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The Proceedings of the American Thoracic Society 1:329-337 (2004)
© 2004 The American Thoracic Society

Imaging Drug Delivery and Drug Responses in the Lung

Myrna Dolovich and Renee Labiris

Departments of Medicine and Radiology, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada

Correspondence and requests for reprints should be addressed to Myrna Dolovich, P.Eng., McMaster University, Health Sciences Centre, Room 1V18, 1200 Main Street West, Hamilton, ON, L8N 3Z5 Canada. E-mail: mdolovic{at}mcmaster.ca


   ABSTRACT
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ISOTOPES FOR IMAGING THE...
 LUNG IMAGING
 IMAGING DRUG RESPONSES
 CONCLUSIONS
 REFERENCES
 
Conventional two-dimensional and three-dimensional single photon emission computed tomography and positron emission tomography imaging tools and specific inhaled radiotracers allow accurate and reliable measurements of drug delivery to the lung. Pharmacokinetics and patterns of drug distribution can be monitored over time. In addition, physiologic measurements of ventilation, perfusion, mucociliary clearance, inflammation, and respiratory absorption can be determined using imaging; the results correlate with "black-box" outcomes (for example, spirometry, airway responsiveness, and inflammatory markers in sputum, and bronchoalveolar lavage fluid), providing an indication of the disease state in situ and the effectiveness of therapeutic and other interventions on these critical lung functions. Imaging is widely used in drug discovery. Screening of new drugs using animal models and specifically molecular imaging before human studies is an approach used extensively by the pharmaceutical industry. Topical drug delivery to the lung remains the route of choice for administering respiratory therapies; recently, inhaled therapies have been formulated to gain access to the systemic circulation via the distal lung. Imaging provides a means of validating drug delivery to the site of action in the lung and of measuring the resulting pharmacokinetics of these therapies. No other tool or test provides this type of visual detail supported by numerical information related to a specific drug molecule.

Key Words: deposition • drug delivery • inflammation • pharmacokinetics • positron emission tomography

Determining the topical dose and distribution of inhaled therapies can be accomplished using radio-labeled tracers and imaging (1–3). The most widely used techniques are those employing the conventional two-dimensional (2D) planar gamma camera and three-dimensional (3D) single photon emission computed tomography (SPECT) camera. The use of positron emission tomography (PET) and magnetic resonance imaging (MRI) for clinical diagnostic purposes and research at the molecular level is increasing as the advances in technology and the possibilities for developing novel radiotracers are realized and become more readily available for human use. The substantial number of publications in the field of molecular imaging and biology in the last several years is an indicator that this area has become extremely important to clinical medicine.

PET is a 3D functional imaging technique that provides accurate and highly specific information on dose, distribution, and kinetics of an inhaled or injected radiotracer in the lung (4). PET offers several advantages over 2D and SPECT imaging. First, it provides increased image resolution, with millimeter slices of lung visualized in all three planes (namely, coronal, sagittal, and transaxial), allowing greater detail and accuracy of the regional distribution of the drug (5). Second, with this imaging technique, an in vivo estimate of large airway/small airway deposition of the inhaled drug can be made using direct-radiolabeled drug molecules. Patterns of inhaled drug deposition throughout the lung can be matched to anatomic structures by overlying the emission (radioactivity) scan on the transmission (density) scan. The subsequent fate of the drug particle, whether it is absorbed from, cleared, or retained in the lung can be measured. Third, the PET technology also uses radiolabeled molecular markers to obtain functional imaging of physiologic and biologic processes in vivo (6). Changes to ventilation and blood flow in response to a direct stimulus can be measured, location of receptors within the lung can be mapped, and lung injury and inflammation can be monitored (7).

