BMS-986327 as a novel PET imaging agent for assessment of LPA1 receptors in IPF

Rationale and Aim: Studies linking the lysophosphatidic acid 1 receptor (LPA1) to the pathogenesis of lung and kidney fibrosis have identified LPA1 as a potential clinical target for idiopathic pulmonary fibrosis (IPF). LPA1 antagonism has shown efficacy in a Phase 2 clinical IPF trial. Here we report the evaluation of BMS-986327 as a PET ligand to detect LPA1 expression and assess engagement and occupancy of LPA1-targeted drugs. Methods: BMS-986327 binding was measured in competition with LPA1 antagonists in a whole-cell binding assay. PET imaging was performed in wild-type (WT) and pulmonary fibrosis (PF) rat models to determine target expression and drug target engagement. Similar PET studies were carried out in healthy non-human primates (NHPs) as a prelude to clinical studies. Results: In vitro studies showed tracer binding to LPA1 and concentration-dependent inhibition with LPA1 antagonists. In vivo, preferential tracer accumulation was measured in the lungs of PF rats compared to WT controls. Drug competition studies showed a correlation between tracer signal in the lungs of PF rats and the plasma concentration of LPA1 antagonist. PET studies in NHPs confirmed lung tracer localization and dose-dependent blockade with LPA1 antagonist, with test-retest variability within typical limits of PET. Conclusions: In vitro and in vivo studies demonstrated specific binding of BMS-986327 to LPA1. Increased lung tracer accumulation in PF compared to WT animals and displacement with LPA1 antagonists showed the ability of BMS-986327 to assess LPA1 expression and drug target engagement in vivo in both rat and NHP models. Minimal test-retest variability supports the translatability of this tracer to clinical study.