*Article* **Brain Distribution of Dual ABCB1**/**ABCG2 Substrates Is Unaltered in a Beta-Amyloidosis Mouse Model**

**Thomas Wanek 1, \* , Viktoria Zoufal 1 , Mirjam Brackhan 2 , Markus Krohn 2 , Severin Mairinger 1 , Thomas Filip 1 , Michael Sauberer 1 , Johann Stanek 1 , Thomas Pekar 3 , Jens Pahnke 2,4,5 and Oliver Langer 1,6,7**


Received: 12 October 2020; Accepted: 28 October 2020; Published: 3 November 2020

**Abstract:** Background: ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) are co-localized at the blood-brain barrier (BBB), where they restrict the brain distribution of many different drugs. Moreover, ABCB1 and possibly ABCG2 play a role in Alzheimer's disease (AD) by mediating the brain clearance of beta-amyloid (Aβ) across the BBB. This study aimed to compare the abundance and activity of ABCG2 in a commonly used β-amyloidosis mouse model (APP/PS1-21) with age-matched wild-type mice. Methods: The abundance of ABCG2 was assessed by semi-quantitative immunohistochemical analysis of brain slices of APP/PS1-21 and wild-type mice aged 6 months. Moreover, the brain distribution of two dual ABCB1/ABCG2 substrate radiotracers ([11C]tariquidar and [ <sup>11</sup>C]erlotinib) was assessed in APP/PS1-21 and wild-type mice with positron emission tomography (PET). [ <sup>11</sup>C]Tariquidar PET scans were performed without and with partial inhibition of ABCG2 with Ko143, while [ <sup>11</sup>C]erlotinib PET scans were only performed under baseline conditions. Results: Immunohistochemical analysis revealed a significant reduction (by 29–37%) in the number of ABCG2-stained microvessels in the brains of APP/PS1-21 mice. Partial ABCG2 inhibition significantly increased the brain distribution of [ <sup>11</sup>C]tariquidar in APP/PS1-21 and wild-type mice, but the brain distribution of [ <sup>11</sup>C]tariquidar did not differ under both conditions between the two mouse strains. Similar results were obtained with [ <sup>11</sup>C]erlotinib. Conclusions: Despite a reduction in the abundance of cerebral ABCG2 and ABCB1 in APP/PS1-21 mice, the brain distribution of two dual ABCB1/ABCG2 substrates was unaltered. Our results suggest that the brain distribution of clinically used ABCB1/ABCG2 substrate drugs may not differ between AD patients and healthy people.

**Keywords:** ABCG2; ABCB1; blood-brain barrier; PET; Alzheimer's disease; beta-amyloid; tariquidar; erlotinib