There are a number of outcome measurements specific to lung function that can be obtained with 2D and 3D SPECT and PET imaging and have been used to estimate responses to inhaled therapies. These protocols assess changes in drug distribution related to changes in airway caliber with therapy, changes to the distribution of ventilation with therapy or in response to a challenge aerosol, the measurement of surface transport of secretions (mucociliary clearance), and the transepithelial transport of fluid and hydrophilic solutes (respiratory clearance or epithelial permeability). The latter two techniques are used to assess the integrity of the lung epithelium under a variety of conditions (8). Several PET markers have now been synthesized that allow a visualization of pulmonary ß-receptor distribution in vivo, as well as providing an estimation of function (9, 10). Recent use of hyperpolarized helium-3 (HHe3) magnetic resonance to image the lung in disease (11) and to assess the effects of interventions and drug therapies on lung ventilation has produced striking 3D images of central airway structure, including details of the peripheral airways down to approximately the seventh generation (12).

This paper discusses several studies illustrating the use of inhaled 2D and 3D SPECT and PET tracers in determining drug delivery efficiency and drug distribution to the lung, the monitoring of responses to inhalant therapies and the assessment of inflammation in lung disease. Some of the results of these studies have been previously reported in the form of abstracts (13–18).


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2D . and SPECT Tracers
The isotope most commonly used for 2D planar and 3D SPECT imaging is 99m-technetium, i.e., pertechnetate (99mTcO4–). The physical half-life (t1/2) of 99mTc is 6.0 hours, with a range of effective t1/2s in the body of 0.16 to 6.0 hours, depending on the compound labeled for the specific test measurement. Few 2D and SPECT drug deposition studies involve direct labeling of a drug. Rather, the tracer is associated with, but not part of, the drug formulation, whether the drug formulation is a suspension, a solution, or a powder. This means that imaging must be completed within 2 to 3 minutes as the label rapidly dissociates from the drug following deposition on the airway surface, and therefore no longer provides a marker for the drug. Because of these limitations, tracking the drug in vivo is not possible without a directly labeled drug.

Radiopharmaceutical agents for small proteins and peptides, for example (123I-interleukin-1, 123I-interleukin-8, and the neuropeptide 111In-substance P) that allow direct (2D or SPECT) imaging of acute inflammation and infection are currently available (19, 20), while others continue to be developed (21). Animal studies have shown that these novel tracers can be used to target cells that accumulate at sites of lung injury in vivo, but further work is needed before many of these products can be used in humans.

PET Tracers
Table 1 gives a list of isotopes, characteristics, and uses for a number of PET labels. The radionuclides used in PET—namely, carbon, nitrogen, and oxygen—are constituents of any organic molecule, so it is possible that an actual drug molecule may be labeled. Fluorine, a constituent of a number of drugs can also be used to label analogs with physico-chemical properties that are similar to the parent molecule. A number of medications used to treat respiratory conditions have been successfully labeled with PET emitters, with imaging after inhalation to determine the deposition and kinetics of the specific drug molecule. It is also possible to map receptor locations in vivo and drug kinetics by displacing the labeled drug from receptor sites with an unlabeled compound (13, 22).


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  		TABLE 1. Characteristics of radiolabels for use with positron emission tomography

 
18-Fluorodyoxyglucose (FDG) is the PET agent used to detect the presence of acute infection and inflammatory processes in the body (23). Measurement of 18FDG uptake using PET imaging has been well validated as an in vivo measure of tissue glucose metabolism and has been extensively used to monitor the metabolic activity of cells in the brain and in the detection of some tumors (24–35).

Hyperpolarized Gases and Other Tracers for MRI
Hyperpolarized helium (HHe3) gas and its alternative, the more abundant, hyperpolarized xenon-129 gas, are used to measure lung ventilation with MRI. Another tracer, gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA), can also be polarized and has been given to animals as an aerosol to measure epithelial permeability (36), lung ventilation, and with the intravenous preparation, lung perfusion (37). Further developments of tracers for MR have shown that hematopoietic progenitor cells can be detected using a variety of MR contrast agents. This raises the possibility that these cells can be tracked in vivo as they move from the bone marrow to the lung (38).


