TY - JOUR
T1 - Characterization of a radiolabeled small molecule targeting leukocyte function-associated antigen-1 expression in lymphoma and leukemia
AU - Poria, Rahul B.
AU - Norenberg, Jeffrey P.
AU - Anderson, Tamara L.
AU - Erion, Jack
AU - Wagner, Carston R.
AU - Arterburn, Jeffrey B.
AU - Larson, Richard S.
PY - 2006
Y1 - 2006
N2 - Objective: Leukocyte function-associated antigen-1 (LFA-1) is constitutively expressed on leukocytes, including overexpression on lymphomas and leukemias. We have developed a derivative of BIRT 377, an allosteric inhibitor of LFA-1, which may be chemically tagged without affecting binding. In this study, we modified this derivative, (R)-1-(4-aminobutyl)-5-(4-bromobenzyl) -3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dione (butylamino-NorBIRT), and demonstrated its potential as a noninvasive imaging agent. Methods: Specific binding of fluorescein-labeled butylamino-NorBIRT to both human and murine cells was demonstrated using equilibrium binding and dissociation techniques. A radiometal, lutetium-177 (Lu-177), was incorporated into the butylamino-NorBIRT through 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) as a chelator. Results: Equilibrium-binding experiments demonstrated that fluorescein-labeled butylamino-NorBIRT specifically binds human and murine LFA-1 with affinity constants of 135 and 186 nM, respectively. Dissociation kinetic experiments demonstrated an off-rate of 0.168/second -1 on murine cells, consistent with the observed affinity constant. Lutetium-177 was used for labeling, with ≥99.99% radiochemical purity and incorporation yield. This radiolabeled derivative exhibited high stability in fetal bovine serum (FBS) at 37°C over 72 hours. 177Lu-DOTA- butylamino-NorBIRT showed a binding affinity of 235 nM to human LFA-1 for equilibrium binding and competitive binding experiments. Conclusions: The radiolabeled DOTA-butylamino-NorBIRT may have potential as a noninvasive imaging or therapeutic agent in both human and mouse models.
AB - Objective: Leukocyte function-associated antigen-1 (LFA-1) is constitutively expressed on leukocytes, including overexpression on lymphomas and leukemias. We have developed a derivative of BIRT 377, an allosteric inhibitor of LFA-1, which may be chemically tagged without affecting binding. In this study, we modified this derivative, (R)-1-(4-aminobutyl)-5-(4-bromobenzyl) -3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dione (butylamino-NorBIRT), and demonstrated its potential as a noninvasive imaging agent. Methods: Specific binding of fluorescein-labeled butylamino-NorBIRT to both human and murine cells was demonstrated using equilibrium binding and dissociation techniques. A radiometal, lutetium-177 (Lu-177), was incorporated into the butylamino-NorBIRT through 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) as a chelator. Results: Equilibrium-binding experiments demonstrated that fluorescein-labeled butylamino-NorBIRT specifically binds human and murine LFA-1 with affinity constants of 135 and 186 nM, respectively. Dissociation kinetic experiments demonstrated an off-rate of 0.168/second -1 on murine cells, consistent with the observed affinity constant. Lutetium-177 was used for labeling, with ≥99.99% radiochemical purity and incorporation yield. This radiolabeled derivative exhibited high stability in fetal bovine serum (FBS) at 37°C over 72 hours. 177Lu-DOTA- butylamino-NorBIRT showed a binding affinity of 235 nM to human LFA-1 for equilibrium binding and competitive binding experiments. Conclusions: The radiolabeled DOTA-butylamino-NorBIRT may have potential as a noninvasive imaging or therapeutic agent in both human and mouse models.
KW - Butylamino-NorBIRT
KW - Leukocyte function-associated antigen-1
KW - Lutetium-177
KW - Lymphoma
KW - Radionuclide imaging
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U2 - 10.1089/cbr.2006.21.418
DO - 10.1089/cbr.2006.21.418
M3 - Article
C2 - 17105416
AN - SCOPUS:33750982424
VL - 21
SP - 418
EP - 426
JO - Cancer Biotherapy and Radiopharmaceuticals
JF - Cancer Biotherapy and Radiopharmaceuticals
SN - 1084-9785
IS - 5
ER -