Document Detail

Preparation and biological evaluation of 111In-, 177Lu- and 90Y-labeled DOTA analogues conjugated to B72.3.
MedLine Citation:
PMID:  17591549     Owner:  NLM     Status:  MEDLINE    
Three 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) analogues were evaluated for relative in vivo stability when radiolabeled with (111)In, (90)Y and (177)Lu and conjugated to the monoclonal antibody B72.3. The DOTA analogues evaluated were "NHS-DOTA" [N-hydroxysuccinimdyl (NHS) group activating one carboxylate], "Arm-DOTA" (also known as MeO-DOTA; with a p-NCS, o-MeO-benzyl moiety on the methylene group of one acetic acid arm) and "Back-DOTA" (with a p-NCS-benzyl moiety on a backbone methylene group of the macrocycle). The B72.3 was conjugated to the DOTA analogues to increase the retention time of the radioloabeled conjugates in vivo in mice. The serum stability of the various radiometalated DOTA conjugates showed them to have good stability out to 168 h (all >95% except (111)In-NHS-DOTA-B72.3, which was 91% stable). Hydroxyapatite stability for the (111)In and (177)Lu DOTA-conjugates was >95% at 168 h, while the (90)Y DOTA-conjugates were somewhat less stable (between 90% and 95% at 168 h). The biodistribution studies of the radiometalated DOTA-conjugates showed that no significant differences were observed for the (111)In and (177)Lu analogues; however, the (90)Y analogues showed lower stabilities, as evidenced by their increased bone uptake relative to the other two [2-20% injected dose per gram (% ID/g) for (90)Y and 2-8% ID/g for (111)In and (177)Lu]. The lower stability of the (90)Y analogues could be due to the higher beta energy of (90)Y and/or to the larger ionic radius of Y(3+). Based on the bone uptake observed, the (177)Lu-NHS-DOTA-B72.3 had slightly lower stability than the (177)Lu-Arm-DOTA-B72.3 and (177)Lu-Back-DOTA-B72.3, but not significantly at all time points. For (90)Y, the analogue showing the lowest stability based on bone uptake was (90)Y-Arm-DOTA-B72.3, perhaps because of the metal's larger ionic radius and potential steric interactions minimizing effective complexation. The (111)In analogues all showed similar biological distributions at the various time points. This study suggests that care must be taken when evaluating (90)Y-labeled antibodies and in using NHS-DOTA-antibody conjugates with (177)Lu. All evaluations should be extended to time points relevant to the half-life of the radiometal and the therapy applications.
Huma Mohsin; Jonathan Fitzsimmons; Tiffani Shelton; Timothy J Hoffman; Cathy S Cutler; Michael R Lewis; Phillip S Athey; Gyongyi Gulyas; Garry E Kiefer; R Keith Frank; Jaime Simon; Susan Z Lever; Silvia S Jurisson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-06-08
Journal Detail:
Title:  Nuclear medicine and biology     Volume:  34     ISSN:  0969-8051     ISO Abbreviation:  Nucl. Med. Biol.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-06-26     Completed Date:  2007-10-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9304420     Medline TA:  Nucl Med Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  493-502     Citation Subset:  IM    
Chemistry Department, University of Missouri, Columbia, MO 65211, USA.
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MeSH Terms
Antibodies, Neoplasm / chemistry,  diagnostic use,  metabolism*
Bone and Bones / metabolism*,  radionuclide imaging
Drug Evaluation, Preclinical
Heterocyclic Compounds, 1-Ring / chemical synthesis,  diagnostic use,  pharmacokinetics*
Isotope Labeling / methods
Metabolic Clearance Rate
Organ Specificity
Radioisotopes / chemistry,  diagnostic use,  pharmacokinetics*
Radiopharmaceuticals / chemical synthesis,  diagnostic use,  pharmacokinetics
Tissue Distribution
Reg. No./Substance:
0/Antibodies, Neoplasm; 0/B72.3 antibody; 0/Heterocyclic Compounds, 1-Ring; 0/Radioisotopes; 0/Radiopharmaceuticals; 60239-18-1/1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid

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