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2D Planar
There are many examples in the literature of studies where 2D imaging has been used to evaluate the dose and deposition of inhaled pharmaceuticals from pressurized metered dose inhalers, dry powder inhalers, and nebulizers, and to assess the performance of these inhalers under a variety of inhalation conditions and in various patient populations. Figure 1 is an example of 2D planar images illustrating the deposition of two technetium-99m–labeled corticosteroid aerosol formulations of beclomethasone dipropionate (BDP); hydrofluoroalkane (HFA) BDP or QVAR (3M Pharmaceuticals, St. Paul, MN), an extra-fine solution aerosol with mass median aerodynamic diameter (MMAD) of 1.1 µm; and CFC BDP or Beclovent (BV, GlaxoSmithKline, Research Triangle Park, NC), a suspension aerosol with a MMAD of 3.4 µm (14). Calibration factors for both the radiolabeled drugs and the individual subjects were applied to the radioactivity data to convert the counts obtained on imaging to micrograms of drug deposited in the lung, oropharynx, and stomach (39). Doses of drug deposited in the lung from this study were found to be approximately 53 and 17%, respectively for QVAR and Beclovent. Data from Leach and colleagues (40) showed similar values for QVAR but much lower lung deposition for Beclovent. This information has been used to support the clinical comparisons indicating a dosing regimen of 1 puff of QVAR (50 µg/puff) to be used for every 2 puffs (100 µg) of Beclovent (50 µg/puff) prescribed. The calculations shown in Table 2 using the average measured deposition values for subjects with asthma may partially explain why, in a number of clinical trials, enhanced effects are still seen with QVAR despite the 50% reduction in the prescribed nominal dose for treatment: the 3-fold higher lung deposition efficiency for QVAR still results in a 1.77-fold greater microgram dose of QVAR to the lung compared with Beclovent.



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  		Figure 1. Scintigraphic anterior and posterior images from one subject with asthma following inhalation of radiolabeled beclomethasone dipropionate (BDP) pressurized aerosols. The dose deposited from QVAR (the HFA solution formulation of BDP) versus Beclovent (the CFC suspension formulation) is fourfold greater and appears to be distributed more toward the periphery in this example. The 133Xenon gas outline is shown on each panel to indicate the peripheral edge of the lung. (Data taken from Dolovich and coworkers [14].)

 

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  		TABLE 2. Dose calculations for inhaled qvar versus beclovent

 
2D imaging has been used extensively to compare the efficiency of delivery of drugs to the lung from a wide variety of aerosol delivery systems and in many different patient populations, and the effects of breathing parameters and airway disease on drug delivery and distribution within the lung. Drug distribution is typically done by defining regions of interest (ROIs) within the lung. These ROIs have encompassed apical to basal regions as well as central versus peripheral lung regions, the latter mapped to loosely to follow the structure of the airways (41). As there is no consensus as to the geometric definition of these 2D regions, the presentation of regional deposition data varies significantly between laboratories (15). There are a number of published studies correlating deposited drug and the pattern of distribution with changes in lung function or other physiologic parameters. A recent 2D imaging study from Alexis and coworkers (42) used the preferential deposition and subsequent clearance of inhaled boluses of 99mTc-sulphide colloid to confirm that the production of induced sputum was localized to the central airways.

SPECT Imaging
SPECT imaging is more complex than planar imaging; the SPECT camera rotates through a full 360° around the subject to obtain anterior and posterior cumulative 2D images of the thorax (43). Subsequent computer manipulation of the data permits tomographic images to be constructed. SPECT imaging of the lung has the potential advantage of improving the accuracy of assessing the pattern of deposition within the lungs compared to 2D planar imaging (44). However, it has the associated disadvantages of longer acquisition times and the requirement of relatively high doses of radioactivity to be administered to improve the counting efficiency per slice. Unless a direct, nonabsorbable radiolabel can be demonstrated for the drug under investigation, SPECT cannot be used to assess drug deposition. It can, however, be used to investigate variables associated with inhalation of drug as mentioned above for 2D imaging but only using inhalation of nonabsorbable tracers. Fleming and colleagues, along with others, have developed methods for analyzing SPECT lung images to obtain information of tracer distribution in multiple regions of interest (45). Their shells are defined through a transformation algorithm to create hemispherical regions of equal volumes concentric about the hilus.

