ABC transporter-dependent brain uptake of the 5-HT1B receptor radioligand [11C]AZ10419369: a comparative PET study in mouse, rat, and guinea pig

Miklós Tóth, Jenny Häggkvist, Andrea Varrone, Sjoerd J Finnema, Janine Doorduin, Masaki Tokunaga, Makoto Higuchi, Balázs Gulyás, Christer Halldin

We have explored the possibility that the serotonin 1B receptor radioligand [(11)C]AZ10419369 is a substrate for adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), Mrp4, and Bcrp, in rodents and whether there is a species difference regarding its blood-brain barrier (BBB) penetration. In a series of preclinical positron emission tomography measurements, we have administered [(11)C]AZ10419369 to mice, rats, and guinea pigs under baseline conditions and, on separate experimental days, after administration of the ABC transporter inhibitor, cyclosporin A (CsA). During baseline conditions, the brain uptake was low in mice and rats, but not in guinea pigs. After CsA pretreatment, the peak whole brain uptake values of [(11)C]AZ10419369 increased by 207% in mice, 94% in rats, and 157% in guinea pigs. Binding potentials (BPND) could not be estimated during baseline conditions in mice and rats. After CsA pretreatment, the highest BPND values were obtained in the striatum and thalamus (BPND ≈ 0.4) in mice, while in rats, the highest binding areas were the striatum, thalamus, hypothalamus, and periaqueductal gray (BPND ≈ 0.5). In guinea pigs, we did not find any significant changes in BPND between baseline and CsA pretreatment, except in the striatum. The results indicate that BBB penetration of [(11)C]AZ10419369 was hindered by ABC transporter activity in mouse, rat, and guinea pig. This study highlights the importance of ABC transporters in the design of preclinical positron emission tomography (PET) studies.