PET-based approaches to studying the size-dependence of leptomeningeal drug clearance

Elena Belova,1-3 Lloyd Vallance,2,4 Vasily Belov,1-3 Matthew Gagne,1 Caitlin Gillooly1 and Mikhail Papisov1-3

1Massachusetts General Hospital, Boston, MA 02114; 2Harvard University, Cambridge, MA 02138, 3Shriners Hospitals for Children–Boston, Boston, MA 02114; and 4Shire HGT, Lexington, MA 02421

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Summary
Leptomeningeal space (LMS) provides a promising avenue for delivery of macro- and supramolecular drugs to central nervous system (CNS).1 Leptomeningeal pharmacokinetics significantly depends on the turnover of the cerebrospinal fluid (CSF). Drug molecules dissolved in CSF escape to the systemic circulation along the CSF drainage routes. One of such routes is through leptomeningeal pores, which have not been sufficiently studied. The goal of this work was to identify approaches to predict the size dependence of the drug clearance from LMS.

We have investigated the process of clearance of macromolecules and particles of various sizes, from ca. 3 nm to 0.6 μm, by Positron Emission Tomography (PET). The early data suggest that although the major population of leptomeningeal pores is large (>1 μm), there is apparently another, previously unknown subset of smaller pores. The effective/functional size distributions of the pore populations as well as the anatomical location of the smaller subset are unknown and require further investigation.

 

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