Preparation and biological evaluation of111 In-,177 Lu- and90 Y-labeled DOTA analogues conjugated to B72.3

• Published in: Nuclear medicine and biology 2007, Vol.34 (5), p.493-502
• Main Authors: Mohsin, Huma, Fitzsimmons, Jonathan, Shelton, Tiffani, Hoffman, Timothy J, Cutler, Cathy S, Lewis, Michael R, Athey, Phillip S, Gulyas, Gyongyi, Kiefer, Garry E, Frank, R. Keith, Simon, Jaime, Lever, Susan Z, Jurisson, Silvia S
• Format: Article
• Language: English
• Subjects: Radiology
• ISSN: 0969-8051
• DOI: 10.1016/j.nucmedbio.2007.03.006

Abstract Three 1,4,7,10-tetraazacyclododecane- N,N′,Nʺ,Nʺ′ -tetraacetic acid (DOTA) analogues were evaluated for relative in vivo stability when radiolabeled with111 In,90 Y and177 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% except111 In-NHS-DOTA-B72.3, which was 91% stable). Hydroxyapatite stability for the111 In and177 Lu DOTA-conjugates was >95% at 168 h, while the90 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 the111 In and177 Lu analogues; however, the90 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) for90 Y and 2–8% ID/g for111 In and177 Lu]. The lower stability of the90 Y analogues could be due to the higher beta energy of90 Y and/or to the larger ionic radius of Y3+ . Based on the bone uptake observed, the177 Lu-NHS-DOTA-B72.3 had slightly lower stability than the177 Lu-Arm-DOTA-B72.3 and177 Lu-Back-DOTA-B72.3, but not significantly at all time points. For90 Y, the analogue showing the lowest stability based on bone uptake was90 Y-Arm-DOTA-B72.3, perhaps because of the metal's larger ionic radius and potential steric interactions minimizing effective complexation. The111 In analogues all showed similar biological distributions at the various time points. This study suggests that care must be taken when evaluating90 Y-labeled antibodies and in using NHS-DOTA-antibody conjugates with177 Lu. All evaluations should be extended to time points relevant to the half-life of the radiometal and the therapy applications.