12388 in the human lung are presented in Table 2 . No significant differences were observed between baseline and drug treatment. The mean radioactivity in the central lung was 3,841 ± 1,342 Bq/mL at baseline and 3,224 ± 1,472 Bq/mL after drug treatment. The values listed in Table 2 indicate that maximally about 60% of the inhaled dose is deposited in the lungs, with the remainder being swallowed after deposition in the mouth, pharynx, and esophagus. Whole-body images made 70 to 140 min after inhalation clearly showed lungs and trachea, but also showed the pharynx, larynx, stomach, intestines, kidneys, and/or urinary bladder (Fig 2 ).


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  		Table 2.. Pulmonary Deposition of the Radioligand*

 


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  		Figure 2.. Whole-body scan of volunteer 5.

 
Inhalation of the ß2-agonist salbutamol resulted in a slight (49%) increase in the rate of washout of the radioligand from the peripheral lung (Fig 3 , Table 3 ). The mean half-life of the washout decreased from 207 ± 48 to 135 ± 16 min. This decrease was statistically significant (p = 0.002). The oral administration of the ß-blocker pindolol caused a more pronounced (167%) increase of the clearance rate of the 11C radioligand from the peripheral lung (Fig 3, Table 3). The mean half-life of the washout was then decreased from 207 ± 48 to 75 ± 10 min (p < 0.0001). The effect of pindolol on the washout rate was significantly greater than that of salbutamol (p < 0.002).



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  		Figure 3.. Washout kinetics of 11C from the peripheral lung (data from all volunteers included, each volunteer was also the control subject)

 

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  		Table 3.. Washout Kinetics of 11C in the Peripheral Lung

 
Similar drug effects were observed in the central lung (Table 4 ). The inhalation of salbutamol caused a 42% increase in the rate of washout from this area. The mean half-life of the washout decreased from 139 ± 17 to 97 ± 6 min; this decrease was statistically significant (p < 0.0005). The ingestion of the ß-blocker pindolol also increased the clearance rate of 11C from the central lung. The mean half-life of the washout was then decreased from 139 ± 17 to 80 ± 12 min (p = 0.0001). In contrast to the data acquired for the peripheral lung, the effect of pindolol on washout of the tracer from the central lung was not significantly greater than that of salbutamol (p = 0.07).


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  		Table 4.. Washout Kinetics of 11C in the Central Lung

 
The tracer was washed out significantly faster from the central lung than from the peripheral lung, both at baseline (p < 0.0005) and after the treatment of subjects with salbutamol (p < 0.005). However, there was no significant difference between the rates of washout from the central and peripheral lung in pindolol-treated subjects (p = 0.64).

The drug effects on tracer washout were observed not only in the central and peripheral lung, but also in ROIs placed on the tracheobronchial region (Table 5 ). At baseline, the tracer was washed out faster from this area than from the central lung (p < 0.02) and the peripheral lung (p = 0.0001). The mean half-life of the washout was decreased from 108 ± 26 to 62 ± 9 min after the inhalation of salbutamol (p < 0.001). A similar decrease (to 60 ± 8 min) was observed after the oral administration of pindolol (p < 0.001) [Table 5]. The baseline scans of two volunteers (No. 2 and 5) showed a relatively poor fit, probably because of subject movement during the last 40 min of the dynamic PET scan.


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  		Table 5.. Washout Kinetics of 11C in the Tracheobronchial ROI

 
Transaxial images of the human thorax showed tracer uptake in the lungs but not in the heart, in contrast to images acquired after the IV administration of the radioligand (Fig 4 ).16



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  		Figure 4.. Transaxial images of the human thorax acquired with S-[11C]CGP12388. Left: image acquired after IV administration of the radioligand, showing both the heart and lungs (from Elsinga et al16). Right: image acquired after the inhalation of the radioligand, showing the lungs only (from the present study).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although both ß1-adrenoceptors and ß2-adrenoceptors are present in the human lung, the ß2-subtype predominates, comprising 70 to 75% of the total ß-adrenoceptor population.101819 The ß-adrenoceptors on smooth muscle from large and small airways are entirely of the ß2-subtype.10 Salbutamol is an agonist drug with moderate ß2-selectivity,2021 and pindolol is a non-subtype-selective ß-adrenoceptor antagonist.2122 The bronchodilatory effect of inhaled salbutamol starts within 5 min, is maximal after 30 to 90 min, and lasts 4 to 6 h.21 Thus, the time frame of the maximal occupancy of airway ß-adrenoceptors by salbutamol (30 to 90 min after inhalation) coincided with the time frame of our dynamic PET scan, which was performed 25 to 75 min after salbutamol inhalation. The dose of 3 x 5 mg pindolol that we employed here has in previous PET studies been shown to result in virtually complete occupancy of the pulmonary and myocardial ß1-adrenoceptor and ß2-adrenoceptor pools.1623

The site of deposition of the aerosol particles in the ventilatory tree depends on particle velocity and size.2425 Larger particles will deposit more proximally in the airways, while very small and uniform particles (size, < 2 µm) can travel distally into the alveoli.2526 The aerosol droplets that were produced by our commercial jet nebulizer (size, 3.7 µm) will be deposited not only in the central lung, but partially also in peripheral regions of the human lung.27282930 Nevertheless, the inhalation of S-[11C]CGP12388 appeared to result in better delineation of the large airways than IV injection of the radioligand (Fig 4). Discrimination between alveolar and airways deposition and clearance was possible by placing ROIs over different areas, as follows: (1) peripheral lung (mainly alveoli); (2) central lung (mainly airways) and; (3) tracheobronchial region (airways only) [Fig 1]. In previous studies with IV administered ß-adrenoceptor ligands, this could not be done since the trachea and main bronchi were not visualized under such conditions.

