Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates numerous aspects of cellular function and has been recognized as a novel mediator of wound healing and tissue fibrosis. LPA mediates its biological effects through the LPA receptors, of which at least six isoforms have currently been identified. Recently, LPA1 has been linked to the pathogenesis of lung fibrosis and antagonism of LPA1 is currently being explored as a target for the treatment of idiopathic pulmonary fibrosis (IPF). It has been hypothesized that blocking LPA1 will reduce lung injury by mediating fibroblast recruitment and vascular leakage. The development of a specific PET radioligand having high affinity for LPA1 may provide a method to evaluate both target engagement and drug exposure, receptor occupancy relationships of LPA1 antagonists in the human lung. Both [18F]-BMT-083133 and [11C]-BMT-136088 were designed to be LPA1 PET radioligands, and have low nanomolar affinity for the LPA1 receptor. These molecules are functional in ex-vivo autoradiography studies and in-vivo imaging of LPA1 expression in lung tissue. Here, we describe the discovery and design of these potent LPA1 PET ligands and their preclinical validation using disease state induced models.

Design, synthesis, and development of fluorine-18 and carbon-11 labeled lysophosphatidic acid receptor 1 (LPA1) PET radioligands for lung receptor occupancy imaging

249th National Meeting (2015)

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