Two recent SPECT studies have compared HFA and CFC formulations of flunisolide (MMAD 1.2 µm) and fluticasone (MMAD 2.4 µm) in an attempt to separate small airway drug deposition from that on larger, overlapping airways (16, 17). Although greater total deposition of HFA flunisolide was demonstrated, only a slight increase in the percentage of extra-fine HFA steroid deposited in the lung periphery was measured. The results from the second SPECT study also showed no difference in the percent distribution of drug to the peripheral lung for HFA flunisolide when compared with CFC fluticasone.

Lung ventilation and perfusion, mucociliary clearance, and epithelial permeability have been used as measures of response to inhaled therapies and interventions such as exercise (46), kinetic therapy (47), and physiotherapy (48), as well as to assess the effect of underlying disease on these physiologic functions. 2D imaging has been the technique commonly used for these measurements. However, studies using dynamic SPECT to measure clearance have recently been published (49). For both imaging methods, nonabsorbable radiotracers must be used. The imaging time varies from 2 to 24 hours and one needs to avoid uptake of the inhaled tracer during this time to minimize background buildup of radioactivity that would interfere with the acquisition and analysis of the deposited dose.

PET Imaging
PET imaging offers the important advantage that the drug under study can be firmly labeled with the appropriate positron-emitting isotope, usually 11C or 18F. Thus, deposition reflects the pharmaceutical itself and not just free isotope. Fluticasone dipropionate, triamcinolone acetonide, and zanamivir have all been labeled and their dose and distribution in the respiratory tract assessed with PET (18, 50, 51).

Determining Regional Dose and Distribution Data
PET images are analyzed in our laboratory to obtain the total dose deposited in the lung and the dose per 5-mm slice of lung tissue. Regional data is obtained from an analysis program developed at McMaster University that divides the lung into 10 concentric (hilar to periphery) shells or regions (39). These irregular regions are constructed from the PET transmission scan and provide the geometry and actual volume for the individual lung slices as well as tissue attenuation factors. The number of shells per lung varies with each slice geometry and is specific to an individual subject. The shell information is then applied to the PET emission (radioactivity) data to determine shell activity (dose), and hence the regional distribution of the inhaled dose. Absolute doses (of deposited drug) and doses per unit lung volume can be calculated for the whole lung, each lung slice, ten lung shells, and the portion of each shell in a lung slice. The delineation of shells on several transaxial and coronal transmission slices is shown in Figure 2. The shell geometry is applied to its paired emission slice to calculate the drug dose for that slice and in the specific shells within the slice to characterize the distribution of drug for each lung slice. The specific shell contributions are then summed over all the slices to give the shell or regional dose and plotted versus cumulative volume or distance from the hilus. We calculate the coefficient of variation (CV) of the radioactivity for each lung slice, each shell, and the slices within a shell to give an estimate of the homogeneity of the distribution of the dose. This approach has been previously described but used to calculate the CVs for selected areas in lung images obtained by SPECT (52–54). Figure 3 shows a 3D plot of the radioactivity in three shells plotted for each shell slice, giving an estimate of the distribution of the activity (dose) within the shells and the variability (CV) of the activity (dose) distribution.



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  		Figure 2. A series of transmission slices from the transaxial plane (upper panel) and the coronal plane (lower panel), with the shells outlined on each slice. It is evident from the slices that the geometry changes from the apex to the base of the lung and the anterior to posterior sections in the lung and accordingly, the number of shells that are accommodated by each slice varies. The shell structure is applied to the matching emission slices and the regional distribution of the inhaled dose is calculated.

