Abstract
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Objectives: Cardiovascular related disease has become the leading cause of death and caused significantly heavy and ongoing medical burden worldwide for decades. Myocardial perfusion imaging (MPI) by either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) remains the most effective and noninvasive method to detect and identify the risk index of coronary artery disease (CAD). It can also be used to assess hemodynamic significances and document myocardial ischemia. Currently, the most commonly used cardiac PET tracers (13NH3, H215O etc.) presented certain disadvantages in clinical applications due to the short half-life of the radio-isotopes. In recent years, studies have been concentrated in the development of longer half-life 18F-labeled PET perfusion tracers. Recent studies revealed a traditional Chinese medicine, Rhizomes of Coptis chinensis, exhibited potent inhibitory activity against acetylcholinesterase (AChE), activation of AMP-activated protein kinase and efficacy in congestive heart failure. The aim of this study is to develop a derivative of the main active extract of Coptis chinensis, berberine (BBR) to evaluate the potential diagnostic and therapeutic applications of Coptis chinensis, and radiolabel the compound with 18F to assess the potential of 18F-BBR as a novel MPI imaging agent both in vitro and in vivo.
Methods: The precursor and reference standard of 18F-BBR were synthesized from berberrubine through a nucleophilic substitution. 18F-BBR was labeled with K18F following the methods adapted from literatures. The in vitro stability in human serum were measured at 37 oC. 18F-BBR was also assayed for in vitro cell uptake in cardiomyocyte H9c2 and fibroblast NIH/3T3 cell lines. Biodistribution study was carried out with mice and PET imaging in mice heart was also conducted to gather the in vivo tissue biodistribution properties and binding characteristics.
Results: The precursor and reference standard of 18F-BBR was successfully synthesized. 18F-BBR was produced in ~ 30% radiochemical yield (n = 5, decay uncorrected), greater than 99% radiochemical purity, and with 6.5 ± 2.1 (n = 3) GBq/µmol of molar activity at the end of synthesis. The logP of 18F-BBR was 0.65 ± 0.02 (n = 3). 18F-BBR displayed high stability in human serum in vitro, maintained 98% after 6 hours. The results of cellular uptake assay showed no uptake of 18F-BBR in fibroblast NIH/3T3 cells, but selective uptake in cardiomyocyte H9c2 cells. 18F-BBR displays substantially high myocardial uptake at 5, 30 and 240 minutes (34.6 ± 3.9%, 31.6 ± 2.2% and 30.1 ± 0.2% %ID/g respectively, n = 4). Uptake ratios of heart to lung and liver at 5 minutes were also high (25 ± 1.2 and 2.7 ± 0.2, respectively, n = 2) in biodistribution study. PET imaging with 18F-BBR showed clear and sustained cardiac uptake in mice with minimal lung interference and rapid liver clearance. The tracer accumulation in gallbladder was also observed after 20 min of tracer injection.
Conclusions: 18F-BBR was successfully synthesized. It exhibited high stability in human serum and selective uptake in cardiomyocyte cells in vitro. 18F-BBR displays high and persistent cardiac uptake over 2 h with high myocardium-to-lung and myocardium-to-liver ratio in healthy mice in PET imaging. The mechanism of selective uptake of 18F-BBR in cardiomyocyte cells and the tracer accumulation in gallbladder is currently under investigation. Figure 1. Structure, synthesis route and in vivo PET imaging of 18F-BBR
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