In our studies with an aerosolized radiolabeled ß-adrenoceptor antagonist, about 54% of the inhaled dose was deposited within the lungs (average value of baseline studies reported in Table 2). These data are in accordance with values from the literature for the deposition of drug aerosols using a nebulizer. In healthy subjects who were breathing at their own frequency (mean respiration rate, 16 ± 5 breaths/min), a mean proportion of 48 ± 14% of an inhaled 99mTc-diethylenetriaminepentaacetate aerosol was found to be deposited in the lungs. If the subjects were instructed to breath slowly and in a well-controlled fashion (mean respiratory rate, 11 ± 5 breaths/min), the pulmonary deposition of the inhaled dose increased significantly to 60 ± 17%.31 We observed values ranging from 47.6 to 62.7% at baseline (Table 2), which are comparable to these previous single-photon emission CT scan data. Larger variation (and lower deposition in some individuals) were observed in the salbutamol-treated group (Table 2). Increased nervousness (a well-known side effect of inhaled salbutamol, especially in drug-naive subjects21) may have resulted in more rapid breathing within the salbutamol group and, correspondingly, to lower values for the pulmonary deposition of the radioligand.

Apparently, the remaining 45.9% of the S-[11C]CGP12388 dose was deposited in the mouth, pharynx, larynx, and esophagus. Part of this material was swallowed and transported to the stomach and intestines during the 2.5-h study period. Radioactivity in the kidney and urinary bladder originates from the radioligand entering the blood from the intestines and the lungs, followed by renal clearance. IV-administered S-[11C]CGP12388 and S-[11C]CGP12177 are predominantly excreted intact via the urine.1432

In PET studies involving the IV administration of a radioligand, pretreatment with receptor blockers should result in a lower uptake of the tracer within target organs. However, after the administration of a radioligand by inhalation, lower initial uptake is not to be expected. The deposition of radioactivity within the lungs will then depend on the size of the aerosol particles, but not on the pulmonary receptor density. The high-affinity binding of the radioligand to ß-adrenoceptors will result in the prolonged retention of radioactivity within lung tissue, whereas nonspecifically bound ligand will be washed out relatively rapidly. Our observation of identical deposition (Table 2) but accelerated washout (Tables 3Go to 5) of the label after pretreatment of the volunteers with ß-adrenergic drugs is what one would expect to find. During the initial 10 min of the dynamic PET scan, a more rapid washout of the tracer may be observed than in the subsequent study period if there is relatively much nonspecific binding within the ROI. We did observe this in the tracheobronchial region, but not in other parts of the ventilatory tree. In the central and peripheral lung, there was no significant change of washout rate during the scanning period.

When a radiopharmaceutical or drug is inhaled, it first reaches the airway surface liquid (surfactant), including mucus. The thickness of this layer will determine the concentration of the drug in solution and, therefore, the rate of its entry into the tissue. The drug must then cross the airway epithelium, which is a substantial barrier, especially for hydrophilic compounds. Subsequently, it must diffuse through the epithelial basement membrane and the interstitium. Finally, it may be taken up into the mucosal vasculature from where it can reach target organs such as the airway smooth muscle.33

Both an agonist and antagonist will compete with an inhaled radioligand for binding to ß-adrenoceptors, resulting in a loss of apparent binding sites within lung tissue and a more rapid tracer washout. However, an agonist and an antagonist can be expected to have opposite or different effects on other pulmonary parameters, such as mucus secretion, mucociliary clearance, airway blood flow, and epithelial permeability.3435 The similar effect of salbutamol and pindolol on tracer kinetics that we observed in this study (Fig 3, Tables 345) suggests that the accelerated washout of the tracer is due to blockade of ß-adrenoceptors. ß-adrenoceptor occupancy by an unlabeled drug will result in an increased concentration of "free" ligand within tissue and accelerated diffusion of S-[11C]CGP12388 from mucosa to the blood.

Two observations support this interpretation. First, when volunteers undergo PET scanning under baseline conditions, the slowest washout of S-[11C]CGP 12388 is observed in the peripheral lung. A more rapid washout occurs in the central lung, and the most rapid washout occurs in the tracheobronchial region. Consequently, the effect of pindolol is strongest in the peripheral lung, is intermediate in the central lung, and is smallest in the tracheobronchial area (Tables 345). This observation is consistent with the well-known fact that ß-adrenoceptor density is about three times higher in the alveolar wall than in the smooth muscle of the airways.10 Second, the washout rate that we observed in the peripheral lung (mean half-life, 207 ± 48 min) [Table 3] after the inhalation of S-[11C]CGP12388 is identical to the slow kinetic phase that we observed in the human lung after IV injection of the same radiotracer (mean half-life, 218 ± 66 min).16 This slow kinetic phase has been shown to correspond to the binding of the radioligand to pulmonary ß-adrenoceptors, both in experimental animals14 and in humans.16 Apparently, the pulmonary washout rate of inhaled S-[11C]CGP12388 is mainly determined by ß-adrenoceptor binding, and the interaction of drugs with airway ß-adrenoceptors can be visualized with PET scanning.


   Footnotes
 
Abbreviations: PET = positron emission tomography; ROI = region of interest

Received for publication February 8, 2005. Accepted for publication May 5, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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