A PET Tracer For Renal Organic Cation Transporters, ¹¹C-metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies

Abstract

Organic cation transporters (OCT) in the kidney proximal tubule (PT) participate in renal excretion of drugs and endogenous compounds. PT function is commonly impaired in kidney diseases and consequently quantitative measurement of OCT function may provide an important estimate of kidney function. Metformin is a widely used drug and targets OCT-type 2 (OCT2) located in PT. Thus, we hypothesize that ¹¹C -labeled metformin would be a suitable PET tracer for quantification of renal function. Methods: ¹¹C-metformin was prepared by ¹¹C-methylation of 1-methylbiguanide. In vitro cell uptake of ¹¹C-metformin was studied in LLC-PK₁ cells in the presence of increasing doses of unlabelled metformin. In vivo microPET studies in Sprague Dawley rats were performed at baseline and after treatment with OCT-inhibitors to evaluate renal uptake of ¹¹C-metformin. Kidney and liver pharmacokinetics of ¹¹C-metformin was investigated in vivo by dynamic ¹¹C-metformin PET/CT in six anesthetized pigs, and renal clearance of ¹¹C-metformin was compared with renal clearance of ⁵¹Cr-EDTA. Formation of ¹¹C-metabolites was investigated by analysis of blood and urine samples. Results: The radiochemical yield of ¹¹C-metformin was 15 ± 3% (n = 40, decay-corrected) and up to 1.5 GBq tracer was produced with a radiochemical purity >95% in less than 30 min. Dose-dependent uptake of ¹¹C-metformin in LLC-PK₁ cells was rapid. Rat microPET images showed ¹¹C-metformin uptake in kidney and liver, the kinetics of which was changed after challenging animals with OCT inhibitors. In pigs, 80% of the injected metformin dose was rapidly present in the kidney and a high dose of metformin caused a delayed renal uptake and clearance compared to baseline consistent with transporter-mediated competition. Renal clearance of ¹¹C-metformin was approximately 3 times the renal clearance of ⁵¹Cr-EDTA. Conclusion: We have successfully synthesized a novel ¹¹C-metformin tracer and PET studies in rats and pigs showed rapid kidney uptake from the blood and excretion into the bladder similar to other radiopharmaceuticals developed for gamma-camera renography.