Synthesis and evaluation of a novel bis-zinc(II)-dipicolylamine derivative for dual-modality PET/NIRF imaging of phosphatidylserine exposure

Objectives Anionic phosphatidylserine (PS) is highly exposed on the surfaces of cancer cells and tumor blood vessels. Synthetic bis-zinc(II)-dipicolylamine (Zn-DPA) derivatives have high selectivity for biological membranes enriched with PS. This study was designed to investigate the feasibility of a novel Zn-DPA containing probe for dual-modality PET/NIRF imaging of PS exposure.

Methods Bis-dipicolylamine was conjugated with a NIRF dye using lysine as a linker. The precursor with a free epsilon amine group was radiolabeled with 4-nitrophenyl 2-[18F]fluoropropinate ([18F]NFP) to provide 18F-PS-TumorVue® which was then subjected to in vitro and in vivo evaluations, including U87MG cell uptake, PET/NIRF imaging, and direct tissue sampling biodistribution studies in a U87MG tumor xenografted mouse model.

Results The synthesis of precursor was accomplished in five steps with >60% yield in each step. The F-18 radiolabeling was achieved with overall radiochemical yield of 60 ± 7% (decay corrected, n = 6) and radiochemical purity of >99%. The specific activity of 18F-PS-TumorVue® was 300-650 mCi/umol. The tumor-targeting efficacy and biodistribution pattern of 18F-PS-TumorVue® were evaluated in nude mice bearing U87MG xenografts (n = 5) at 1, 2, and 4 h with static microPET scans. The U87MG tumors were all clearly visible with good contrast to contralateral background at all measured time points. Ex vivo PET imaging of tumor and normal tissues of 18F-PS-TumorVue® confirmed the in vivo findings. NIRF imaging with 19F-PS-TumorVue® exhibited rapid U87MG tumor targeting at 0.5 h pi, and high tumor-to-background contrast at 4 h pi.

Conclusions We have successfully developed a novel Zn-DPA derivative for dual-modality PET/NIRF imaging of PS exposure. The PET/NIRF probe offers synergistic advantages, not only allowing comprehensive collection of physiological information, but also facilitating clinical applications of image-guided surgery.

Research Support This work was supported by the USC Department of Radiology.