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Subcellular Distribution and Metabolism Studies of the Potential Myocardial Imaging Agent [^99mTc(N)(DBODC)(PNP5)]⁺

¹ ICIS–CNR, Corso Stati Uniti, Padova, Italy; ² Department of Pharmaceutical Sciences, University of Padua, Padova, Italy; ³ Research Center, Nihon Medi-Physics Co., Ltd., Chiba, Japan; and ⁴ Nuclear Medicine Service, Istituto Oncologico Veneto (IOV), Padova, Italy

Correspondence: For correspondence contact: Cristina Bolzati, ICIS, CNR Corso Stati Uniti, 4, 35127 Padova, Italy. E-mail: bolzati{at}icis.cnr.it

^99mTc(N)-DBODC(5) is the lead compound of a new series of monocationic ^99mTc(N)-based potential myocardial imaging agents that exhibit original biodistribution properties. This study was addressed to elucidate the mechanisms of distribution, retention, and elimination of this promising ^99mTc(N)-agent. Methods: The sex-related in vitro and in vivo stability and the subcellular distribution of ^99mTc(N)-DBODC(5) were investigated. Studies were performed by considering binding to the serum proteins; stability in rat serum, human serum, and rat liver homogenates; and the chemical integrity of the complex after extraction from rat tissues such as heart, liver, and kidney, as well as from intestinal fluids and urine. The effect of cyclosporin A on the in vivo pharmacokinetic properties of ^99mTc(N)-DBODC(5) was also evaluated. Subcellular distribution of ^99mTc(N)-DBODC(5) in ex vivo rat heart was determined by standard differential centrifugation techniques. Results: No significant in vitro serum protein binding and no notable biotransformation of the native compound into different species by the in vitro action of the serum and liver enzymes was evidenced. In vivo experiments showed that sex affects the pharmacokinetic profile of the ^99mTc(N)-complexes including metabolism and excretion. Chromatographic profiles of ^99mTc(N)-radioactivity extracted from tissues and fluids of female rats were always coincident with the control. Conversely, a small percentage of metabolized species was detected by high-performance liquid chromatography in liver extracts of male rats. Furthermore, administration of cyclosporin A caused a significant reduction of lung, liver, and kidney washout along with a considerable variation in activity distribution in the intestinal tract in both male and female rats, thus indicating a possible implication of Pgp transporters in determining the biologic behavior of ^99mTc(N)-DBODC(5). However, this phenomenon was more pronounced in females. Subcellular distribution studies showed that 86.3% ± 7.4% of ^99mTc(N)-DBODC(5) was localized into mitochondrial fraction as a result of the interaction with the negative membrane potential. Conclusion: Evidence showing that the new ^99mTc(N)-myocardial tracers behave as multidrug resistance–associated protein P-glycoprotein substrates, combined with their selective mitochondrial accumulation, strongly supports the possibility that diagnostic application of ^99mTc(N)-DBODC(5) can be extended to tumor imaging and noninvasive multidrug resistance studies.

Key Words: DBODC • myocardial imaging agent • technetium • metabolism • MDR

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