Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 418-426 |
| Number of pages | 9 |
| Journal | Cancer Biotherapy and Radiopharmaceuticals |
| Volume | 21 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 20 2006 |
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Keywords
- Butylamino-NorBIRT
- Leukocyte function-associated antigen-1
- Lutetium-177
- Lymphoma
- Radionuclide imaging
Cite this
Characterization of a radiolabeled small molecule targeting leukocyte function-associated antigen-1 expression in lymphoma and leukemia. / Poria, Rahul B.; Norenberg, Jeffrey P.; Anderson, Tamara L.; Erion, Jack; Wagner, Carston R.; Arterburn, Jeffrey B.; Larson, Richard S.
In: Cancer Biotherapy and Radiopharmaceuticals, Vol. 21, No. 5, 20.11.2006, p. 418-426.Research output: Contribution to journal › Article
}
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 - 2006/11/20
Y1 - 2006/11/20
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
UR - http://www.scopus.com/inward/record.url?scp=33750982424&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33750982424&partnerID=8YFLogxK
U2 - 10.1089/cbr.2006.21.418
DO - 10.1089/cbr.2006.21.418
M3 - Article
VL - 21
SP - 418
EP - 426
JO - Cancer Biotherapy and Radiopharmaceuticals
JF - Cancer Biotherapy and Radiopharmaceuticals
SN - 1084-9785
IS - 5
ER -