Abstract
Radiation-induced lung injury (RILI) is a severe side effect of radiotherapy (RT) for thoracic malignancies and we currently lack established means for the early detection of RILI. In this study, we synthesized a new tracer, [18F]AlF-NOTA-QHY-04, targeting C-X-C-chemokine-receptor-type-4 (CXCR4) and investigated the feasibility of using this tracer in positron emission tomography combined with computed tomography (PET/CT) for detecting RILI. An RILI model was established using a high-dose single RT (50 Gy/Fraction) to the right lung of female Wistar rats. Experimental animals were scanned with [18F]AlF-NOTA-QHY-04 PET/CT and [18F]FDG PET/CT at various time-points post-RT. MicroCT imaging was conducted weekly till 11 weeks post-RT. Dynamic, competition, autoradiography and histopathological studies were performed on day 14 post-RT. Biodistribution study was further performed on day 18 post-RT. Lung QHY-04 uptake was analyzed in twelve patients with radiation pneumonia, developed during or after thoracic RT. The yield of [18F]AlF-NOTA-QHY-04 was 28.5-43.2%, and the specific activity was 27-33 GBq/μmol. Significantly increased [18F]AlF-NOTA-QHY-04 uptake in the damaged lung compared with that in the normal lung was observed in the experimental animal model on 6 post-RT and peaked on day 14 post-RT (0.96 ± 0.06 vs. 0.50 ± 0.05 %ID/mL, P<0.05), whereas no apparent uptake of [18F]FDG was shown on day 7 and 15 post-RT. Significant intense [18F]AlF-NOTA-QHY-04 uptake was confirmed by autoradiography. No significant difference in CT density was observed between the damaged and normal lung tissues until six weeks post-RT. Immunofluorescence staining demonstrated expression of CXCR4 was significantly increased in the damaged lung tissue, which correlated with results obtained from hematoxylin-eosin and Masson's trichrome staining. Maximum standardized uptake values (SUVmax) were significantly higher in the irradiated lung compared with that in the normal lung in 12 patients with radiation pneumonia (3.07 ± 0.86 vs. 0.585 ± 0.17, P<0.001). SUVmax of patients with grade 2 RILI was significantly higher than that of patients with grade 1 RILI (3.30 ± 0.65 vs. 1.64 ± 0.08, P<0.05). This study indicated that [18F]AlF-NOTA-QHY-04 PET/CT imaging can detect RILI noninvasively and earlier than [18F]FDG PET/CT in a rat model. Clinical studies verified its' feasibility, suggesting the clinical potential of [18F]AlF-NOTA-QHY-04 as a PET/CT tracer for early monitoring of RILI.
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