A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood–brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood–brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[¹¹C]verapamil and positron emission tomography. The aim of this study was to assess blood–brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[¹¹C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[¹¹C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[¹¹C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[¹¹C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[¹¹C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood–brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease.

Tariquidar, a potent, nontoxic, third-generation P-glycoprotein (P-gp) inhibitor, is a possible reversal agent for central nervous system drug resistance. In animal studies, tariquidar has been shown to increase the delivery of P-gp substrates into the brain by severalfold. The aim of this study was to measure P-gp function at the human blood–brain barrier (BBB) after tariquidar administration using PET and the model P-gp substrate (R)-¹¹C-verapamil. Methods: Five healthy volunteers underwent paired (R)-¹¹C-verapamil PET scans and arterial blood sampling before and at 2 h 50 min after intravenous administration of tariquidar (2 mg/kg of body weight). The inhibition of P-gp on CD56-positive peripheral lymphocytes of each volunteer was determined by means of the ¹²³Rh efflux assay. Tariquidar concentrations in venous plasma were quantified using liquid chromatography/mass spectrometry. Results: Tariquidar administration resulted in significant increases (Wilcoxon test for paired samples) in the distribution volume (DV, +24% ± 15%) and influx rate constant (K₁, +49% ± 36%) of (R)-¹¹C-verapamil across the BBB (DV, 0.65 ± 0.13 and 0.80 ± 0.07, P = 0.043; K₁, 0.034 ± 0.009 and 0.049 ± 0.009, P = 0.043, before and after tariquidar administration, respectively). A strong correlation was observed between the change in brain DV after administration of tariquidar and tariquidar exposure in plasma (r = 0.90, P = 0.037). The mean plasma concentration of tariquidar achieved during the second PET scan (490 ± 166 ng/mL) corresponded to 100% inhibition of P-gp function in peripheral lymphocytes. Conclusion: Tariquidar significantly increased brain penetration of (R)-¹¹C-verapamil–derived activity due to increased influx. As opposed to peripheral P-gp function, central P-gp inhibition appeared to be far from complete after the administered tariquidar dose.

As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate ( R)-[¹¹C]verapamil in five healthy volunteers during continuous intravenous tariquidar infusion. Total distribution volume ( V_T) of ( R)-[¹¹C]verapamil in whole-brain gray matter increased by 273 ± 78% relative to baseline scans without tariquidar, which was higher than previously reported V_T increases. During tariquidar infusion whole-brain V_T was comparable to V_T in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB.