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

Abstract

Purpose To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [18F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1–3) substrate, using PET to measure local tissue concentrations. Methods Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 minutes. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. Results FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT exposure following both IN and IV administration, suggesting that NBMPR decreases the clearance rate of FLT from the brain. When FLT and NBMPR were co-administered IN, there was a decrease in the OB AUC while an increase in the brain AUC was observed. The decrease in OB exposure was likely the result of inhibition of ENT1 uptake activity in the nose-to-brain transport pathway. Conclusion FLT distribution patterns show that nucleoside transporters, including ENT1, play a key role in the distribution of transporter substrates between the nasal cavity and the brain via the OB.

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

“…The “gold standards” for the assessment of spillover and partial volume effects are comparisons of imaging-based results with measurements derived from ex vivo tissue analyses. In a follow-up study(30), ex vivo findings are presented that support the reliability of the imaging-based results to accurately determine the OB and brain radiotracer concentrations. Concentrations of FLT in specific anatomical brain regions provided parallel results to imaging studies and provided further evidence for the direct nose-to-brain transfer of FLT to the olfactory bulb.…”

Transporter-Mediated Drug Delivery

“…To date, many ABC and SLC drug transporters have been reported to be present in the nasal cavity [ 515 , 516 ]. While there is evidence that some of these transporters, such as the equilibrative nucleoside transporter ENT1/SLC29A1, can readily mediate the uptake of substrates such as [ 18 F]fluorothymidine into the brain through the nasal route [ 517 ], these mechanisms appear to be underutilized in the development of new formulations. While certain nanoparticle formulations designed for nasal-to-brain delivery use functionalization through receptor ligands, there do not appear to be any reports of targeting transporters in the nasal cavity for drug delivery [ 518 ].…”

Transporter-Mediated Drug Delivery

“…To date, many ABC and SLC drug transporters have been reported to be present in the nasal cavity [393,394]. While there is evidence that some of these transporters, such as the equilibrative nucleoside transporter ENT1/SLC29A1, can readily mediate the uptake of substrates such as [ 18 F]fluorothymidine into the brain through the nasal route [395], these mechanisms appear to be underutilized in the development of new formulations. While certain nanoparticle formulations designed for nasal-to-brain delivery use functionalization through receptor ligands, there do not appear to be any reports of targeting transporters in the nasal cavity for drug delivery [396].…”