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

BACKGROUND: 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. METHODS: 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). RESULTS: 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 (BP(ND)) could not be estimated during baseline conditions in mice and rats. After CsA pretreatment, the highest BP(ND) values were obtained in the striatum and thalamus (BP(ND) ≈ 0.4) in mice, while in rats, the highest binding areas were the striatum, thalamus, hypothalamus, and periaqueductal gray (BP(ND) ≈ 0.5). In guinea pigs, we did not find any significant changes in BP(ND) between baseline and CsA pretreatment, except in the striatum. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13550-014-0064-0) contains supplementary material, which is available to authorized users

Positron Emission Tomography studies with [C-11]PBR28 in the Healthy Rodent Brain: Validating SUV as an Outcome Measure of Neuroinflammation

Molecular imaging of the 18 kD Translocator protein (TSPO) with positron emission tomography (PET) is of great value for studying neuroinflammation in rodents longitudinally. Quantification of the TSPO in rodents is, however, quite challenging. There is no suitable reference region and the use of plasma-derived input is not an option for longitudinal studies. The aim of this study was therefore to evaluate the use of the standardized uptake value (SUV) as an outcome measure for TSPO imaging in rodent brain PET studies, using [C-11]PBR28. In the first part of the study, healthy male Wistar rats (n = 4) were used to determine the correlation between the distribution volume (V-T, calculated with Logan graphical analysis) and the SUV. In the second part, healthy male Wistar rats (n = 4) and healthy male C57BL/6J mice (n = 4), were used to determine the test-retest variability of the SUV, with a 7-day interval between measurements. Dynamic PET scans of 63 minutes were acquired with a nanoScan PET/MRI and nanoScan PET/CT. An MRI scan was made for anatomical reference with each measurement. The whole brain V-T of [C-11]PBR28 in rats was 42.9 +/- 1.7. A statistically significant correlation (r(2) = 0.96; p <0.01) was found between the V-T and the SUV. The test-retest variability in 8 brain region ranged from 8 to 20% in rats and from 7 to 23% in mice. The interclass correlation coefficient (ICC) was acceptable to excellent for rats, but poor to acceptable for mice. In conclusion: The SUV of [C-11]PBR28 showed a high correlation with V-T as well as good test-retest variability. For future longitudinal small animal PET studies the SUV can thus be used to describe [C-11]PBR28 uptake in healthy brain tissue. Based on the present observations, further studies are needed to explore the applicability of this approach in small animal disease models, with special regard to neuroinflammatory models