DIPG-20. THE DEVELOPMENT OF THERANOSTIC 18FF2B-CONJUGATES FOR PHARMACOKINETIC MONITORING OF DIRECT DRUG DELIVERY

摘要

Diffuse intrinsic pontine gliomas (DIPG) carry a particularly poor prognosis, with median survival shorter than one year. Recent efforts aimed at traversing the blood-brain barrier have explored the capability of convection-enhanced delivery (CED) as a possible alternative to systemic delivery. Accurate pharmacokinetic information (distribution and clearance) is problematic since most agents have no intrinsic imaging capacity. This information however is critical in designing optimal infusion parameters and monitoring response. The mainstay of current practice is to rely on imaging surrogates to estimate molecular kinetics. These imaging tracers, however, have no homologous bioactive profile with the therapeutic molecule. Our objective of the current work was to perform direct labeling using a positron-emitting [¹⁸F]F2B- moiety that could be imaged by PET/CT. In the initial phase of this project, we first coupled the kinase-inhibitor dasatinib, a therapeutic chosen for its ability to tolerate the alteration of its molecular-structure. In vitro cell viability assays were performed to confirm that our modifications did not affect drug bioactivity. Labelled therapeutics were then delivered via CED to the frontal lobe in mice. We observed that the clearance properties vary greatly depending on the functional group added to the dasatinib backbone, with both distribution and clearance following injection being group-specific. We subsequently repeated these modifications with panobinostat. We observed that panobinostat distributes very differently from dasatinib, despite their similar molecular weight, both spatially (i.e. brain regions involved) and temporally (different clearance following infusion). This data suggests that surrogate tracers may not adequately estimate pharmacokinetics of locally delivered therapeutic compounds. If chemically possible, PET-imaging affords a more representative assessment of drug kinetics which would be more beneficial in defining dosing and scheduling. Our findings demonstrate the feasibility of designing theranostic compounds that are suitable for accurate pharmacokinetic monitoring with CED.