The Effect of P-glycoprotein and breast cancer resistance protein on the brain uptake of [¹⁸F]Mefway

Objectives The aim of this research is to determine if the brain uptake of [¹⁸F]MEFWAY is influenced by the action of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)

Methods FVB/N wild-type, mdr1a/b(-/-), bcrp1(-/-), mdr1a/b(-/-)bcrp1(-/-), and Sprague-Dawley (SD) rats were used. Each animal was anesthetized with 2.0 % isoflurane in oxygen and placed in the gantry with its head centered in the field of view. A catheter was inserted into the tail vein and fluconazole was injected at an infusion rate for 1 h to suppress in vivo defluorination of radiotracer. Radioactivity was promptly injected the catheter then dynamic PET scan were performed for 90 min. SD rats were divided two groups: tariquidar (TQD, 6 mg/kg) pre-treated and control groups. PET data were reconstructed in user-defined time frames in length by OSEM algorithm. Regions of interests are hippocampus, and cerebellum. The cerebellum was used as the reference region because it contains very few 5-HT_1A receptors in the rats. Non-displaceable binding potential values were derived from non-invasive graphical method of Logan.

Results A maximal SUV value of 3.2 for triple knockout mdr1a/b(-/-)bcrp1(-/-) mice was comparable to that of the double knockout mdr1a/b(-/-) mice and this value was two folder than those of the wild type or bcrp1(-/-) knockout mice. The brain uptake of bcrp1(-/-) showed similar pattern to that of wild type. In vitro experiment, brain-to-plasma ratio for triple knockout mice was also 2-5 times higher than those for other groups. Pretreatment of TQD results in 160% higher hippocampal uptake, compared with the control animals. Whereas, binding potential values showed similar values for each group.

Conclusions Our research firstly demonstrated that [¹⁸F]MEFWAY is the substrate for P-gp.