title: A preclinical investigation of the saturation and dosimetry of 153Sm-DOTMP as a bone-seeking radiopharmaceutical.
abstract: BACKGROUND
  The therapeutic potential of the bone-seeking radiopharmaceutical 153Sm-labeled 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (153Sm-DOTMP) was assessed by measuring its dosage-dependent skeletal uptake at two chelant-to-metal ratios and its source organ residence times at a chelant-to-metal ratio of 1.5:1. A similar agent, 153Sm-labeled ethylenediaminetetramethylenephosphonic acid (153Sm-EDTMP), has been reported to exhibit dosage-limiting skeletal saturation.
  
  
  METHODS
  Sm-DOTMP was prepared with tracer activity of 153Sm and sufficient stable, unenriched Sm to simulate different activities. Cohorts of seven 280-g Sprague-Dawley rats were administered the equivalent of 296, 592, 888, 1184 and 1480 MBq (8, 16, 24, 32 and 40 mCi) at a fixed chelant-to-metal ratio of 1.5:1 and euthanized 3 h after administration. Cohorts of three 128-g Sprague-Dawley rats were administered equivalent dosages of 10.4, 592 and 888 (0.28, 16 and 32 mCi) at a fixed chelant-to-metal ratio of 270:1 and euthanized 2 h after administration. A simulated activity of 1480 MBq (40 mCi) at a chelant-to-metal ratio of 1.5:1 was administered to cohorts of seven rats that were euthanized at 2, 4, 24 or 48 h postadministration. The heart, lungs, liver, spleen, kidneys, small intestine, large intestine, urinary bladder, muscle and a femur were excised, weighed and counted. The data were analyzed to determine skeletal uptake and source organ residence times.
  
  
  RESULTS
  No statistically significant skeletal saturation was observed up to human-equivalent dosages of 370 GBq (10 Ci) at a chelant-to-metal ratio of 1.5:1, but the skeletal uptake dropped by 40% over the range of dosages at a chelant-to-metal ratio of 270:1. At a chelant-to-metal ratio of 1.5:1, the preferred ratio, the skeletal uptake fraction in rats was 0.408 (95% confidence interval 0.396-0.419) with an effective half-life of 47.3 h (95% confidence interval 42.3-53.7; the physical half-life of 153Sm is 46.3 h). Extrapolating to an adult human model, 52.9 GBq (1.43 Ci) of 153Sm-DOTMP would deliver 40 Gy to the red marrow.
  
  
  CONCLUSIONS
  153Sm-DOTMP has dosimetry equivalent to that of 153Sm-EDTMP at low dosages, yet with no skeletal saturation at higher administered activities.
authors.affiliation: IsoTherapeutics Group, LLC, Angleton, TX 77515, USA. jimsimon@isotherapeutics.com
authors.forename: Jaime
authors.initials: J
authors.lastname: Simón
authors.forename: R Keith
authors.initials: RK
authors.lastname: Frank
authors.forename: Druce K
authors.initials: DK
authors.lastname: Crump
authors.forename: William D
authors.initials: WD
authors.lastname: Erwin
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.forename: Richard E
authors.initials: RE
authors.lastname: Wendt
mesh_terms: D000328:Adult; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D006801:Humans; D008297:Male; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000493:pharmacokinetics; D011868:Radioisotopes; D011874:Radiometry; D019275:Radiopharmaceuticals / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012493:Samarium
chemical_list: D009943:Organophosphorus Compounds; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D012493:Samarium; C082084:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylenephosphonic acid)