title: Effects of recombinant human thyroid-stimulating hormone superagonists on thyroidal uptake of 18F-fluorodeoxyglucose and radioiodide.
abstract: BACKGROUND
  Superagonist analogs of human thyroid-stimulating hormone (hTSH) may stimulate the uptake of (131)I-iodide and (18)F-fluorodeoxyglucose ((18)F-FDG) in thyroid carcinomas to a greater degree than hTSH. We herein report the potency and efficacy of two hTSH analogs, TR1401 and TR1402, to stimulate radioiodide and (18)F-FDG uptake in FRTL-5 cells and compared the effects of hTSH and TR1401 on radioiodide uptake in the thyroid in vivo in mice.
  
  
  METHODS
  The effects of hTSH analogs on intracellular levels of cAMP, uptake of (131)I-iodide, and (18)F-FDG were studied in FRTL-5 cells to determine the stimulatory potency and efficacy of the compounds by calculating half-maximum effective concentration (EC(50)) values and maximal stimulatory effects (E(max)). Biodistribution studies (n = 96) and positron emission tomography/computed tomography imaging studies (single animals) on thyroid (125)I/(124)I-iodide uptake were performed with T3-suppressed CD-1 mice in a dose-dependent manner (3, 10, and 30 μg/animal).
  
  
  RESULTS
  The EC(50) values of TR1401 and TR1402 demonstrated a 90-fold or 800-fold higher potency for their capacity to increase intracellular cAMP levels in comparison with hTSH (p < 0.05). Similar results were demonstrated for the stimulation of (18)F-FDG uptake. Bovine TSH, TR1401, and TR1402 were 85%-490% more potent to increase iodide uptake than hTSH (p < 0.05). TR1402 was 30% more efficacious to stimulate iodide uptake than hTSH. The agonist-induced increase in radiotracer uptake was paralleled by increases in NIS and GLUT-1 expression. Ex vivo biodistribution studies showed an increased iodide uptake in the thyroid of TR1401-treated mice at the low dose of 3 μg/animal in comparison with hTSH-treated mice (n = 16, p < 0.05). Positron emission tomography/computed tomography imaging studies confirmed the increased thyroidal iodide uptake in TR1401-treated mice in vivo.
  
  
  CONCLUSIONS
  TR1401 and TR1402 have considerably higher potency than hTSH to stimulate thyroidal iodide and (18)F-FDG uptake in vitro. Moreover, in vivo studies indicated that at low but not higher doses, TR1401 induced an enhanced ability for the thyroid to concentrate iodide compared with hTSH. These properties makes TR1401 and TR1402 interesting candidates for use in humans to enhance uptake of radioiodine and (18)F-FDG by metastases and recurrences of thyroid carcinoma.
authors.affiliation: Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Friedrich-Alexander University, Erlangen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Reinfelder
authors.forename: Simone
authors.initials: S
authors.lastname: Maschauer
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Foss
authors.forename: Sridhar
authors.initials: S
authors.lastname: Nimmagadda
authors.forename: Valerie
authors.initials: V
authors.lastname: Fremont
authors.forename: Vladimir
authors.initials: V
authors.lastname: Wolf
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Weintraub
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Mariusz W
authors.initials: MW
authors.lastname: Szkudlinski
authors.forename: Torsten
authors.initials: T
authors.lastname: Kuwert
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D051381:Rats; D011989:Receptors, Thyrotropin / Q000187:drug effects / Q000378:metabolism; D012974:Sodium Iodide / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000819:agonists* / Q000031:analogs & derivatives* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D011989:Receptors, Thyrotropin; C561864:TR1401 peptide; C561865:TR1402 peptide; D019788:Fluorodeoxyglucose F18; D013972:Thyrotropin; D000242:Cyclic AMP; D012974:Sodium Iodide