 


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  		Figure 3. (A) A three-dimensional plot of activity for the lung slices within shells 5, 6, and 10 showing the variability of dose per slice and between shells. (B) The coefficient of variation (CV, %) plotted per slice for the three shells, showing the nonhomogeneity of the distribution of the inhaled drug dose.

 
Using PET as an Outcome Measurement
Ventilation as an index of response.
Changes in ventilation/perfusion (/) using 13N and PET imaging in response to a variety of stimuli has recently been demonstrated by Musch and coworkers (55) and by Vidal Melo and coworkers (56) in a series of elegant experiments in both animals and humans. In our laboratory, we use the inhalation of an extra-fine aerosol of 18FDG to assess ventilation in patients with respiratory disease and to assess changes in ventilation following interventions that may or may not alter lung function measured in the conventional way. In the hierarchy of imaging modalities, 2D planar studies of and/or / appear to be less sensitive in identifying ventilation defects than SPECT or PET. High-resolution computerized tomography (HRCT) imaging, with a resolution of 1 mm, fivefold greater than PET, has been shown to be more sensitive than standard pulmonary function testing in detecting these types of abnormalities in disease (57).

In our laboratory, aerosolized 18FDG has been used to investigate differences in distribution in the lung as a function of aerosol droplet size. Images from one normal subject and one subject with cystic fibrosis are shown in Figure 4. The aerosols were produced by two different nebulizers, with mass median diameters of 1.5 µm and 4.5 µm. The volumetric droplet distributions were determined using a Laser Diffraction Particle Size Analyzer (Sympatec Inc., Princeton, NJ) and assuming a density of 1.0 g · cc–1. The 1.5-µm aerosol, produced as 99mTc-DTPA or sulphide colloid, is used daily by nuclear medicine departments in North America and Europe to obtain diagnostic (2D or 3D SPECT) ventilation scans, whereas the larger aerosol is typical of a nebulized therapeutic aerosol for treating asthma and other respiratory conditions. To compensate for the different aerosol delivery efficiencies of the two nebulizers, the starting concentrations of drug were adjusted so that subjects would inhale the same radioactive dose from either system. The images in Figure 4 show marked differences in distribution of the aerosols between the normal and CF subject. As described above, our data analysis protocol calculates the amount of aerosol deposited in the whole lung, the distribution of the aerosol in 10 concentric volumetric regions (shells) within each lung and the amount of aerosol deposited in approximately 80 individual lung slices. To determine the uniformity or lack of uniformity of the distribution of radioactivity through the lung, counts of radioactivity, count density, and coefficient of variation (CV) are calculated per shell and per slice and compared. A preliminary analysis of this data from 11 subjects has shown that within the two groups of subjects, normal and CF, the distribution of the activity of the two aerosols within the shells is similar throughout the lung, but is more uniform (lower CV) in the normal subjects (5). In addition, the standard comparisons of aerosol deposited in the central shells to that in the peripheral shells have been made, including compensating for the effect of the increase in shell volume from the central part of the lung to the lung periphery. Our study design and method of analysis, but not necessarily our results, are contrary to that published for the 2D and 3D SPECT data of Phipps and colleagues (44) and the bolus method of Kim and coworkers (58). These investigators also assessed the deposition of different sized aerosols by analyzing penetration to the lung periphery, studying normal, healthy subjects only, rather than subjects with airways obstruction. A number of other methodologic variables, which undoubtedly influenced their measurements of central/peripheral ratios and which were different from our study, were inhalation of stable, nonradioactive, monodisperse aerosols at variable inspiratory flow rates (Kim and colleagues) and the delineation of only three regions of interest with much greater combined volumes (Phipps and coworkers) than the 10-shell structure mapped onto each lung in our study.



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  		Figure 4. Selected coronal slices from positron emission tomography (PET) images acquired in a normal subject (N) and a subject with cystic fibrosis (CF) following inhalation of a 1.5-µm aerosol of 18FDG from the Ultravent jet nebulizer compared with a 4.5-µm aerosol from the PARI LC Star jet nebulizer. A preliminary analysis of the shell data showed that the two aerosols gave similar deposition patterns for each group of subjects. "Hot spots" of radioactivity are more evident in the subject with CF (1).

