Mechanism of Tc-d,l-HMPAO Retention in Brain Cells

Received 2/13/2001; revised 8/10/2001; accepted 11/1/2001. For correspondence or reprints contact: Jem-Mau Lo, Department of Nuclear Science, National Tsing Hua University, 101 Section 2, Kuang-Fu Road, Hsinchu 300, Taiwan. Tel: (886)3-5727308, Fax: (886)3-5718649, E-mail: [email protected] The intracellular distributions of Tc-d,l-HMPAO, Tcmeso-HMPAO and Tc-PnAO in rat brains were explored in vivo and in vitro. Tc-d,l-HMPAO and Tcmeso-HMPAO were found to distribute in the mitochondria of rat brain cells with radioactivity prominent throughout the whole brain (ca. 33.1% and 26.5%, respectively) at 10 min post-injection in the in vivo study. Binding to the cerebral mitochondria appeared sensitive to tissue viability or other physiological parameters. This sensitivity was evidenced by the corresponding in vitro study which revealed significantly less radioactivity than that of in vivo in the mitochondria. The binding of both Tc-HMPAO diastereomers to the mitochondria was stable after washing with SEH buffer. Extremely low radioactivity of Tc-PnAO (~10%) was found in the mitochondria in both in vivo and in vitro studies; the complex proved to be loosely bound and was readily washed out with SEH buffer. The preferential internalization of Tc-d,l-HMPAO and Tc-mesoHMPAO in the mitochondria could be a step towards an enzymatic degradation in the viable brain cells, for instance through acid hydrolase. The difference in the extent of binding between two Tc-HMPAO diastereomers might depend on acid susceptibility, which might be related to the enzymatic acid hydrolysis in the mitochondria. From this study, intracellular binding to mitochondria may be the major mechanism for trapping Tc-HMPAO in the brain cells.