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Molecular imaging of the pulmonary circulation in health and disease.

Dupuis J, Harel F, Nguyen QT - Clin Transl Imaging (2014)

Bottom Line: The pulmonary circulation, at the unique crossroads between the left and the right heart, is submitted to large physiologic hemodynamic variations and possesses numerous important metabolic functions mediated through its vast endothelial surface.There are many pathologic conditions that can directly or indirectly affect the pulmonary vasculature and modify its physiology and functions.By targeting endothelial, medial and adventitial targets of the pulmonary vasculature, novel molecular imaging agents could provide early detection of physiologic and biologic perturbation in the pulmonary circulation.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8 Canada ; Department of Medicine, Université de Montréal, Montreal, QC Canada.

ABSTRACT
The pulmonary circulation, at the unique crossroads between the left and the right heart, is submitted to large physiologic hemodynamic variations and possesses numerous important metabolic functions mediated through its vast endothelial surface. There are many pathologic conditions that can directly or indirectly affect the pulmonary vasculature and modify its physiology and functions. Pulmonary hypertension, the end result of many of these affections, is unfortunately diagnosed too late in the disease process, meaning that there is a crying need for earlier diagnosis and surrogate markers of disease progression and regression. By targeting endothelial, medial and adventitial targets of the pulmonary vasculature, novel molecular imaging agents could provide early detection of physiologic and biologic perturbation in the pulmonary circulation. This review provides the rationale for the development of molecular imaging agents for the diagnosis and follow-up of disorders of the pulmonary circulation and discusses promising targets for SPECT and positron emission tomographic imaging.

No MeSH data available.


Related in: MedlinePlus

Molecular imaging of pulmonary arterial hypertension using an adrenomedullin receptor ligand. Images obtained 30 min after an i.v. injection of 99mTc-PulmoBind in a vehicle-treated Sprague–Dawley rat and b monocrotaline-treated rat (pulmonary arterial hypertension model). c Static evaluations of the presence of the radiotracer in lungs 30 and 60 min after injection. *p < 0.05 for vehicle-treated rats (white bars) versus monocrotaline-treated rats (black bars). This research was originally published in the Journal of Nuclear Medicine: Letourneau et al., PulmoBind an adrenomedullin-based molecular lung imaging tool, 2013; vol. 54, 1789–1796. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. [51]
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Fig3: Molecular imaging of pulmonary arterial hypertension using an adrenomedullin receptor ligand. Images obtained 30 min after an i.v. injection of 99mTc-PulmoBind in a vehicle-treated Sprague–Dawley rat and b monocrotaline-treated rat (pulmonary arterial hypertension model). c Static evaluations of the presence of the radiotracer in lungs 30 and 60 min after injection. *p < 0.05 for vehicle-treated rats (white bars) versus monocrotaline-treated rats (black bars). This research was originally published in the Journal of Nuclear Medicine: Letourneau et al., PulmoBind an adrenomedullin-based molecular lung imaging tool, 2013; vol. 54, 1789–1796. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. [51]

Mentions: Human AM, a member of the calcitonin gene-related peptide family, is a 52-amino-acid multifunctional regulatory peptide expressed in a wide range of tissues but mainly in the adrenal medulla, ventricle, kidneys and lungs [40–42]. Its specific heterodimeric receptor is composed of the calcitonin-like receptor and the receptor activity-modifying protein 2 or 3 [43]. The AM receptor is abundantly expressed in human alveolar capillaries and mostly distributed at the luminal surface of the vascular endothelium [44–47]. Accordingly, the lungs contain specific AM-binding sites at a density higher than any other organ studied [47]. We have previously established that the lungs are a primary site for plasma AM clearance and therefore modulate its circulating levels [48]. In fact, the AM receptor acts as a clearance receptor in the pulmonary vascular bed [49]. On the basis of this evidence, we hypothesized that radiolabeled AM derivatives could be used as non-invasive imaging tracers to evaluate the integrity of the pulmonary circulation. Through rational design and structure–activity relationship studies we developed various AM derivatives [50] able to maintain binding affinity with the specific receptor without significant biologic effects at the lung scan dose, while enabling the addition of a chelating moiety for a suitable radioisotope [51]. These derivatives allowed good quality lung imaging enabling the detection of large pulmonary perfusion defects mimicking pulmonary embolism [52], but also microcirculatory pulmonary occlusion in the monocrotaline model of PAH [53] (Fig. 3). A lead compound possessing the desired properties was selected [51] and called PulmoBind. In pre-clinical studies, 99mTc-PulmoBind displays all the qualities desired of a molecular imaging agent in nuclear medicine: sizeable first pass and prolonged uptake by the lungs and quick plasma clearance with elimination by both the liver and kidneys [51]. A human phase I study of PulmoBind in normal human subjects was recently completed (Clinicaltrials.gov NCT01539889) [54]. We demonstrated that PulmoBind is safe while providing superior quality lung imaging compared to 99mTc-MAA. A phase II study of safety and proof of concept in subjects with PAH is in the planning phase. We hypothesize that quantitative total lung uptake and kinetic parameters after PulmoBind injection will be of value in the evaluation of all the PH groups (Table 1). Furthermore, evaluation of the spatial distribution of PulmoBind uptake may provide a unique insight into modifications of the metabolically active pulmonary vascular surface area in both physiology and pathology.Fig. 3


Molecular imaging of the pulmonary circulation in health and disease.

