PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

Abstract

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.

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

“…Adrenomedullin (AM), a ubiquitously expressed peptide hormone that binds calcitonin receptor-like receptor on lung endothelial cells promoting intercellular adherence, improved endothelial barrier function in preclinical acute lung injury (ALI) and ventilator associated lung injury (VALI) models 114–116. Given the abundance of binding sites on the pulmonary endothelium, AM also holds promise as a lung endothelial imaging tool using 99mTechnetium labelling 117. Finally, hepatocyte growth factor has recently been shown to suppress LPS-induced endothelial activation and barrier disruption possibly via a guanine nucleotide exchange factor 118 119…”

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

“…Pulmonary vascular diseases can lead to PH, a devastating condition often diagnosed late in the evolution process, as a substantial proportion of the pulmonary vascular bed must be affected before an elevation of pulmonary pressures is clinically detectable at rest. We developed PulmoBind, an AM receptor ligand, for the diagnosis of pulmonary vascular disease [5, 7, 8, 11, 12]. PulmoBind specifically binds to the human AM receptor that is densely expressed in the pulmonary vascular endothelium, mostly in capillaries [2, 3].…”

“…Specific AM receptors are present in the pulmonary vascular endothelium with dense expression in capillaries [2, 3]. The lungs are a major site for circulating AM clearance [4] and pulmonary clearance of AM is reduced in animal models of pulmonary arterial hypertension (PAH) with reduced AM receptor expression [5–7]. Based on these premises, we developed AM derivatives that can be labeled with 99m Tc for molecular SPECT imaging of the pulmonary circulation [7].…”

“…The lead derivative is called PulmoBind. PulmoBind binds with excellent affinity to the human AM receptor but lacks the hypotensive effects of native adrenomedullin [7]. 99m Tc-PulmoBind is effective to detect reduced lung perfusion in the monocrotaline and hypoxia-Sugen models of PAH [6, 7].…”

“…PulmoBind binds with excellent affinity to the human AM receptor but lacks the hypotensive effects of native adrenomedullin [7]. 99m Tc-PulmoBind is effective to detect reduced lung perfusion in the monocrotaline and hypoxia-Sugen models of PAH [6, 7]. In a phase I trial (study PB-01, ClinicalTrials.gov NCT01539889) of healthy human subjects, PulmoBind was safe and resulted in excellent quality SPECT imaging of the lungs [8].…”