 
Ventilation changes following administration of a challenge aerosol.
Bronchoconstriction has been shown to alter the distribution of aerosol in the lung. With 2D imaging, the scan obtained is a summation of radioactivity distributed in the lung; the pattern of bronchoconstriction throughout the lung cannot be determined. Figure 5 shows an example of two PET 18FDG aerosol scans from one subject with asthma, obtained at baseline and again following a 20% decrease in FEV1 after methacholine challenge. Matching coronal slices from each study show the variability in the distribution of bronchoconstriction between the lung slices, evident by the distribution of "hot spots" following challenge. The reduced ventilation of the lung distal to the constriction can be seen when comparing the cross-sectional area of the slices, given by the transmission scan (not shown) or compared to the baseline emissions images, with that of the emission slices after challenge. The analysis of the data shows that the distribution of hot spots varies throughout the lung (slices) and between the lung shells. This pattern may be dependent on the severity of the asthma and is currently being investigated.



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  		Figure 5. Coronal slices from a PET baseline ventilation scan (upper panel) and the scan immediately following a 20% fall in FEV1 due to inhalation of methacholine aerosol (lower panel). The bronchoconstriction markedly altered the distribution of ventilation throughout the lung in this subject with asthma, with more aerosol concentrated around the hilus.

 
Ventilation changes following inhaled therapy.
In addition to investigating the deposition and pharmacokinetics of inhaled drugs labeled with positron emitters, the effect of treatment on lung ventilation can also be assessed by monitoring changes before and after therapy. Improvement in peripheral deposition of the aerosol throughout the lung as an indicator of improved ventilation due to increased airway caliber is currently being investigated in our laboratory in symptomatic individuals with asthma following inhaled corticosteroid therapy. Findings will be correlated with improvement in symptoms and spirometry and changes in sputum eosinophil counts.


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Measurement of Lung Inflammation Using 18FDG and PET Technology
Injected 18FDG preferentially accumulates in areas with increased energy metabolism, such as tumors in which the rate of uptake is six to seven times higher than normal tissue (59). Inflammatory cells, such as neutrophils, use glucose as a source of energy during their activation. Therefore, sites of infection where the metabolic rate of glucose (MRglu) is elevated, as in activated inflammatory cells, should preferentially accumulate 18FDG (60, 61).

It is hypothesized that 18FDG uptake by inflammatory cells in the lung could be used as an in vivo measurement of both total and regional lung inflammation. Although the use of 18FDG–PET in detecting and monitoring inflammatory events in the lung is relatively new, studies have shown an increase in 18FDG uptake in patients with acute lobar pneumonia, active sarcoidosis, cryptogenic fibrosing alveolitis, and atopic asthma after allergen challenge (62–66).

We have demonstrated an increased lung 18FDG uptake in inactive sarcoidosis (67). In the same study, however, patients with cystic fibrosis (CF) in stable clinical condition did not have an elevated uptake of 18FDG, despite the presence of sputum neutrophilia (Figure 6). This negative result (also seen in bronchiectasis [66]) raises questions about neutrophil functioning in the CF lung and is presently being investigated.



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  		Figure 6. Glucose use of the right lung, before and after 28 days of inhaled tobramycin therapy (160 mg twice daily) (filled circles). Cystic fibrosis mean glucose use in the lung (red diamond) was 1.3 µmol · g–1 · hour–1, 95% confidence interval (CI) 0.55–2.10. Nonactive sarcoidosis mean glucose use in the lung (green diamond) was 2.8 µmol · g–1 · hour–1, 95% CI 2.65–2.99. The shaded area represents normal glucose use in the lung of 1.2 µmol · g–1 · hour–1, 95% CI 0.94–1.46. Patients with nonactive sarcoidosis have a significantly higher lung glucose use than normal. Despite the presence of chronic sputum neutrophilia, lung glucose use was not elevated in patients with CF and did not change with inhaled tobramycin therapy (67).

