Abstract
1207
Objectives Lysophosphatidic acid receptor 1 (LPA1) has been implicated in the development of idiopathic pulmonary fibrosis (IPF). BMS-986020, a high-affinity, selective, small-molecule antagonist of LPA1, is presently in Phase two development for IPF. [18F]BMT-083133, a radioligand targeting LPA1 was developed as a translational research tool for assessment of lung LPA1 engagement of BMS-986020 using in vitro autoradiography (ARG).
Methods Sections from healthy and diseased lungs from different species, as well as heterologous cells over-expressing LPA1 were studied. LPA1 target engagement was assessed at various concentrations of BMS-986020 (0.1nM-10nM). Sections and cells were pre-incubated in BMS-986020/buffer solution, followed by incubation with [18F]BMT-083133/BMS-986020/buffer solution and assayed for LPA1 binding using a wash protocol. The ARG images were directly correlated with trichrome collagen staining. ANOVA single factor analysis was performed on ARG results (p< 0.05).
Results A ~2.6 fold increase in specific [18F] BMT-083133 binding was detected using ARG in diseased mouse lung compared to healthy mouse lung (187 PSL/mm2 vs. 487 PSL/mm2, p<0.001). A BMS-986020 concentration-dependent displacement of [18F]BMT-083133 binding was observed in LPA1(+) cells and lung sections. At 0.1nM of BMS-986020, the percent displacement in healthy mice, bleomycin mice, and IPF lungs was 18%, 24%, and 31%, respectively; and at 10nM, the percent displacement was 73%, 76%, and 64%, respectively.
Conclusions [18F]BMT-083133 was demonstrated as the first translational radioligand for the assessment of lung LPA1 target engagement using in vitro ARG.