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

Abstract

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.

PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension

“…The specific AM receptor (AM 1 ), a heterodimer composed of CLR and RAMP2, is densely distributed on the vascular endothelium of alveolar capillaries 8,9 . Accordingly, AM is rapidly extracted upon its first passage through the pulmonary circulation 4,6,10 . PB is a molecular tracer derived from human AM that was specifically engineered to bind to the AM 1 receptor to detect PVD 1 .…”

“…In the rat monocrotaline model of PAH, 99m Tc-PB uptake is markedly reduced with a reduction of RAMP2 lung expression 22 . In human PH, a recent phase II study showed that PulmoBind could detect large defects in patients with unoperated chronic thromboembolic PH, as well as smaller heterogenous defects or “drop out” zones in subjects with group I PH 4 . The current study was a first attempt at evaluating the effect of PAH specific therapy on lung 99m Tc-PB uptake.…”

“…AM 1 receptors, a dimer composed of the calcitonin like receptor (CLR) and the receptor activity modifying protein-2 (RAMP2) 7 , are densely expressed on the endothelial surface of human alveolar capillaries 8,9 where they mediate the predominant lung clearance of this peptide 10 . A safety and dosimetric phase I study of PB in humans was recently completed 6 , as well as a phase II study in 30 patients with group I and group IV PH 4 . PB was found to be safe with rapid and important lung uptake providing excellent quality imaging.…”

Activated Protein C has No Effect on Pulmonary Capillary Endothelial Function in Septic Patients with Acute Respiratory Distress Syndrome: Association of Endothelial Dysfunction with Mortality

“…It should be noted that the indicator-dilution techniques are arduous procedures, not easily performed in the everyday clinical practice. Future studies using “less demanding” techniques at the bedside are needed in an effort to develop clinically useful tests [ 23 ].…”

Vasodilator responsiveness in idiopathic pulmonary arterial hypertension: identifying a distinct phenotype with distinct physiology and distinct prognosis

“…In support of this, a recent nuclear imaging study, using a radiolabeled adrenomedullin derivative, assessed pulmonary blood flow patterns in PAH patients. 77 It showed a completely normal perfusion pattern in one VR-PAH patient on calcium blockers, compared with persistently abnormal perfusion patterns in VN-PAH patients treated with approved PAH therapies ( Fig. 9 ).…”