Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

Dupuis, Jocelyn; Caron, Alexandre; Ruel, Nathalie

doi:10.1042/cs20040357

Cited by 38 publications

(39 citation statements)

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“…Adrenomedullin is a multifunctional peptide mostly expressed in endothelial cells and distributed in various tissues, such as the lung, kidney, and heart (3,5). Previous studies have observed a high density of binding sites for adrenomedullin, with high affinity in lung tissues (4,5), which act as clearance receptors for the peptide (3,6).…”

Section: Discussionmentioning

confidence: 99%

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Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Dupuis

Harel

et al. 2009

J Nucl Med

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No test currently exists for molecular imaging of pulmonary arterial hypertension (PAH). Adrenomedullin is a vasodilator peptide predominantly cleared by pulmonary endothelial receptors. We developed a linear adrenomedullin derivative radiolabeled with 99m Tc ( 99m Tc-AM-L) for imaging of pulmonary circulation and tested its capacity to detect anomalies of pulmonary circulation caused by PAH. Methods: PAH was induced by monocrotaline in rats and compared with controls. After 5 wk, 99m Tc-AM-L was injected intravenously. Plasma kinetics were measured, lung activity was determined in vivo after 30 min using a nuclear camera, and lung activity was determined ex vivo in explanted lungs. Expression of adrenomedullin receptors was measured in lung homogenates. Results: The plasma levels of 99m Tc-AM-L significantly increased in PAH by approximately 2-fold. Uptake by the lungs was homogeneous but greatly reduced in PAH by about 70%. In vivo retention was 14% 6 1% (mean 6 SD) of the injected dose in controls and 4% 6 1% in PAH (P , 0.0001). A similar reduction was measured ex vivo (6.0 6 1.6 percentage injected dose per gram [%ID/g] vs. 0.95 6 0.21 %ID/g, P , 0.0001). The expression of the heterodimeric component of the adrenomedullin receptor, receptor activity modifying protein 2, was also greatly reduced in PAH lungs (P , 0.001). Interestingly, right ventricular uptake of 99m Tc-AM-L was increased by PAH (P 5 0.02) and correlated with the degree of right ventricular hypertrophy (r 5 0.83, P 5 0.001). Conclusion: Pulmonary uptake of 99m Tc-AM-L is greatly reduced in monocrotaline-induced PAH. This novel molecular imaging agent may be useful in the diagnosis and follow-up of pulmonary vascular disorders. No clinically available test currently exists that can provide both anatomic and functional information on the status of pulmonary circulation. Pulmonary arterial hypertension (PAH) is a disorder characterized by endothelial dysfunction, with intimal and vascular smooth muscle proliferation leading to gradual obliteration of pulmonary arterioles (1). PAH is screened by transthoracic Doppler echocardiography, with the estimation of pulmonary artery systolic pressure obtained using the tricuspid valve regurgitant jet. Although this approach correlates with hemodynamically measured pulmonary pressure, it does not provide direct information on the biology of pulmonary circulation and may miss the early presence of pulmonary vascular disease (1). The recent availability of oral therapies for PAH such as endothelin receptor antagonists and phophodiesterase inhibitors advocates for earlier diagnosis of this condition and treatment of subjects in functional class II (1). There is, therefore, a clinical need for novel diagnostic approaches toward pulmonary vascular disease that could provide an earlier and more precise diagnosis.Adrenomedullin is a vasodilator peptide produced by the vascular endothelium. When injected intravenously, adrenomedullin is predominantly cleared by pulmonary circulation by specific adrenomedullin rec...

