Molecular Imaging of the Human Pulmonary Vascular Endothelium Using an Adrenomedullin Receptor Ligand

Abstract

This phase I study (NCT01539889) evaluated the safety, efficacy, and dosing of PulmoBind for molecular imaging of pulmonary circulation. PulmoBind is a ligand of the adrenomedullin receptor abundantly distributed in lung capillaries. Labeled with 99mTc, it allows single-photon emission computed tomographic (SPECT) imaging of lung perfusion. In preclinical studies, PulmoBind scans enabled detection of lung perfusion defects and quantification of microcirculatory occlusion caused by pulmonary hypertension. Healthy humans (N = 20) were included into escalating groups of 5 mCi (n = 5), 10 mCi (n = 5), or 15 mCi (n = 10) 99mTc-PulmoBind. SPECT imaging was serially performed, and 99mTc-PulmoBind dosimetric analysis was accomplished. The radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the three dosages studied. Imaging revealed predominant and prolonged lung uptake with a mean peak extraction of 58% ± 7%. PulmoBind was well tolerated, with no clinically significant adverse event related to the study drug. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent imaging. The postural lung perfusion gradient was detectable. 99mTc-PulmoBind is safe and provides good quality lung perfusion imaging. The safety/efficacy of this agent can be tested in disorders of pulmonary circulation such as pulmonary arterial hypertension.

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

“…Animals were anesthetized by isoflurane (1.5–2%). 99m Tc-labeled PB (37–58 MBq) was prepared as previously described in details 6 and intravenously injected in a volume of 300 μL via the caudal vein. In vivo whole-body biodistribution of radioactivity was measured by a nuclear medicine camera (Ecam, Siemens) equipped with an on-board computer and a low-energy high resolution parallel-hole collimator.…”

“…Additionally, 99m Tc-MAAs obstruct small arteries in subjects with an already reduced lung perfusion with inherent risks associated with the use of a human-derived product. PulmoBind (PB) is a novel molecular SPECT imaging agent that distributes according to the lung capillaries perfusion by binding to the vascular endothelium 1–6 . PB is a specific ligand of the adrenomedullin receptor (AM 1 ).…”

“…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.…”

Adrenomedullin – new perspectives of a potent peptide hormone

“…Because of its antagonistic properties it is only binding but not activating ADM receptors in the vascular endothelium. Therefore, it allows the detection of lung perfusion defects and microcirculatory occlusions in early stages of the disease, which has been already proven in phase I clinical trials [200].…”

Molecular imaging of the pulmonary circulation in health and disease

“…In pre-clinical studies, 99m Tc-PulmoBind displays all the qualities desired of a molecular imaging agent in nuclear medicine: sizeable first pass and prolonged uptake by the lungs and quick plasma clearance with elimination by both the liver and kidneys [ 51 ]. A human phase I study of PulmoBind in normal human subjects was recently completed (Clinicaltrials.gov NCT01539889) [ 54 ]. We demonstrated that PulmoBind is safe while providing superior quality lung imaging compared to 99m Tc-MAA.…”