l18F标记白蛋白结合剂修饰的PARP靶向显像探针的制备及初步生物学评价

Background] Poly(ADP-ribose) polymerase (PARP) is an important therapeutic target in cancer treatment, and dynamic assessment of its expression level is essential for achieving precision therapy. [Purpose] In this study, a novel 18F-labeled PARP-targeted PET imaging probe was designed and synthesized based on the core structure of the PARP inhibitor olaparib, by conjugating it with an albumin-binding moiety. Preliminary biological evaluations were conducted to assess the feasibility of using this probe to detect PARP expression levels. [Methods] The precursor NOTA-LA was synthesized using 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one and 4-(4-iodophenyl)butanoic acid as starting materials. The target imaging probe [18F]AlF-NOTA-LA was obtained using the [18F]AlF non-covalent radiochemical fluorination method. The radiolabeling yield, radiochemical purity, molar activity, log P, and stability were subsequently determined. The imaging performance of the probe was evaluated through a combination of in vitro experiments and in vivo microPET imaging in tumor-bearing mice. [Results] The radiolabeling of [18F]AlF-NOTA-LA was completed in approximately 15 min, yielding a radiolabeling efficiency of 49.2 2.5%, with radiochemical purity exceeding 99%, a molar activity of 3.14 GBq/mol, a log P value of -1.1 0.013, and excellent in vitro stability. After 60 min, the cellular uptake of [18F]AlF-NOTA-LA in MDA-MB-453 cells was 3.83 0.26%AD, significantly higher than that in A549 cells 1.89 0.12%AD. MicroPET imaging revealed that in MDA-MB-453 tumor-bearing mice, the probes tumor uptake peaked at 10 min, reaching a maximum value of 5.31 0.20%ID/g (percentage injected dose per gram of tissue). In contrast, A549 tumor-bearing mice and blocking group showed significantly lower peak uptakes of 3.04 0.03%ID/g and 2.23 0.11%ID/g, respectively. [Conclusion] This preclinical study demonstrated its potential as a novel PARP-targeted PET imaging probe.