 
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality throughout the world. It is a disease state characterized by airflow limitation that is not fully reversible, and chronic lung inflammation. The predominant inflammatory cells are macrophages, CD8+ lymphocytes, and neutrophils (68–70). Recent findings by Jones and coworkers suggest that 18FDG uptake is greater in the lungs of patients with COPD with moderate to severe airflow obstruction than in the normal lung (71). A significant correlation was found between 18FDG uptake and sputum neutrophils (r = 0.5, p = 0.04) (Figure 7), KCO (r = –0.8, p = 0.0001), and FEV1/VC (r = –0.72, p = 0.001) when COPD, asthma, and healthy volunteer results were pooled.



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  		Figure 7. 18FDG uptake in the lung correlates with the sputum neutrophil counts (r = 0.50, p = 0.04). In patients with chronic obstructive pulmonary disease (COPD) the mean 18FDG uptake was 4.0 minute–1 (SD 0.88), mean sputum neutrophil counts was 5.26 x 106 cells/g sputum (SD 3.75). In individuals with asthma, the mean 18FDG uptake was 1.7 minute–1 (SD 0.56), mean sputum neutrophil counts was 2.27 x 106 cells/g sputum (SD 1.15). In normal subjects, the mean 18FDG uptake was 1.5 minute–1 (SD 0.77), mean sputum neutrophil counts was 0.41 x 106 cells/g sputum (SD 0.43). Data from Jones and colleagues (71).

 
In patients with active sarcoidosis treated with high doses of prednisone (>= 40 mg), a significant decrease in lung glucose use was observed (mean pretreatment MRglu of 4.56 µmol · g–1 · hour–1 versus post-treatment MRglu of 1.43 µmol · g–1 · hour–1, p = 0.05) (62). However, these same authors found that in patients treated with either low dose prednisone (<= 15 mg) or no steroid therapy, no significant change in lung MRglu was seen (pretreatment MRglu of 3.39 µmol · g–1 · hour–1 versus post-treatment MRglu of 3.71 µmol · g–1 · hour–1). This study suggests that 18FDG–PET technology could be used to measure the efficacy of antiinflammatory therapies.

Table 3 gives a summary of the data from several studies using injected 18FDG as an indicator of lung inflammation in a variety of patient populations and settings. Despite the various methods used to calculate uptake, values greater than normal were seen in those patients with acute infections and a demonstrated lung inflammatory process, with the exception of CF and bronchiectasis, although both diseases are characterized by lung neutrophilia.


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  		TABLE 3. Lung 18fdg uptake in various respiratory diseases

 

   CONCLUSIONS
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The use of imaging to investigate drug delivery, response to drug therapy, and to monitor disease progression is becoming more widely accepted and will continue to increase in usefulness as the technology improves and more receptor-specific radiotracers are developed. The use of microPET and animal models in drug discovery has become an important means of screening new compounds, determining their pharmacokinetic and safety profiles in vivo before testing in humans. Conventional 2D planar imaging will continue to be used in situations where resolution is not critical and comparisons (for example, of drug delivered from different inhaler devices) can be reasonably estimated and with a lower radiation exposure to the subjects. However, when greater accuracy in measuring the inhaled dose and its distribution and behavior in the lung and body are required to be known, the preferred strategy may be, whenever possible, to synthesize the drugs with positron emitters and to use PET imaging.


   FOOTNOTES
 
Funded in part by 3M Pharmaceuticals Inc USA and the Canadian Cystic Fibrosis Foundation SPARX II Research Grant.

Conflict of Interest Statement: M.D. received $4,000 in 2002 and $5,600 in 2001 for speaking at conferences sponsored by 3M Canada and received $205,000 in research grants from 3M Pharmaceuticals US; R.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form April 16, 2004; accepted in final form July 9, 2004)


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