Optimization of a Collagen-Targeted PET Probe for Molecular Imaging of Pulmonary Fibrosis.
There is a large unmet need for a simple, accurate, noninvasive, quantitative, and high-resolution imaging modality to detect lung fibrosis at early stage and to monitor disease progression. Overexpression of collagen is a hallmark of organ fibrosis. Here, we describe the optimization of a collagen-targeted PET probe for staging pulmonary fibrosis. Methods: Six peptides were synthesized, conjugated to a copper chelator, and radiolabeled with 64Cu. The collagen affinity of each probe was measured in a plate-based assay. The pharmacokinetics and metabolic stability of the probes were studied in healthy rats. The capacity of these probes to detect and stage pulmonary fibrosis in vivo was assessed in a mouse model of bleomycin-induced fibrosis using PET imaging. Results: All probes exhibited affinities in the low micromolar range (1.6 μM < Kd < 14.6 μM) and had rapid blood clearance. The probes showed 2- to 8-fold-greater uptake in the lungs of bleomycin-treated mice than sham-treated mice, whereas the distribution in other organs was similar between bleomycin-treated and sham mice. The probe 64Cu-CBP7 showed the highest uptake in fibrotic lungs and the highest target-to-background ratios. The superiority of 64Cu-CBP7 was traced to a much higher metabolic stability compared with the other probes. The specificity of 64Cu-CBP7 for collagen was confirmed by comparison with a nonbinding isomer. Conclusion:64Cu-CBP7 is a promising candidate for in vivo imaging of pulmonary fibrosis.
['Désogère|Pauline|P|', 'Tapias|Luis F|LF|', 'Rietz|Tyson A|TA|', 'Rotile|Nicholas|N|', 'Blasi|Francesco|F|', 'Day|Helen|H|', 'Elliott|Justin|J|', 'Fuchs|Bryan C|BC|', 'Lanuti|Michael|M|', 'Caravan|Peter|P|']
D000818:Animals D000903:Antibiotics, Antineoplastic D001761:Bleomycin D002614:Chelating Agents D003094:Collagen D003301:Copper Radioisotopes D018450:Disease Progression D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D049268:Positron-Emission Tomography D011658:Pulmonary Fibrosis D019275:Radiopharmaceuticals D051381:Rats D014018:Tissue Distribution
fibrosis lung 64Cu PET imaging type I collagen