Évaluation de l'innocuité et de l'efficacité d'un dérivé synthétique marqué de l'adrénomédulline dans l'imagerie moléculaire pulmonaire chez l'humain

L’HTP est une maladie caractérisée par une élévation de la pression artérielle pulmonaire moyenne au-delà de 25 mmHg au repos. Dans le but de trouver un meilleur outil diagnostique pour cette affection, notre laboratoire a synthétisé puis expérimenté un radiotraceur nommé PulmoBind. Celui-ci s’avère être un dérivé synthétique de l’AM : un peptide vasodilatateur endogène de 52 acides aminés sécrété par de nombreux organes. Une fois couplé au 99mTechnétium, le PulmoBind permet par méthode scintigraphique la visualisation de la circulation pulmonaire métaboliquement active. Suite à notre étude de phase I, le PulmoBind s’est avéré sécuritaire et efficace. De plus, des analyses plus approfondies de la distribution spatiale ont démontré la capacité du PulmoBind à imager les divers gradients de la perfusion pulmonaire. À ce jour, aucun produit sur le marché n’emploie des données de captation et de distribution spatiale pour effectuer l’évaluation de la circulation respiratoire. Par conséquent, cette nouvelle méthodologie constitue une approche inédite et prometteuse pour le diagnostic de l’HTP et de son suivi. Background. The pulmonary circulation is submitted to large physiologic hemodynamic variations and possesses numerous important metabolic functions mediated through its vast endothelial surface. Unfortunately, no test is currently available that can directly evaluate endothelial integrity and pulmonary perfusion gradients at the same time. We developed PulmoBind, a chelated derivative of human adrenomedullin labeled with 99m-Tc for nuclear medicine SPECT imaging. By specifically binding to its endothelial receptors, abundantly expressed in human alveolar capillaries, PulmoBind can provide a non-invasive evaluation of pulmonary function that can help in the diagnosis of disorders affecting the pulmonary circulation. This thesis represents my doctoral work to determine the safety of PulmoBind in humans and its capacity to generate good quality imaging for diagnosis purposes. Methods. Twenty healthy participants were included into escalating doses groups of 5 mCi (n=5), 10 mCi (n=5) or 15 mCi (n=10) 99mTc-PulmoBind. Vital signs were closely monitored and safety biochemistry and hematology parameters obtained. SPECT imaging was serially performed and 99mTc-PulmoBind dosimetric and spatial distribution analysis accomplished. Imaging quality of the lungs was assessed serially. Results. Radiochemical purity of 99mTc-PulmoBind was greater than 95%. There were no safety concerns at the 3 dosages studied. Imaging revealed a predominant and prolonged lung uptake with mean peak pulmonary extraction of 58% ± 7% (mean ± SD) of the injected dose. PulmoBind was well tolerated and resulted in no clinically significant adverse events. The highest dose of 15 mCi provided a favorable dosimetric profile and excellent quality tomographic imaging of the lungs. The postural lung perfusion gradient was detectable. Indeed, dorsal activity was 18.1 ± 2.1% greater than ventral activity, and caudal activity was 25.7 ± 1.6% greater than cranial activity. The intensity of PB activity followed a normal distribution while macro aggregated albumin (MAA) activity was importantly skewed and bimodal. Conclusion. 99mTc-PulmoBind up to a dose of 15 mCi is safe and provides good quality lung perfusion imaging that can reveal the heterogeneity of the pulmonary perfusion. Therefore, the safety and efficacy of this agent could be tested in disorders of the pulmonary circulation such as pulmonary arterial hypertension.

Keyphrases: Adrénomédulline, Médecine nucléaire, Technétium, Peptide, Radiotraceur, Imagerie moléculaire, Étude clinique, Hypertension artérielle pulmonaire, Circulation pulmonaire, Physiologie circulatoire, Sécurité, Endothélium, Marqueur moléculaire, Physique nucléaire, Imagerie diagnostique, Endothélium pulmonaire, Dosimétrie, PAH, Phase I, SPECT, Innocuité, RAMP, Receptor activity modifying protein, Hypertension pulmonaire, HTAP, Calcitonin receptor-like receptor, Adrenomedullin, Nuclear medicine, Radiotracer, Molecular imaging, Clinical study, Pulmonary arterial hypertension, Pulmonary circulation, Safety, Molecular marker, Nuclear physics, Diagnostic imaging, Pulmonary endothelium, Pulmonary hypertension, Dosimetry