In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using [¹⁸F]Me4FDG PET in Rats

Abstract

Background. Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[18F]fluoro-D-glucopyranoside ([18F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport. Methods. We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), or the SGLT-targeting agent, [18F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [18F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV). Results. Serving as reference, intestinal administration of [18F]FDG led to slow absorption with retention of 89.2 ± 3.5 % of administered radioactivity at 15 min. [18F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of 18.5 ± 1.2 % ( P < 0.0001 ). Intraintestinal phlorizin led to marked increase of [18F]Me4FDG uptake (15 min, 99.9 ± 4.7 %; P < 0.0001 vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [18F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (%ID/g at 60 min, 0.42 ± 0.10 vs. untreated controls, 1.20 ± 0.03 ; P < 0.0001 ). Conclusion. As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [18F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [18F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies.

In vivo assessment of safety, biodistribution, and radiation dosimetry of the [18F]Me4FDG PET-radiotracer in adults

“…In particular, it was shown that renal uptake can be altered due to SGLT inhibition treatments, which was also already implied by our study [10]. Moreover, the animal data found that Me4FDG can be used to determine the effects of SGLT inhibition in the digestive tract [20], suggested to be used as patient selection tool for diabetic patients designated for SGLT inhibition therapy. Additionally, from the outcome of our earlier study, we are aware that the degree of washout of this tracer from the blood pool is comparable to that of [ 18 F]FDG, allowing static PET acquisition 60 min after tracer injection without expecting a high degree of tracer circulation in the blood pool [10].…”

Excretion of glucose analogue with SGLT2 affinity predicts response effectiveness to sodium glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus

“…In fact, the function of SGLT2 protein can be studied in vivo using positron emission tomography (PET) and the glucose analogue alpha-methyl-4-deoxy-4-[ 18 F]fluoro- d -glucopyranoside (abbreviated as: Me4FDG). In contrary to the most commonly used glucose-analogue tracer 2-deoxy-2-[ 18 F]fluoro- d -glucose (FDG), Me4FDG is a substrate with high affinity for SGLT1 and SGLT2, meaning that this tracer is specifically binding to SGLT proteins and thus the organ-specific Me4FDG uptake allows the evaluation of the according SGLT function [ 13 ]. Applying this method, SGLT2 reabsorption performance can be assessed indirectly from Me4FDG excretion by measuring the Me4FDG concentration in the urinary bladder.…”