Type I collagen-targeted PET probe for pulmonary fibrosis detection and staging in preclinical models.

166 Objectives There is an unmet need to develop effective methods for non invasive detection of pulmonary fibrosis (1). Overexpression of collagen is a hallmark of organ fibrosis (2). Here, we report a new peptide-based PET probe (68Ga-CBP8) that targets collagen type I. We tested whether the collagen-specific PET probe 68Ga-CBP8 is suitable for pulmonary fibrosis detection and collagen content estimation in preclinical models. Methods The collagen-binding probe 68Ga-CBP8 was synthesized by conjugation of a cyclic peptide with high affinity for collagen to a macrocyclic chelator (NODAGA), followed by labeling with 68Ga. The non-binding analogue 68Ga-CBP12 was also synthesized. 68Ga-CBP12 has an identical structure to 68Ga-CBP8 except that one of cysteine moieties is changed from L-Cys in 68Ga-CBP8 to D-Cys in 68Ga-CBP12 to eliminate collagen binding (3). Both probes were evaluated in the well established bleomycin (BM) mouse model of pulmonary fibrosis. The efficacy of 68Ga-CBP8 and its capacity to monitor treatment response were also evaluated in a second mouse model of pulmonary fibrosis associated with vascular leak. In vivo studies include biodistribution, small animal PET-CT imaging, evaluation of pharmacokinetic and metabolic stability, characterization of collagen content and histology. Results Probe 68Ga-CBP8 showed high specificity for pulmonary fibrosis and high target:background ratios in diseased animals in the BM mouse of pulmonary fibrosis. The control probe, 68Ga-CBP12, showed similar, weak uptake in the lungs of both fibrotic and control mice. Lung PET signal and ex vivo quantification of lung 68Ga-CBP8 uptake correlated linearly (r2=0.84) with increased lung collagen levels in fibrotic mice. In a second mouse model of pulmonary fibrosis associated with vascular leak, we showed that PET imaging of collagen with 68Ga-CBP8 can successfully identify animals with pulmonary fibrosis, and additionally, it can detect a blunted disease progression in treated animals. Conclusions We demonstrated that 68Ga-CBP8-PET represents a feasible approach for non-invasive evaluation of collagen content. Collagen-PET imaging represents a novel and valuable diagnostic strategy for translation in clinical imaging of pulmonary fibrosis.