Radiosynthesis and Biological Evaluation of a Novel Berberine Derivative for Cardiac PET Imaging

Methods: The purpose of this study is to explore the suitability of a novel berberine derivative ¹⁸F-HX-01 for cardiac PET imaging.

Methods: The tosylate labeling precursor of 9-hydroxy-10-methoxy-5,6- dihydro-[1,3] dioxolo [4,5-g] isoquinolino [3, 2-a] isoquinolin-7-ium chloride (Ots-HX-01) and the nonradioactive reference compound (¹⁹F-HX-01) were synthesized and characterized by ¹H nuclear magnetic resonance and mass spectrometry analysis. The cell uptake and distribution of ¹⁹F-HX-01 and its mitochondrion targeting in primary neonatal rat ventricular myocytes (NRVMs) were determined by confocal microscopy. ¹⁸F-HX-01 was prepared by 1-step nucleophilic replacement of the tosyl group by ¹⁸F and evaluated in vitro and in vivo.

Results: Total radiosynthesis time of ¹⁸F-HX-01 was about 50-70 min. Typical decay-corrected radiochemical yield was > 30 %. Radiochemical purity was > 99 %. Specific activity was 8.5 GBq/mmol. The log P value of ¹⁸F-HX-01 was 0.94 ± 0.02. ¹⁸F-HX-01 had high human serum stability. NRVMs selectively accumulated ¹⁸F-HX-01 and this could not be inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP). NRVMs uptake of ¹⁹F-HX-01 followed dose-dependent pattern. ¹⁹F-HX-01 selectively accumulated primarily in mitochondria of NRVMs at lower doses (< 50 uM). In biodistribution studies, ¹⁸F-HX-01 had high heart uptake (34.6 ± 3.9, 31.6 ± 2.2 and 30.1 ± 0.2 %ID/g at 5, 30 and 240 min post-injection in mice respectively). The heart-to-liver and heart-to-lung ratios were > 2 and 25 respectively at 5 min after injection. High contrast cardiac PET images of ¹⁸F-HX-01 were obtained in healthy rabbits at 10 min after injection. Inhibition PET imaging showed that the heart uptake could be blocked effectively by nonradioactive ¹⁹F-HX-01 (p < 0.005). Conclusion: ¹⁸F-HX-01 is a mitochondrion targeting agent. It has high initial heart uptake and persistent retention over 2 h with better myocardium-to-background ratio at 30 min after injection in healthy mice and rabbits. This radiotracer merits further evaluation in myocardial disease models as a novel myocardium perfusion imaging agent. Fig. 1 Typical dynamic PET/CT images of ¹⁸F-HX-01 in a healthy New Zealand white rabbit. Images were obtained with 30 MBq of ¹⁸F-HX-01 in normal saline containing 5 % V/V ethanol at 10, 30, 45, 60, 75 and 120 min after injection. H: heart; L: Liver.

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