title: Comparison of high-specific-activity ultratrace 123/131I-MIBG and carrier-added 123/131I-MIBG on efficacy, pharmacokinetics, and tissue distribution.
abstract: Metaiodobenzylguanidine (MIBG) is an enzymatically stable synthetic analog of norepinephrine that when radiolabled with diagnostic ((123)I) or therapeutic ((131)I) isotopes has been shown to concentrate highly in sympathetically innervated tissues such as the heart and neuroendocrine tumors that possesses high levels of norepinephrine transporter (NET). As the transport of MIBG by NET is a saturable event, the specific activity of the preparation may have dramatic effects on both the efficacy and safety of the radiodiagnostic/radiotherapeutic. Using a solid labeling approach (Ultratrace), noncarrier-added radiolabeled MIBG can be efficiently produced. In this study, specific activities of >1200 mCi/micromol for (123)I and >1600 mCi/micromol for (131)I have been achieved. A series of studies were performed to assess the impact of cold carrier MIBG on the tissue distribution of (123/131)I-MIBG in the conscious rat and on cardiovascular parameters in the conscious instrumented dog. The present series of studies demonstrated that the carrier-free Ultratrace MIBG radiolabeled with either (123)I or (131)I exhibited similar tissue distribution to the carrier-added radiolabeled MIBG in all nontarget tissues. In tissues that express NETs, the higher the specific activity of the preparation the greater will be the radiopharmaceutical uptake. This was reflected by greater efficacy in the mouse neuroblastoma SK-N-BE(2c) xenograft model and less appreciable cardiovascular side-effects in dogs when the high-specific-activity radiopharmaceutical was used. The increased uptake and retention of Ultratrace (123/131)I-MIBG may translate into a superior diagnostic and therapeutic potential. Lastly, care must be taken when administering therapeutic doses of the current carrier-added (131)I-MIBG because of its potential to cause adverse cardiovascular side-effects, nausea, and vomiting.
authors.affiliation: Research & Development Department, Molecular Insight Pharmaceuticals, Inc., Cambridge, Massachusetts, USA. jbarrett@molecularinsight.com
authors.forename: John A
authors.initials: JA
authors.lastname: Barrett
authors.forename: John L
authors.initials: JL
authors.lastname: Joyal
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Hillier
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Maresca
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Femia
authors.forename: James F
authors.initials: JF
authors.lastname: Kronauge
authors.forename: Marie
authors.initials: M
authors.lastname: Boyd
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mairs
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
mesh_terms: D019797:3-Iodobenzylguanidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001853:Bone Marrow / Q000378:metabolism; D001919:Bradycardia / Q000139:chemically induced; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry* / Q000627:therapeutic use; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009206:Myocardium / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology / Q000532:radiotherapy; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D019797:3-Iodobenzylguanidine