PT  - JOURNAL ARTICLE
AU  - Neves, André A.
AU  - Xie, Bangwen
AU  - Fawcett, Sarah
AU  - Alam, Israt S.
AU  - Witney, Timothy H.
AU  - de Backer, Maaike M.
AU  - Summers, Julia
AU  - Hughes, William
AU  - McGuire, Sarah
AU  - Soloviev, Dmitry
AU  - Miller, Jodi
AU  - Howat, William J.
AU  - Hu, De-en
AU  - Rodrigues, Tiago B.
AU  - Lewis, David Y.
AU  - Brindle, Kevin M.
TI  - Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I
AID  - 10.2967/jnumed.116.183004
DP  - 2017 Jun 01
TA  - Journal of Nuclear Medicine
PG  - 881--887
VI  - 58
IP  - 6
4099  - http://jnm.snmjournals.org/content/58/6/881.short
4100  - http://jnm.snmjournals.org/content/58/6/881.full
SO  - J Nucl Med2017 Jun 01; 58
AB  - Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of a phosphatidylserine-binding agent for detecting tumor cell death in vivo based on the C2A domain of synaptotagmin-I. Methods: The capability of near-infrared fluorophore-labeled and 99mTc- and 111In-labeled derivatives of C2Am for imaging tumor cell death, using planar near-infrared fluorescence imaging and SPECT, respectively, was evaluated in implanted and genetically engineered mouse models of lymphoma and in a human colorectal xenograft. Results: The fluorophore-labeled C2Am derivative showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (2%–5%). There was a significant correlation (R > 0.9, P < 0.05) between fluorescently labeled C2Am binding and histologic markers of cell death, including cleaved caspase-3, whereas there was no such correlation with a site-directed mutant of C2Am (iC2Am) that does not bind phosphatidylserine. 99mTc-C2Am and 111In-C2Am also showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the liver and spleen at 24 h after probe administration. 99mTc-C2Am and 111In-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration. Conclusion: Given the favorable biodistribution profile of 99mTc- and 111In-labeled C2Am, and their ability to produce rapid and cell death–specific image contrast, these agents have potential for clinical translation.