Abstract
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Objectives: Pulmonary fibrosis (PF) involves scarring of the lung tissue. This scarring is essentially buildup of the deposition of extracellular matrices such as collagen, elastin and glycoproteins. Over time this buildup results in decreased pulmonary function and usually proves to be a fatal condition. Causes of PF are wide ranging but most cases are idiopathic, having no known cause. In this study, we aimed to assess the use of a novel 89Zr PET imaging agent, [89Zr]JLB-01, to monitor the progression of the disease on a weekly basis in mice whose lungs were injured with bleomycin, an agent known to induce PF in animal models. Methods: D-Hphe-AMBH-DFO was synthesized in 6 steps starting with N-boc-homo-phenylalanine and 4-aminobenzoic acid. D-Hphe-AMBH-DFO was dissolved into DMSO and incubated in a solution with 89Zr at a pH of 7.2 in HEPES buffer to yield the desired compound of [89Zr]JLB-01. Specific activity was calculated based off the starting compound and radiochemical purity was determined via instant thin layer chromatography. At T0 (week 1), a group of mice (n=6/group) were injured accordingly, with either bleomycin or saline, injected with ~225 μCi of [89Zr]JLB-01 via tail vein, then imaged at 1 h and 4 h post injection. Each group was studied on subsequent days. Four weeks post injury, 3 mice per group were sacrificed post PET imaging for biodistribution purposes. The remaining mice were injected, imaged and sacrificed during week 5.
Results: Synthesis of the precursor D-Hphe-AMBH-DFO proved challenging with the lowest yielding step being the coupling between the hydrazide and the carboxylic acid of 4-aminobenzoic acid (scheme not shown). The final synthetic yield over 6 steps was ~5% For radiolabeling purposes, [89Zr]JLB-01, was easily synthesized within 15 min at 95oC resulting in >95% purity, and acceptable specific activity at 4 mCi/μg. The preliminary biodistribution studies showed that at week 4 (the week expected to have the most fibrotic tissue), 3.4 + 0.1% ID/g was observed in the bleomycin injured lungs vs. just 1.0 + 0.2 % ID/g in the saline injured lungs (p = .0007). At week 5, when the lungs were expected to start recovering from the injury, the uptake of [89Zr]JLB-01 was just 0.6 + 0.1 %ID/g in the bleomycin injured group vs. 0.4 + 0.3 %ID/g in the saline injured group.
Conclusion: The synthesis of the radiolabeling precursor, D-Hphe-AMBH-DFO, was short and low yielding however radiolabeling proved to be high yielding with good radiochemical purity and specific activity. Overall the compound [89Zr]JLB-01 showed that it is possible to study the progression of the development of pulmonary fibrosis in mice injured with bleomycin.
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