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Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, emphasizing the need to directly measure the intratumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we contribute to this endeavor by reporting on the development of an 18 F-labeled carboplatin derivative ( 18 F-FCP) that has the potential to image drug uptake and retention, including intratumoral distribution, by PET. Methods: Fluorinated carboplatin ( 19 F-FCP) was synthesized using 19 F-labeled 2-(5-fluoro-pentyl)-2-methyl malonic acid ( 19 F-FPMA) as the labeling agent to coordinate with the cisplatin-aqua complex. It was then used to treat cell lines and compared with cisplatin and carboplatin at different concentrations. Manual radiosynthesis and characterization of 18 F-FCP were performed using 18 F-FPMA for coordination with the cisplatin-aqua complex. Automated radiosynthesis of 18 F-FCP was optimized on the basis of manual synthesis procedures. The stability of 18 F-FCP was verified using high-performance liquid chromatography. 18 F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor-bearing animals as well as in KB-3-1 and COLO-205 tumor xenograft-bearing nude mice. Results: In vitro cytotoxicity studies demonstrated that 19 F-FCP has an antitumor activity profile similar to that of the parent drug carboplatin. In vivo plasma and urine stability analysis showed intact 18 F-FCP at 24 h after injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in the kidneys, indicating substantial renal clearance of 18 F-FCP. Using 18 F-FCP PET, we could image and identify the intratumor drug profile. Conclusion: Our results demonstrated that 19 F-FCP, like carboplatin, retains antitumor activity in various cell lines. 18 F-FCP could be a useful imaging tool for measuring the intratumor drug distribution. This strategy of using a new therapeutic carboplatin derivative to quantify and track platinum drugs in tumors using PET has the potential to translate into a clinically useful imaging tool for individual patients.

18F-Labeled Carboplatin Derivative for PET Imaging of Platinum Drug Distribution

¹⁸F-Labeled Carboplatin Derivative for PET Imaging of Platinum Drug Distribution