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SPECT and PET imaging of adrenomedullin receptors: a promising strategy for studying pulmonary vascular diseases.

ABSTRACT: Circulating adrenomedullin (AM) levels are elevated in several cardiovascular diseases, including pulmonary vascular diseases causing pulmonary hypertension. To date the perfusion agent 99mTc-albumin macroaggregates (MAA) is the only approved radiopharmaceutical used for imaging of pulmonary circulation. Unlike 99mTc-MAA, imaging the AM receptors involves a molecular process dependent on the density of the receptors and the affinity of specific radioligands. The AM receptors are abundantly distributed in lung capillaries and its integrity provides protection in the development of pulmonary vascular diseases. This review summarizes the development and characterization of radioligands for in vivo imaging of AM receptors as an early predictor of the onset of a pulmonary vascular disease.

SUBMITTER: Alonso Martinez LM

PROVIDER: S-EPMC6872478 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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SPECT and PET imaging of adrenomedullin receptors: a promising strategy for studying pulmonary vascular diseases.

Alonso Martinez Luis Michel LM Harel François F Létourneau Myriam M Finnerty Vincent V Fournier Alain A Dupuis Jocelyn J DaSilva Jean N JN

American journal of nuclear medicine and molecular imaging 20191015 5

Circulating adrenomedullin (AM) levels are elevated in several cardiovascular diseases, including pulmonary vascular diseases causing pulmonary hypertension. To date the perfusion agent <sup>99m</sup>Tc-albumin macroaggregates (MAA) is the only approved radiopharmaceutical used for imaging of pulmonary circulation. Unlike <sup>99m</sup>Tc-MAA, imaging the AM receptors involves a molecular process dependent on the density of the receptors and the affinity of specific radioligands. The AM receptor ...[more]

PMID: 31772819

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Project description:BackgroundPulmonary hypertension (PH) complicating idiopathic pulmonary fibrosis (IPF) is associated to worse outcome. There is a great need for a non-invasive diagnostic modality to detect and evaluate the severity of pulmonary vascular disease (PVD). 99mTc-PulmoBind is a novel imaging agent that binds to the adrenomedullin (AM) receptor on the pulmonary microvascular endothelium. SPECT imaging employing the endothelial cell tracer 99mTc-PulmoBind was used to assess PVD associated with lung fibrosis.MethodsRats with selective right lung bleomycin-induced fibrosis were compared to control rats. SPECT imaging was performed after three weeks with 99mTc-PulmoBind and 99mTc-macroaggregates of albumin (MAA). PH and right ventricular (RV) function were assessed by echocardiography. Lung perfusion was evaluated by fluorescent microangiography. Lung AM receptor expression was measured by qPCR and by immunohistology. Relevance to human IPF was explored by measuring AM receptor expression in lung biopsies from IPF patients and healthy controls.ResultsThe bleomycin group developed preferential right lung fibrosis with remodeling and reduced perfusion as assessed with fluorescent microangiography. These rats developed PH with RV hypertrophy and dysfunction. 99mTc-PulmoBind uptake was selectively reduced by 50% in the right lung and associated with reduced AM receptor expression, PH and RV hypertrophy. AM receptor was co-expressed with the endothelial cell protein CD31 in alveolar capillaries, and markedly reduced after bleomycin. Quantitative dynamic analysis of 99mTc-PulmoBind uptake in comparison to 99mTc-MAA revealed that the latter distributed only according to flow, with about 60% increased left lung uptake while left lung uptake of 99mTc-PulmoBind was not affected. Lung from human IPF patients showed important reduction in AM receptor expression closely associated with CD31.ConclusionsSPECT imaging with 99mTc-PulmoBind detects PVD and its severity in bleomycin-induced lung fibrosis. Reduced AM receptor expression in human IPF supports further clinical development of this imaging approach.

Project description:UNLABELLED:Atherosclerosis is the pathophysiologic process behind lethal cardiovascular diseases. It is a chronic inflammatory progression. Chemokines can strongly affect the initiation and progression of atherosclerosis by controlling the trafficking of inflammatory cells in vivo through interaction with their receptors. Some chemokine receptors have been reported to play an important role in plaque development and stability. However, the diagnostic potential of chemokine receptors has not yet been explored. The purpose of this study was to develop a positron emitter-radiolabeled probe to image the upregulation of chemokine receptor in a wire-injury-accelerated apolipoprotein E knockout (ApoE(-/-)) mouse model of atherosclerosis. METHODS:A viral macrophage inflammatory protein II (vMIP-II) was used to image the upregulation of multiple chemokine receptors through conjugation with DOTA for (64)Cu radiolabeling and PET. Imaging studies were performed at 2 and 4 wk after injury in both wire-injured ApoE(-/-) and wild-type C57BL/6 mice. Competitive PET blocking studies with nonradiolabeled vMIP-II were performed to confirm the imaging specificity. Specific PET blocking with individual chemokine receptor antagonists was also performed to verify the upregulation of a particular chemokine receptor. In contrast, (18)F-FDG PET imaging was performed in both models to evaluate tracer uptake. Immunohistochemistry on the injury and sham tissues was performed to assess the upregulation of chemokine receptors. RESULTS:(15)O-CO PET showed decreased blood volume in the femoral artery after the injury. (64)Cu-DOTA-vMIP-II exhibited fast in vivo pharmacokinetics with major renal clearance. PET images showed specific accumulation around the injury site, with consistent expression during the study period. Quantitative analysis of tracer uptake at the injury lesion in the ApoE(-/-) model showed a 3-fold increase over the sham-operated site and the sites in the injured wild-type mouse. (18)F-FDG PET showed significantly less tracer accumulation than (64)Cu-DOTA-vMIP-II, with no difference observed between injury and sham sites. PET blocking studies identified chemokine receptor-mediated (64)Cu-DOTA-vMIP-II uptake and verified the presence of 8 chemokine receptors, and this finding was confirmed by immunohistochemistry. CONCLUSION:(64)Cu-DOTA-vMIP-II was proven a sensitive and useful PET imaging probe for the detection of 8 up-regulated chemokine receptors in a model of injury-accelerated atherosclerosis.

Dataset Information

SPECT and PET imaging of adrenomedullin receptors: a promising strategy for studying pulmonary vascular diseases.

Publications

SPECT and PET imaging of adrenomedullin receptors: a promising strategy for studying pulmonary vascular diseases.

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