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Open Access 01-12-2020 | Original research

¹⁸F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography

Authors: Flaviu Bulat, Friederike Hesse, De-En Hu, Susana Ros, Connor Willminton-Holmes, Bangwen Xie, Bala Attili, Dmitry Soloviev, Franklin Aigbirhio, Finian. J. Leeper, Kevin M. Brindle, André A. Neves

Published in: EJNMMI Research | Issue 1/2020

Abstract

Introduction

Trialing novel cancer therapies in the clinic would benefit from imaging agents that can detect early evidence of treatment response. The timing, extent and distribution of cell death in tumors following treatment can give an indication of outcome. We describe here an ¹⁸F-labeled derivative of a phosphatidylserine-binding protein, the C2A domain of Synaptotagmin-I (C2Am), for imaging tumor cell death in vivo using PET.

Methods

A one-pot, two-step automated synthesis of N-(5-[¹⁸F]fluoropentyl)maleimide (60 min synthesis time, > 98% radiochemical purity) has been developed, which was used to label the single cysteine residue in C2Am within 30 min at room temperature. Binding of ¹⁸F-C2Am to apoptotic and necrotic tumor cells was assessed in vitro, and also in vivo, by dynamic PET and biodistribution measurements in mice bearing human tumor xenografts treated with a TRAILR2 agonist or with conventional chemotherapy. C2Am detection of tumor cell death was validated by correlation of probe binding with histological markers of cell death in tumor sections obtained immediately after imaging.

Results

¹⁸F-C2Am showed a favorable biodistribution profile, with predominantly renal clearance and minimal retention in spleen, liver, small intestine, bone and kidney, at 2 h following probe administration. ¹⁸F-C2Am generated tumor-to-muscle (T/m) ratios of 6.1 ± 2.1 and 10.7 ± 2.4 within 2 h of probe administration in colorectal and breast tumor models, respectively, following treatment with the TRAILR2 agonist. The levels of cell death (CC3 positivity) following treatment were 12.9–58.8% and 11.3–79.7% in the breast and colorectal xenografts, respectively. Overall, a 20% increase in CC3 positivity generated a one unit increase in the post/pre-treatment tumor contrast. Significant correlations were found between tracer uptake post-treatment, at 2 h post-probe administration, and histological markers of cell death (CC3: Pearson R = 0.733, P = 0.0005; TUNEL: Pearson R = 0.532, P = 0.023).

Conclusion

The rapid clearance of ¹⁸F-C2Am from the blood pool and low kidney retention allowed the spatial distribution of cell death in a tumor to be imaged during the course of therapy, providing a rapid assessment of tumor treatment response. ¹⁸F-C2Am has the potential to be used in the clinic to assess early treatment response in tumors.

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Title: 18F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography
Authors: Flaviu Bulat
Friederike Hesse
De-En Hu
Susana Ros
Connor Willminton-Holmes
Bangwen Xie
Bala Attili
Dmitry Soloviev
Franklin Aigbirhio
Finian. J. Leeper
Kevin M. Brindle
André A. Neves
Publication date: 01-12-2020
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2020
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-020-00738-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

¹⁸F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography

Abstract

Introduction

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

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