RT Journal Article
SR Electronic
T1 Radiolabeled inhibitors of seprase targeting the tumor microenvironment
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1563
OP 1563
VO 50
IS supplement 2
A1 John Marquis
A1 Jian Wang
A1 Kevin Maresca
A1 Shawn Hillier
A1 Craig Zimmerman
A1 William Eckelman
A1 John Joyal
A1 John Babich
YR 2009
UL http://jnm.snmjournals.org/content/50/supplement_2/1563.abstract
AB 1563 Objectives Seprase is an integral membrane, proline-specific serine protease, and is a key component of the tumor microenvironment. We are developing radiolabeled seprase inhibitors for noninvasive imaging, and targeted cancer radiotherapy. Methods A series of iodine substituted benzamido-glycine-boronoproline seprase antagonists were designed and synthesized. Compounds were assessed for the ability to inhibit the enzymatic activity of seprase in vitro, and for the ability to bind seprase in human cancer cells and tumors. Results ortho (1)-, para (2)- and meta (3)-iodine substituted analogs exhibited high affinity (2-7 nM IC50 values) for seprase. To examine the selectivity for seprase over other prolyl peptidases, compounds were tested for the ability to inhibit the enzymatic activity of the related peptidases, POP and DPPIV. The affinities of all three compounds were ~7-40 -fold weaker for POP and ~1000-fold weaker for DPPIV. To examine binding to seprase in vivo, HEK-293 cells were stably transfected with the human seprase gene, and highly expressing clones were selected. The Kd of 123I-(2) for seprase was 30 nM, whereas there was no specific binding to a non-expressing clone. Compound (2) also inhibited the seprase activity of seprase expressing cells. Overlay studies confirmed selective binding of 123I-(2) to human breast, colon, and lung cancer tissues. Conclusions Antagonists with high affinity and selectivity for seprase were developed. Radiolabeled seprase inhibitors are currently being evaluated for tumor uptake and tissue distribution in mice bearing seprase expressing xenografts, and could be exploited for the diagnosis, staging, prognosis, and potential treatment of solid tumors.