ReviewImaging Probes and Modalities for the Study of Solute Carrier O (SLCO)-Transport Function In Vivo
Introduction
Membrane transporters are now recognized as key players in pharmacokinetics (PK). Each transporter has a specific pattern of substrates and tissue expression. Transporters of the ATP-binding cassette (ABC) and solute carrier (SLC) superfamilies expressed in the intestine, liver, and kidneys have been shown to control the absorption, distribution, and elimination of many drugs and measurably affect PK. Transporter function is also assumed to account for intra- and interindividual variability in drug PK.1 Many clinically relevant drug–drug interactions involving transporter inhibitors, inducers, and substrates have been described.2 In 2007, the International Transporter Consortium, which includes members from academia, industry, and the U.S. Food and Drug Administration, was formed with the goal of determining transporters that are of emerging importance, establishing recommendations, regulatory draft guidance documents on transporter–drug interactions, and highlighting transporter-related challenges in drug development.1, 3 In this framework, imaging is increasingly regarded as a safe and relevant method to elucidate and decipher the intrinsic role of membrane transporters in controlling drug disposition.4
Transporters expressed in blood–tissue barriers have been shown to control the tissue exposure to many compounds.2 These transporters may control the drug tissue distribution with limited impact on the plasma PK. In this framework, several imaging methods have been proposed to noninvasively unveil and quantify the impact of transporter function on drug exposure to nonclearance organs, such as the blood–brain barrier,5, 6, 7 the blood–retina barriers,8 or the blood–tumor barrier9 in animals and humans.
Section snippets
The Solute Carrier O Transporter Family
Among SLC transporters, the solute carrier O (SLCO) transporter family has been detected at many blood–tissue interfaces.10 SLCO were initially identified at the basolateral membrane of hepatocytes where they mediate the transport of bile salt and cholephilic anionic compounds10 (Fig. 1).
Today, 11 members of the SLCO family have been identified in human.11 This superfamily was originally named organic anion-transporting polypeptides (OATP) or SLC21A. The nomenclature of its members was then
Imaging SLCO Transporter Function
Noninvasive approaches are, therefore, required to elucidate or predict the impact of SLCO-mediated transport in clearance organs on drug disposition in plasma. Moreover, imaging methods would be useful to unveil and quantify the role of nonhepatic SLCO transporter function on drug distribution in organs, as a prerequisite to the local pharmacologic/toxicologic effect. In the absence of measurable concentration in tissues, conventional PK approaches do not allow for investigating the role of
Imaging Probes for SPECT
SPECT uses gamma rays detected by gamma cameras that have been readily available in most nuclear medicine departments for decades. The radionuclide gamma emitter most frequently used is metastable technetium-99 (99mTc) because of its medium energy (140 keV), relatively short half-life (T1/2 = 6.0 h), and availability through the molybdene–technetium generator. 99mTc is a radionuclide that requires forming an organic coordination complex, limiting the possibility to radiolabel substrates without
Imaging Probes for MRI
MRI is a nonirradiant imaging technique performed in radiology, using pulses of radio waves that excite the nuclear spin energy transition, and magnetic field gradients localize the signal in space. The result is pictures of anatomy and physiological process with high spatial resolution and excellent soft tissue contrast but with limited sensitivity and quantification challenges (Fig. 2). Compared with nuclear imaging, which can be performed using tracer dose of radioligands, the contrast
Imaging Probes for PET
PET is another nuclear imaging modality using β+-emitting isotopes. Thanks to a high sensitivity of PET scanners, radiopharmaceutical agents used for PET imaging can be administered at tracer dose. The advantages of PET over SPECT include higher sensitivity (detection efficiency), better temporal and spatial resolutions, at least in humans and large animals. PET imaging benefits from straightforward 3D quantifiable recordings (Fig. 2). The β+ emitter most routinely used in clinic is fluorine-18
Conclusion and Perspectives
Molecular imaging aims at developing new compounds dedicated to the study of a specific molecular target. Interestingly, current probes for SLCO imaging have often been used for decades to study hepatobiliary function in patients (99mTc-mebrofenin SPECT imaging, Gd-EOB-DTPA MRI). The importance of SLCO-mediated transport on their hepatic uptake was discovered many years after, thus providing a molecular determinant for their predominant liver accumulation.73 The main advantage of the use of
Acknowledgments
This work was funded by a grant from ANR-16-CE17-0011-001.
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[<sup>11</sup>C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body
2022, Biomedicine and PharmacotherapyCitation Excerpt :The role of SLC transporters did not receive as much attention although their importance for WBPK remains unclear [2,18]. Several probes have been proposed for quantitative PET imaging of liver OATP function [19]. So far, clinically validated PET probes used in humans include (15 R)-[11C]TIC-Me, [11C]dehydropravastatin, [11C]telmisartan, [11C]rosuvastatin, and [11C]erlotinib [20–24].
Imaging techniques to study drug transporter function in vivo
2018, Pharmacology and TherapeuticsCitation Excerpt :Nuclear imaging methods allow assessment of tissue concentrations of radiolabeled drugs and have therefore been proposed as a tool to investigate such silent DDIs (Kusuhara, 2013; Langer, 2016; Wulkersdorfer et al., 2014). Consequently, several groups have developed radiolabeled probe substrates for measuring the activities of ABC and SLC transporters in different organs with PET (e.g. brain, liver and kidney) (Langer, 2016; Marie et al., 2017; Testa et al., 2015). Most of these probes lack selectivity for a single ABC or SLC transporter.
Automated two-step manufacturing of [<sup>11</sup>C]glyburide radiopharmaceutical for PET imaging in humans
2020, Nuclear Medicine and BiologyCitation Excerpt :Glyburide is also known to be a substrate of several membrane transporters that are key players in the distribution and elimination of drugs. In particular, glyburide is an avid substrate of some organic anion-transporting polypeptide (OATP, SLCO) transporters such as OATP1A2, OATP2B1 and OATP1B1 (Fig. 1) [8–10] making an interesting probe to study the importance the OATP-mediated influx at the blood-tissue interface [11]. Glyburide is also carried by efflux ABC transporters such as the breast cancer resistance protein (BCRP, ABCG2), the P-glycoprotein (P-gp, ABCB1) and some multidrug resistance proteins (ABCC1 and 3) [12,13].
Repurposing 99mTc-mebrofenin as a probe for molecular imaging of hepatocyte transporters
2021, Journal of Nuclear Medicine