title: A PET Tracer for Renal Organic Cation Transporters, ¹¹C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies.
abstract: 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 (11)C-labeled metformin would be a suitable PET tracer for quantification of renal function.
  
  
  METHODS
  (11)C-metformin was prepared by (11)C-methylation of 1-methylbiguanide. In vitro cell uptake of (11)C-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 (11)C-metformin. Kidney and liver pharmacokinetics of (11)C-metformin was investigated in vivo by dynamic (11)C-metformin PET/CT in 6 anesthetized pigs, and renal clearance of (11)C-metformin was compared with renal clearance of (51)Cr-ethylenediaminetetraacetic acid (EDTA). Formation of (11)C metabolites was investigated by analysis of blood and urine samples.
  
  
  RESULTS
  The radiochemical yield of (11)C-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 (11)C-metformin in LLC-PK1 cells was rapid. Rat small-animal PET images showed (11)C-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 (11)C-metformin was approximately 3 times the renal clearance of (51)Cr-EDTA.
  
  
  CONCLUSIONS
  We successfully synthesized an (11)C-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.
authors.affiliation: PET Center, Aarhus University Hospital, Aarhus, Denmark jakobsen.steen@gmail.com.
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.affiliation: Department of Experimental Oncology, Aarhus University Hospital, Aarhus, Denmark; and.
authors.forename: Morten
authors.initials: M
authors.lastname: Busk
authors.affiliation: PET Center, Aarhus University Hospital, Aarhus, Denmark Department of Clinical Medicine, Aarhus University, Denmark.
authors.forename: Jonas Brorson
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ole Lajord
authors.initials: OL
authors.lastname: Munk
authors.affiliation: PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Nora Elisabeth
authors.initials: NE
authors.lastname: Zois
authors.affiliation: PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Aage K O
authors.initials: AK
authors.lastname: Alstrup
authors.affiliation: Department of Clinical Medicine, Aarhus University, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Jessen
authors.affiliation: PET Center, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
mesh_terms: D000818:Animals; D001345:Autoradiography; D001645:Biguanides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000493:pharmacokinetics; D007553:Isotope Labeling; D007668:Kidney / Q000000981:diagnostic imaging* / Q000378:metabolism*; D018374:LLC-PK1 Cells; D008099:Liver / Q000378:metabolism; D008687:Metformin / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D008745:Methylation; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D014018:Tissue Distribution
chemical_list: D001645:Biguanides; D027701:Organic Cation Transport Proteins; D019275:Radiopharmaceuticals; D008687:Metformin; D004492:Edetic Acid
keywords: glomerular filtration rate; metformin; organic cation transporter; positron emission tomography; renal function