TY - JOUR T1 - A PET Tracer for Renal Organic Cation Transporters, <sup>11</sup>C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 615 LP - 621 DO - 10.2967/jnumed.115.169292 VL - 57 IS - 4 AU - Steen Jakobsen AU - Morten Busk AU - Jonas Brorson Jensen AU - Ole Lajord Munk AU - Nora Elisabeth Zois AU - Aage K.O. Alstrup AU - Niels Jessen AU - Jørgen Frøkiær Y1 - 2016/04/01 UR - http://jnm.snmjournals.org/content/57/4/615.abstract N2 - Organic cation transporters (OCTs) 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 located in the PT. Thus, we hypothesized 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 unlabeled metformin. In vivo small-animal PET 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 6 anesthetized pigs, and renal clearance of 11C-metformin was compared with renal clearance of 51Cr-ethylenediaminetetraacetic acid (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 of tracer were produced with a radiochemical purity greater than 95% in less than 30 min. Dose-dependent uptake of 11C-metformin in LLC-PK1 cells was rapid. Rat small-animal PET images showed 11C-metformin uptake in the kidney and liver, the kinetics of which were 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 with baseline consistent with transporter-mediated competition. Renal clearance of 11C-metformin was approximately 3 times the renal clearance of 51Cr-EDTA. Conclusion: We successfully synthesized an 11C-metformin tracer, and PET studies in rats and pigs showed a rapid kidney uptake from the blood and excretion into the bladder similar to other radiopharmaceuticals developed for γ-camera renography. ER -