title: Preclinical evaluation of investigational radiopharmaceutical RISAD-P intended for use as a diagnostic and molecular radiotherapy agent for prostate cancer.
abstract: BACKGROUND
  The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-3'-O-(17β-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated.
  
  
  METHODS
  Effects of nonradioactive ISAD-P and RISAD-P labeled with (123) I, (124) I, and (125) I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice.
  
  
  RESULTS
  RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for (18) F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after (125) IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1,240 Gy × MBq(-1)  × g(-1) for (125) I-, (123) I-, and (124) I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed.
  
  
  CONCLUSIONS
  Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.
authors.affiliation: Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Zbigniew P
authors.initials: ZP
authors.lastname: Kortylewicz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mack
authors.forename: Charles A
authors.initials: CA
authors.lastname: Enke
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Estes
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.forename: Janina
authors.initials: J
authors.lastname: Baranowska-Kortylewicz
mesh_terms: D000732:Androstanols / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D003856:Deoxyuracil Nucleotides / Q000493:pharmacokinetics / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational; D007457:Iodine Radioisotopes; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010865:Pilot Projects; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000532:radiotherapy*; D019275:Radiopharmaceuticals; D011879:Radiotherapy Dosage; D011944:Receptors, Androgen / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: C550440:5-iodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridine 5'-monophosphate; D000732:Androstanols; D003856:Deoxyuracil Nucleotides; D015507:Drugs, Investigational; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen
keywords: Auger electrons; androgen receptor; molecular radiotherapy; prostate cancer; theranostic