Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration

Abstract

Purpose To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [18F]fluorothymidine (FLT), and the glucose analogue, [18F]fluorodeoxyglucose (FDG). Methods Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 minutes. Volumes-of-interest (VOIs) for the olfactory bulb (OB) and the remaining brain were created on the CT and transferred to the co-registered dynamic PET. Time-activity curves (TACs) were generated and compared. Results The disposition patterns were successfully visualized and quantified and differences in brain distribution patterns were observed. For FDG, the concentration was substantially higher in the OB than the brain only after IN administration. For FLT, the concentration was higher in the OB than the brain after both IN and IV and higher after IN than after IV administration at all times, whereas, the concentration in the brain was higher after IN than after IV administration at early times only. Approximately 50% and 9% of the IN FDG and FLT doses, respectively, remained in the nasal cavity at 20 minutes post-administration. The initial phase of clearance was similar for both agents (t1/2=2.53 and 3.36 minutes) but the slow clearance phase was more rapid for FLT than FDG (t1/2=32.1 and 85.2 minutes, respectively). Conclusion Pharmacoimaging techniques employing PET/CT can be successfully implemented to quantitatively investigate and compare the disposition of radiolabeled agents administered by a variety of routes.

Demonstration of Nucleoside Transporter Activity in the Nose-to-Brain Distribution of [18F]Fluorothymidine Using PET Imaging

“…Other investigators have utilized PET to evaluate nasal absorption and distribution patterns (24–26), yet none of these reports have focused on the evaluation of the role of epithelial transporters in the enhanced nasal absorption and brain distribution of substrates. The previous imaging results, along with the unique goal of the present work, demonstrate that hybrid imaging techniques are powerful tools to assist in the evaluation of the deposition of drugs and formulations within the nasal cavity (27) along with the determination of the pharmacokinetics and distribution profiles of nasally administered drugs. The selection of FLT, a known nucleoside-transporter substrate, also enabled the evaluation of transporter effects on the absorption and distribution of substrates from the nasal mucosa directly to the brain.…”

“…(28) Both IN and IP inhibitor administration and a “no inhibitor” control were tested for each route (IN or IV) of FLT administration resulting in six different sets of conditions. After instillation (as described in Ponto, et al (27)) or injection of the radiopharmaceutical, the rat was immediately transferred to the bed of an Inveon Docked PET-SPECT-CT system (Siemens Medical, USA), placed in the supine position with the head at an approximately 40 degree angle to the bed that was equipped with an internal heater. Imaging consisted of a list-mode acquisition for up to 40 minutes.…”

Optimization of an Intranasal Route for the Delivery of Human Neural Stem Cells to Treat a Neonatal Hypoxic-Ischemic Brain Injury Rat Model

“…One study showed the deposition and distribution within the nasal cavity in a supine position of the head at a 40° angle to the bed. 38 During 1 h, increasing amounts of the swallowed drug were observed in the oropharynx. Therefore, for intranasal delivery of cells, the head should be as parallel to the floor as possible with a padded pillow under the head of the rat.…”

Diastereoselective Synthesis of the Borylated d-Galactose Monosaccharide 3-Boronic-3-Deoxy-d-Galactose and Biological Evaluation in Glycosidase Inhibition and in Cancer for Boron Neutron Capture Therapy (BNCT)

“…Target compound 7-being a monosaccharide analogue-has the potential to exploit the same entry mechanisms into cells (healthy and cancer) as natural monosaccharides, much like 2-fluodeoxyglucose does [48,49]. 2-Fluodeoxyglucose has the capability to exploit the Warburg effect (this implies cells find it difficult to discriminate this synthetic structure from natural monosaccharide structures) for selective entry into cancer versus healthy cells [49][50][51], to accumulate in cells after phosphorylation at C-6 (again successfully exploiting enzymes that chemically modify natural monosaccharide substrates) [52,53], and to cross the bloodbrain barrier [54]. However, a number of challenges still need to be overcome [43][44][45]55].…”