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Abstract
[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid; anti-[18F]FACBC), a positron emission tomography tracer used for the diagnosis of recurrent prostate cancer, is transported via amino acid transporters (AATs) with high affinity (Km: 97–230 μM). However, the mechanism underlying urinary excretion is unknown. In this study, we investigated the involvement of AATs and drug transporters in renal [18F]fluciclovine reuptake. [14C]Fluciclovine (trans-1-amino-3-fluoro[1-14C]cyclobutanecarboxylic acid) was used because of its long half-life. The involvement of AATs in [14C]fluciclovine transport was measured by apical-to-basal transport using an LLC-PK1 monolayer as model for renal proximal tubules. The contribution of drug transporters herein was assessed using vesicles/cells expressing the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), multidrug resistance-associated protein 4 (MRP4), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) , organic cation transporter 2 (OCT2), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporting polypeptide 1B3 (OATP1B3). The apical-to-basal transport of [14C]fluciclovine was attenuated by l-threonine, the substrate for system alanine-serine-cysteine (ASC) AATs. [14C]Fluciclovine uptake by drug transporter-expressing vesicles/cells was not significantly different from that of control vesicles/cells. Fluciclovine inhibited P-gp, MRP4, OAT1, OCT2, and OATP1B1 (IC50 > 2.95 mM). Therefore, system ASC AATs may be partly involved in the renal reuptake of [18F]fluciclovine. Further, given that [18F]fluciclovine is recognized as an inhibitor with millimolar affinity for the tested drug transporters, slow urinary excretion of [18F]fluciclovine may be mediated by system ASC AATs, but not by drug transporters.
Highlights
[18F]Fluciclovine is a positron emission tomography (PET) tracer that has been approved by the U.S Food and Drug Administration for the detection of recurrent prostate cancer since 2016 [1]
We have shown that two Na+-dependent acid transporters (AATs) subtypes (i.e., alanine-serine-cysteine transporter 2 (ASCT2) and sodium-coupled neutral amino acid transporter 2 (SNAT2)) and Na+-independent L-type amino acid transporter 1 (LAT1) have high affinities for [18F]fluciclovine with Km values of 92.0, 222.0, and 230.4 μM, respectively [11]
Our study suggests that the slow urinary excretion of [18F]fluciclovine is partly mediated by system ASC AATs, which serve as high-affinity transporters for [18F]fluciclovine uptake/efflux, but that the contribution of drug transporters to [18F]fluciclovine distribution is negligible compared to that of AATs
Summary
[18F]Fluciclovine (trans-1-amino-3-[18F]fluorocyclobutanecarboxylic acid, known as anti-[18F]FACBC or AxuminTM) is a positron emission tomography (PET) tracer that has been approved by the U.S Food and Drug Administration for the detection of recurrent prostate cancer since 2016 [1]. Clinical trials have demonstrated that [18F]fluciclovine accumulates readily in the liver and pancreas, mildly in the kidneys, and minimally in the brain after administration as an intravenous bolus infusion; it is excreted slowly in the urine for up to 24 hours, but not in bile [6,7] These results suggest that [18F]fluciclovine-PET may have advantages over [18F]FDG and [18F]FET for imaging tumors in the brain and/or in the pelvis. We have shown that two Na+-dependent AAT subtypes (i.e., alanine-serine-cysteine transporter 2 (ASCT2) and sodium-coupled neutral amino acid transporter 2 (SNAT2)) and Na+-independent L-type amino acid transporter 1 (LAT1) have high affinities for [18F]fluciclovine with Km values of 92.0, 222.0, and 230.4 μM, respectively [11] This suggests that AATs may be involved in the whole-body distribution of [18F]fluciclovine, because these AATs are expressed in the liver, renal proximal tubule, by the blood-brain-barrier (BBB) [12], and/or tumors [13]. Two other SLC transporters, organic anion transporting polypeptide 1B1 (OATP1B1) and organic anion transporting polypeptide 1B3 (OATP1B3), are believed to be critical hepatic transporters of anionic drugs [14]
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