Imaging-Based Characterization of a Slco2b1(-/-) Mouse Model Using [11C]Erlotinib and [99mTc]Mebrofenin as Probe Substrates

Organic anion-transporting polypeptide 2B1 (OATP2B1) is co-localized with OATP1B1 and OATP1B3 in the basolateral hepatocyte membrane, where it is thought to contribute to the hepatic uptake of drugs. We characterized a novel Slco2b1(-/-) mouse model using positron emission tomography (PET) imaging with [11C]erlotinib (a putative OATP2B1-selective substrate) and planar scintigraphic imaging with [99mTc]mebrofenin (an OATP1B1/1B3 substrate, which is not transported by OATP2B1). Dynamic 40-min scans were performed after intravenous injection of either [11C]erlotinib or [99mTc]mebrofenin in wild-type and Slco2b1(-/-) mice. A pharmacokinetic model was used to estimate the hepatic uptake clearance (CL1) and the rate constants for transfer of radioactivity from the liver to the blood (k2) and excreted bile (k3). CL1 was significantly reduced in Slco2b1(-/-) mice for both radiotracers (p < 0.05), and k2 was significantly lower (p < 0.01) in Slco2b1(-/-) mice for [11C]erlotinib, but not for [99mTc]mebrofenin. Our data support previous evidence that OATP transporters may contribute to the hepatic uptake of [11C]erlotinib. However, the decreased hepatic uptake of the OATP1B1/1B3 substrate [99mTc]mebrofenin in Slco2b1(-/-) mice questions the utility of this mouse model to assess the relative contribution of OATP2B1 to the liver uptake of drugs which are substrates of multiple OATPs.

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Characterization of Organic Anion Transporting Polypeptide 1b2-null Mice: Essential Role in Hepatic Uptake/Toxicity of Phalloidin and Microcystin-LR

Toxicological Sciences ◽

10.1093/toxsci/kfn038 ◽

2008 ◽

Vol 103 (1) ◽

pp. 35-45 ◽

Cited By ~ 109

Author(s):

Hong Lu ◽

Supratim Choudhuri ◽

Kenichiro Ogura ◽

Iván L. Csanaky ◽

Xiaohong Lei ◽

...

Keyword(s):

Essential Role ◽

Organic Anion ◽

Hepatic Uptake ◽

Organic Anion Transporting Polypeptide

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Cloning and functional characterization of the pig (Sus scrofa) organic anion transporting polypeptide 1a2

Xenobiotica ◽

10.3109/00498254.2012.760762 ◽

2013 ◽

Vol 43 (8) ◽

pp. 738-744 ◽

Cited By ~ 7

Author(s):

Yejin Yu ◽

Xiaoxiao Liu ◽

Zheren Zhang ◽

Yunpeng Xiao ◽

Mei Hong

Keyword(s):

Sus Scrofa ◽

Organic Anion ◽

Functional Characterization ◽

Organic Anion Transporting Polypeptide

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Characterization of Plasma Membrane Localization and Phosphorylation Status of Organic Anion Transporting Polypeptide (OATP) 1B1 c.521 T>C Nonsynonymous Single-Nucleotide Polymorphism

Pharmaceutical Research ◽

10.1007/s11095-019-2634-3 ◽

2019 ◽

Vol 36 (7) ◽

Cited By ~ 6

Author(s):

Alexandra Crowe ◽

Wei Zheng ◽

Jonathan Miller ◽

Sonia Pahwa ◽

Khondoker Alam ◽

...

Keyword(s):

Single Nucleotide Polymorphism ◽

Plasma Membrane ◽

Organic Anion ◽

Membrane Localization ◽

Nucleotide Polymorphism ◽

Single Nucleotide ◽

Organic Anion Transporting Polypeptide ◽

Plasma Membrane Localization

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Fentanyl Pharmacokinetics is not Dependent on Hepatic Uptake by Organic Anion-Transporting Polypeptide 1B1 in Human Beings

Basic & Clinical Pharmacology & Toxicology ◽

10.1111/bcpt.12066 ◽

2013 ◽

Vol 113 (1) ◽

pp. 43-48 ◽

Cited By ~ 6

Author(s):

Victoria C. Ziesenitz ◽

Sonja K. König ◽

Nina Mahlke ◽

Ricarda Jantos ◽

Gisela Skopp ◽

...

Keyword(s):

Organic Anion ◽

Hepatic Uptake ◽

Human Beings ◽

Organic Anion Transporting Polypeptide

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Characterization of 18F-PM-PBB3 (18F-APN-1607) Uptake in the rTg4510 Mouse Model of Tauopathy

Molecules ◽

10.3390/molecules25071750 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1750 ◽

Cited By ~ 3

Author(s):

Chi-Chang Weng ◽

Ing-Tsung Hsiao ◽

Qing-Fang Yang ◽

Cheng-Hsiang Yao ◽

Chin-Yin Tai ◽

...

Keyword(s):

Mouse Model ◽

Ex Vivo ◽

Standardized Uptake Value ◽

Dynamic Imaging ◽

Scanning Time ◽

Positron Emission ◽

Image Characteristics ◽

Uptake Pattern ◽

Pet Scans

Misfolding, aggregation, and cerebral accumulation of tau deposits are hallmark features of Alzheimer’s disease. Positron emission tomography study of tau can facilitate the development of anti-tau treatment. Here, we investigated a novel tau tracer 18F-PM-PBB3 (18F-APN-1607) in a mouse model of tauopathy. Dynamic PET scans were collected in groups of rTg4510 transgenic mice at 2–11 months of age. Associations between distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) with cerebellum reference were used to determine the optimal scanning time and uptake pattern for each age. Immunohistochemistry staining of neurofibrillary tangles and autoradiography study was performed for ex vivo validation. An SUVR 40–70 min was most consistently correlated with DVR and was used in further analyses. Significant increased 18F-PM-PBB3 uptake in the brain cortex was found in six-month-old mice (+28.9%, p < 0.05), and increased further in the nine-month-old group (+38.8%, p < 0.01). The trend of increased SUVR value remained evident in the hippocampus and striatum regions except for cortex where uptake becomes slightly reduced in 11-month-old animals (+37.3%, p < 0.05). Radioactivity distributions from autoradiography correlate well to the presence of human tau (HT7 antibody) and hyperphosphorylated tau (antibody AT8) from the immunohistochemistry study of the adjacent brain sections. These findings supported that the 40–70 min 18F-PM-PBB3 PET scan with SUVR measurement can detect significantly increased tau deposits in a living rTg4510 transgenic mouse models as early as six-months-old. The result exhibited promising dynamic imaging capability of this novel tau tracer, and the above image characteristics should be considered in the design of longitudinal preclinical tau image studies.

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