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Section: Discussionmentioning

confidence: 99%

“…When injected intravenously, adrenomedullin is predominantly cleared by pulmonary circulation by specific adrenomedullin receptors (2,3). Human and rat lungs indeed contain a high density of specific adrenomedullin binding sites (4,5), mostly distributed on the vascular endothelium.…”

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Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Dupuis

Harel

et al. 2009

J Nucl Med

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“…This value is comparable to the first-pass extraction of 30% 6 5% found in the present study with L-AM. We previously demonstrated that this represents specific binding as 125 I-AM clearance by the lungs of rats is displaced by AM (7).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have established that circulating AM is predominantly cleared by the pulmonary circulation through specific endothelial receptors (7)(8)(9). The AM receptor is a heterodimer composed of the calcitonin receptor-like receptor and receptor activity-modifying protein 2, both of which are highly expressed in the lungs (1,5).…”

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Use of Adrenomedullin Derivatives for Molecular Imaging of Pulmonary Circulation

Harel

Fu²,

Nguyen³

et al. 2008

J Nucl Med

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Currently, there is no low-molecular-weight agent for imaging of the pulmonary circulation. Adrenomedullin (AM) is a peptide predominantly cleared by the pulmonary circulation through specific endothelial receptors. We developed human AM derivatives radiolabeled with 99m Tc and evaluated their biodistribution, plasma kinetics, and utility as pulmonary vascular imaging agents. Methods: Two derivatives radiolabeled with 99m Tc were evaluated: the natural cyclic form of the peptide, to which the chelator diethylenetriaminepentaacetic acid was added (C-DTPA-AM), and the linear form, which allows direct labeling (L-AM). The compounds were injected into dogs, and the activities of the tracers in blood and in organs were determined with a nuclear medicine camera. Single-pass pulmonary clearance was measured by the indicator dilution technique. The capacity to image perfusion defects was evaluated after surgical pulmonary artery ligation. Results: Both derivatives were rapidly cleared from plasma, with elimination half-lives of 42 and 32 min for C-DTPA-AM and L-AM, respectively. The lungs retained most of the activity after 30 min; this activity was higher (P 5 0.02) for L-AM (42% 6 5% [mean 6 SEM]) than for C-DTPA-AM (27% 6 1%). Lung activity slowly declined over time but was maintained after 2 h at approximately 20% for both tracers. The single-pass pulmonary clearance of plasma L-AM was 414 6 85 mL/min. There was a higher level of urinary excretion of L-AM than of C-DTPA-AM. After pulmonary artery ligation, perfusion defects were easily detectable by external imaging. Conclusion: AM derivatives are promising compounds for molecular imaging of the pulmonary circulation. L-AM displayed higher levels of initial lung retention and of kidney excretion.

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“…AM, a peptide from the calcitonin family, allows specific lung imaging through binding with its specific receptor, AM1 (CRLR/RAMP2), which is expressed at a high density in pulmonary vessels (6,7). Enhanced imaging efficiency can be associated with cell internalization after activation of the receptor by its agonist (8,9), but this process is also correlated with inherent biologic activity.…”

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PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

et al. 2013

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Previous studies showed that adrenomedullin (AM) could be a promising agent for molecular imaging of the pulmonary circulation, with abundant specific binding sites at the pulmonary vascular endothelium. The purpose of this work was to design an AM-based compound that encompasses the desired imaging properties without posing safety issues for clinical applications. Methods: AM analogs were synthesized through solid-phase peptide synthesis. They were evaluated for 99m Tc labeling efficiency and in vivo lung uptake. Biodistribution and hemodynamic characteristics of the lead compound were determined in anesthetized dogs as well as by a dosimetric analysis. Lung perfusion was evaluated in the monocrotaline model of pulmonary arterial hypertension in rats. Results: A cyclic AM (residues 22-52) analog encompassing a polyethylene glycol spacer and a tetrapeptide chelating moiety was found to possess the desired characteristics, with 90.7% 6 0.3% (mean 6 SD) labeling efficiency, 40% lung uptake at 10 min after injection, and a favorable safety profile. Lung uptake of the 99m Tc-labeled compound was markedly reduced in rats with pulmonary arterial hypertension. Conclusion: This lead compound could be a suitable clinical imaging agent for the molecular diagnosis of disorders of the pulmonary circulation.

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Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

Cited by 38 publications

References 23 publications

Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Molecular Imaging of Monocrotaline-Induced Pulmonary Vascular Disease with Radiolabeled Linear Adrenomedullin

Use of Adrenomedullin Derivatives for Molecular Imaging of Pulmonary Circulation

PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

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