Use of Adrenomedullin Derivatives for Molecular Imaging of Pulmonary Circulation

Harel, François; Fu, Yan; Nguyen, Quang Trinh; Létourneau, Myriam; Perrault, Louis P.; Caron, Alexandre; Fournier, Alain; Dupuis, Jocelyn

doi:10.2967/jnumed.108.054023

Cited by 12 publications

(14 citation statements)

References 20 publications

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“…We previously showed that the linear AM peptide, once labeled with 99m Tc, was an attractive lung imaging agent for the diagnosis of pulmonary embolism (5). Lung perfusion scintigraphy with 99m Tclabeled macroaggregates of albumin ( 99m Tc-MAA) is generally con- sidered to be the method of choice for the diagnosis of pulmonary embolism.…”

Section: Discussionmentioning

confidence: 99%

“…Linear AM was radiolabeled through its cysteine residues as previously described (5). For AM analogs containing a chelating moiety, 2.29 nmol of lyophilized peptide were suspended in 20 mL of 1 M acetate buffer (pH 5.5), to which 200 mL of 0.1 M Na 3 PO 4 (pH 12) and 31.25 mL of freshly prepared SnCl 2 solution (0.8 mg/mL, in 0.05 M HCl) were added.…”

Section: M Tc Labelingmentioning

confidence: 99%

“…We recently showed that adrenomedullin (AM) is a promising molecular lung imaging tool for the diagnosis of pathologies such as pulmonary embolism and pulmonary hypertension (4,5). 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).…”

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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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Section: Discussionmentioning

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Section: M Tc Labelingmentioning

confidence: 99%

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PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

et al. 2013

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“…We hypothesized that PAH would be associated with reduced density of adrenomedullin receptors, which could be measured using an externally detectable tagged receptor substrate. To that aim, we developed a linear human adrenomedullin derivative enabling direct labeling with 99m Tc ( 99m Tc-AM-L) and recently demonstrated the capacity of this agent to specifically bind to lung adrenomedullin receptors, thus enabling the imaging of pulmonary circulation and the detection of large perfusion defects (6). We also demonstrated that linear adrenomedullin specifically binds to human MCF-7 cells expressing adrenomedullin receptors (6).…”

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“…To that aim, we developed a linear human adrenomedullin derivative enabling direct labeling with 99m Tc ( 99m Tc-AM-L) and recently demonstrated the capacity of this agent to specifically bind to lung adrenomedullin receptors, thus enabling the imaging of pulmonary circulation and the detection of large perfusion defects (6). We also demonstrated that linear adrenomedullin specifically binds to human MCF-7 cells expressing adrenomedullin receptors (6). The rat lungs contained a high density of specific adrenomedullin binding sites (dissociation constant, 0.66 nM; maximum number of binding sites, 1,760 fmol/mg protein) (7).…”

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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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Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial

Harel

Langleben

Provencher

et al. 2017

Eur J Nucl Med Mol Imaging

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PurposeThe adrenomedullin receptor is densely expressed in the pulmonary vascular endothelium. PulmoBind, an adrenomedullin receptor ligand, was developed for molecular diagnosis of pulmonary vascular disease. We evaluated the safety of PulmoBind SPECT imaging and its capacity to detect pulmonary vascular disease associated with pulmonary hypertension (PH) in a human phase II study.MethodsThirty patients with pulmonary arterial hypertension (PAH, n = 23) or chronic thromboembolic PH (CTEPH, n = 7) in WHO functional class II (n = 26) or III (n = 4) were compared to 15 healthy controls. Lung SPECT was performed after injection of 15 mCi 99mTc-PulmoBind in supine position. Qualitative and semi-quantitative analyses of lung uptake were performed. Reproducibility of repeated testing was evaluated in controls after 1 month.ResultsPulmoBind injection was well tolerated without any serious adverse event. Imaging was markedly abnormal in PH with ∼50% of subjects showing moderate to severe heterogeneity of moderate to severe extent. The abnormalities were unevenly distributed between the right and left lungs as well as within each lung. Segmental defects compatible with pulmonary embolism were present in 7/7 subjects with CTEPH and in 2/23 subjects with PAH. There were no segmental defects in controls. The PulmoBind activity distribution index, a parameter indicative of heterogeneity, was elevated in PH (65% ± 28%) vs. controls (41% ± 13%, p = 0.0003). In the only subject with vasodilator-responsive idiopathic PAH, PulmoBind lung SPECT was completely normal. Repeated testing 1 month later in healthy controls was well tolerated and showed no significant variability of PulmoBind distribution.ConclusionsIn this phase II study, molecular SPECT imaging of the pulmonary vascular endothelium using 99mTc-PulmoBind was safe. PulmoBind showed potential to detect both pulmonary embolism and abnormalities indicative of pulmonary vascular disease in PAH. Phase III studies with this novel tracer and direct comparisons to lung perfusion agents such as labeled macro-aggregates of albumin are needed.Clinical trialClinicalTrials.gov, NCT02216279Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-017-3655-y) contains supplementary material, which is available to authorized users.

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Use of Adrenomedullin Derivatives for Molecular Imaging of Pulmonary Circulation

Cited by 12 publications

References 20 publications

PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

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

Molecular imaging of the human pulmonary vascular endothelium in pulmonary hypertension: a phase II safety and proof of principle trial

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