Mechanism of 99mTc-d,l-HMPAO Retention in Brain Cells

The intracellular distributions of 99mTc-d,l-HMPAO, 99mTcmeso-HMPAO and 99mTc-PnAO in rat brains were explored in vivo and in vitro. 99mTc-d,l-HMPAO and 99mTcmeso- 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 99mTc-HMPAO diastereomers to the mitochondria was stable after washing with SEH buffer. Extremely low radioactivity of 99mTc-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 99mTc-d,l-HMPAO and 99mTc-meso- HMPAO 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 99mTc-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 99mTc-HMPAO in the brain cells.