Dupuis J, Harel F, Nguyen QT - Clin Transl Imaging (2014)

Molecular imaging of pulmonary arterial hypertension using an adrenomedullin receptor ligand. Images obtained 30 min after an i.v. injection of 99mTc-PulmoBind in a vehicle-treated Sprague–Dawley rat and b monocrotaline-treated rat (pulmonary arterial hypertension model). c Static evaluations of the presence of the radiotracer in lungs 30 and 60 min after injection. *p < 0.05 for vehicle-treated rats (white bars) versus monocrotaline-treated rats (black bars). This research was originally published in the Journal of Nuclear Medicine: Letourneau et al., PulmoBind an adrenomedullin-based molecular lung imaging tool, 2013; vol. 54, 1789–1796. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. [51]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4209091&req=5

Fig3: Molecular imaging of pulmonary arterial hypertension using an adrenomedullin receptor ligand. Images obtained 30 min after an i.v. injection of 99mTc-PulmoBind in a vehicle-treated Sprague–Dawley rat and b monocrotaline-treated rat (pulmonary arterial hypertension model). c Static evaluations of the presence of the radiotracer in lungs 30 and 60 min after injection. *p < 0.05 for vehicle-treated rats (white bars) versus monocrotaline-treated rats (black bars). This research was originally published in the Journal of Nuclear Medicine: Letourneau et al., PulmoBind an adrenomedullin-based molecular lung imaging tool, 2013; vol. 54, 1789–1796. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. [51]
Mentions: Human AM, a member of the calcitonin gene-related peptide family, is a 52-amino-acid multifunctional regulatory peptide expressed in a wide range of tissues but mainly in the adrenal medulla, ventricle, kidneys and lungs [40–42]. Its specific heterodimeric receptor is composed of the calcitonin-like receptor and the receptor activity-modifying protein 2 or 3 [43]. The AM receptor is abundantly expressed in human alveolar capillaries and mostly distributed at the luminal surface of the vascular endothelium [44–47]. Accordingly, the lungs contain specific AM-binding sites at a density higher than any other organ studied [47]. We have previously established that the lungs are a primary site for plasma AM clearance and therefore modulate its circulating levels [48]. In fact, the AM receptor acts as a clearance receptor in the pulmonary vascular bed [49]. On the basis of this evidence, we hypothesized that radiolabeled AM derivatives could be used as non-invasive imaging tracers to evaluate the integrity of the pulmonary circulation. Through rational design and structure–activity relationship studies we developed various AM derivatives [50] able to maintain binding affinity with the specific receptor without significant biologic effects at the lung scan dose, while enabling the addition of a chelating moiety for a suitable radioisotope [51]. These derivatives allowed good quality lung imaging enabling the detection of large pulmonary perfusion defects mimicking pulmonary embolism [52], but also microcirculatory pulmonary occlusion in the monocrotaline model of PAH [53] (Fig. 3). A lead compound possessing the desired properties was selected [51] and called PulmoBind. In pre-clinical studies, 99mTc-PulmoBind displays all the qualities desired of a molecular imaging agent in nuclear medicine: sizeable first pass and prolonged uptake by the lungs and quick plasma clearance with elimination by both the liver and kidneys [51]. A human phase I study of PulmoBind in normal human subjects was recently completed (Clinicaltrials.gov NCT01539889) [54]. We demonstrated that PulmoBind is safe while providing superior quality lung imaging compared to 99mTc-MAA. A phase II study of safety and proof of concept in subjects with PAH is in the planning phase. We hypothesize that quantitative total lung uptake and kinetic parameters after PulmoBind injection will be of value in the evaluation of all the PH groups (Table 1). Furthermore, evaluation of the spatial distribution of PulmoBind uptake may provide a unique insight into modifications of the metabolically active pulmonary vascular surface area in both physiology and pathology.Fig. 3

Bottom Line: The pulmonary circulation, at the unique crossroads between the left and the right heart, is submitted to large physiologic hemodynamic variations and possesses numerous important metabolic functions mediated through its vast endothelial surface.There are many pathologic conditions that can directly or indirectly affect the pulmonary vasculature and modify its physiology and functions.By targeting endothelial, medial and adventitial targets of the pulmonary vasculature, novel molecular imaging agents could provide early detection of physiologic and biologic perturbation in the pulmonary circulation.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Montreal Heart Institute, 5000 Belanger Street, Montreal, QC H1T 1C8 Canada ; Department of Medicine, Université de Montréal, Montreal, QC Canada.

ABSTRACT
The pulmonary circulation, at the unique crossroads between the left and the right heart, is submitted to large physiologic hemodynamic variations and possesses numerous important metabolic functions mediated through its vast endothelial surface. There are many pathologic conditions that can directly or indirectly affect the pulmonary vasculature and modify its physiology and functions. Pulmonary hypertension, the end result of many of these affections, is unfortunately diagnosed too late in the disease process, meaning that there is a crying need for earlier diagnosis and surrogate markers of disease progression and regression. By targeting endothelial, medial and adventitial targets of the pulmonary vasculature, novel molecular imaging agents could provide early detection of physiologic and biologic perturbation in the pulmonary circulation. This review provides the rationale for the development of molecular imaging agents for the diagnosis and follow-up of disorders of the pulmonary circulation and discusses promising targets for SPECT and positron emission tomographic imaging.

No MeSH data available.


Related in: MedlinePlus