Copper-64 radiolabeling and biological evaluation of bifunctional chelators for radiopharmaceutical development

Abstract Introduction The development of novel bifunctional chelates for attaching copper-64 to biomolecules has been an active area of research for several years. However, many of these64 Cu-chelates have poor in vivo stability or harsh radiolabeling conditions. Methods In this study, two triazacyc...

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Veröffentlicht in:Nuclear medicine and biology 2012-11, Vol.39 (8), p.1099-1104
Hauptverfasser: De Silva, Ravindra A, Jain, Sandeep, Lears, Kimberly A, Chong, Hyun-Soon, Kang, Chi Soo, Sun, Xiang, Rogers, Buck E
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Sprache:eng
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Zusammenfassung:Abstract Introduction The development of novel bifunctional chelates for attaching copper-64 to biomolecules has been an active area of research for several years. However, many of these64 Cu-chelates have poor in vivo stability or harsh radiolabeling conditions. Methods In this study, two triazacyclononane analogs; C -NE3TA (4-carboxymethyl-7-[2-(carboxymethyl-amino)-3-(4-nitro-phenyl)-propyl]-[1,4,7]triazo-nan-1-yl-acetic acid) and N -NE3TA (4-carboxymethyl-7-[2-[carboxymethyl-(4-nitro-benzyl)-amino]-ethyl]-[1,4,7]triazonan-1-yl-acetic acid) were evaluated for their labeling efficiency with64 Cu at room temperature and evaluated in vitro and in vivo. In vitro studies included complexation kinetics with Cu(II) using a spectrophotometric method and rat serum stability, while the in vivo biodistribution was evaluated using SCID mice. Results C -NE3TA and N -NE3TA were labeled at > 95% efficiency up to ~ 3.4 Ci/μmol. Both C -NE3TA and N -NE3TA formed complexes with Cu(II) almost immediately, with the Cu(II) complexation by C -NE3TA being faster than the formation of Cu(II)- N -NE3TA. Both64 Cu- N -NE3TA and64 Cu- C -NE3TA were 96.1% and 90.5% intact after 48 h incubation in rat serum, respectively. This is compared to64 Cu complexes of the control chelators, p -NH2 -Bn-DOTA and p -NH2 -Bn-NOTA, with 93.9% and 97.9% retention of64 Cu in the complex, respectively. In vivo evaluation of64 Cu- N -NE3TA and64 Cu- C -NE3TA demonstrates good clearance from normal tissues except for the liver, where 59% and 51% of the radioactivity is retained at 24 h compared to 1 h for64 Cu- N -NE3TA and64 Cu- C -NE3TA, respectively. This compares to 78% and 3% retention for64 Cu- p -NH2 -Bn-DOTA and64 Cu- p -NH2 -Bn-NOTA. Conclusions These studies demonstrate that while N -NE3TA and C -NE3TA appear to be superior chelators for64 Cu than p -NH2 -Bn-DOTA, they are not better than p -NH2 -Bn-NOTA. Nevertheless, it may still be interesting to evaluate these chelators after conjugation to biomolecules.
ISSN:0969-8051
1872-9614
DOI:10.1016/j.nucmedbio.2012.05.009