Open Access
Journal of Nuclear Medicine, volume 60, issue 1, pages 71-78
Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer
Schottelius M.
1
,
Wurzer Alexander
1
,
Wissmiller Katharina
1
,
Beck Roswitha
1
,
Koch Maximilian
2
,
Gorpas Dimitrios
2
,
Notni Johannes
1
,
Buckle Tessa
3
,
van Oosterom Matthias
3
,
Steiger Katja
4, 5
,
Schwaiger Markus
6
,
van Leeuwen Fijs W.B.
3
,
Wester Hans Jürgen
1
3
Interventional Molecular Imaging Laboratory Department of Radiology Leiden University Medical Center Leiden The Netherlands
|
4
5
and
Publication type: Journal Article
Publication date: 2018-09-20
Journal:
Journal of Nuclear Medicine
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 9.3
ISSN: 01615505, 2159662X
PubMed ID:
30237214
Radiology, Nuclear Medicine and imaging
Abstract
The prostate-specific membrane antigen (PSMA)–targeted radiotracers 68Ga/177Lu-PSMA-I&T and 99mTc-PSMA-I&S (for imaging and surgery) are currently successfully used for clinical PET imaging, radionuclide therapy, and radioguided surgery of metastatic prostate cancer. To additionally exploit the high sensitivity and spatial resolution of fluorescence imaging for improved surgical guidance, a PSMA-I&T–based hybrid tracer, PSMA-I&F (DOTAGA-k(Sulfo-Cy5)-y-nal-k-Sub-KuE), has been developed and evaluated. Methods: The in vitro PSMA-targeting efficiency of PSMA-I&F, the reference PSMA-I&T, and their corresponding natGa-/68Ga- and natLu/177Lu counterparts was determined in LNCaP cells via competitive binding assays (IC50) and dual-tracer radioligand and fluorescence internalization studies. Biodistribution and small-animal PET imaging studies were performed in CB17 SCID and LNCaP xenograft–bearing SHO mice, respectively, and complemented by intraoperative far-red fluorescence imaging using a clinical laparoscope. Additionally, fully automated serial cryosectioning and fluorescence imaging of 1 tumor-bearing animal as well as PSMA immunohistochemistry and fluorescence microscopy of organ cryosections (tumor, kidney, spleen) were also performed. Results: Compared with the parent PSMA-I&T analogs, the PSMA affinities of PSMA-I&F and its natGa-/natLu-complexes remained high and unaffected by dye conjugation (7.9 < IC50 < 10.5 nM for all ligands). The same was observed for the internalization of 68Ga- and 177Lu-PSMA-I&F. In vivo, blood clearance of 68Ga- and 177Lu-PSMA-I&F was only slightly delayed by high plasma protein binding (94%–95%), and very low accumulation in nontarget organs was observed already at 1 h after injection. Dynamic PET imaging confirmed PSMA-specific (as demonstrated by coinjection of 2-PMPA) uptake into the LNCaP xenograft (4.5% ± 1.8 percentage injected dose per gram) and the kidneys (106% ± 23 percentage injected dose per gram). Tumor-to-background ratios of 2.1, 5.2, 9.6, and 9.6 for blood, liver, intestines, and muscle, respectively, at 1 h after injection led to excellent imaging contrast in 68Ga-PSMA-I&F PET and in intraoperative fluorescence imaging. Furthermore, fluorescence imaging of tissue cryosections allowed high-resolution visualization of intraorgan PSMA-I&F distribution in vivo and its correlation with PSMA expression as determined by immunohistochemistry. Conclusion: Thus, with its high PSMA-targeting efficiency and favorable pharmacokinetic profile, 68Ga/177Lu-PSMA-I&F serves as an excellent proof-of-concept compound for the general feasibility of PSMA-I&T–based hybrid imaging. The PSMA-I&T scaffold represents a versatile PSMA-targeted lead structure, allowing relatively straightforward adaptation to the different structural requirements of dedicated nuclear or hybrid imaging agents.
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Schottelius M. et al. Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer // Journal of Nuclear Medicine. 2018. Vol. 60. No. 1. pp. 71-78.
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Schottelius M., Wurzer A., Wissmiller K., Beck R., Koch M., Gorpas D., Notni J., Buckle T., van Oosterom M., Steiger K., Ntziachristos V., Schwaiger M., van Leeuwen F. W., Wester H. J. Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer // Journal of Nuclear Medicine. 2018. Vol. 60. No. 1. pp. 71-78.
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TY - JOUR
DO - 10.2967/jnumed.118.212720
UR - https://doi.org/10.2967%2Fjnumed.118.212720
TI - Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer
T2 - Journal of Nuclear Medicine
AU - Schottelius, M.
AU - Wurzer, Alexander
AU - Wissmiller, Katharina
AU - Beck, Roswitha
AU - Koch, Maximilian
AU - Gorpas, Dimitrios
AU - Notni, Johannes
AU - Buckle, Tessa
AU - van Oosterom, Matthias
AU - Steiger, Katja
AU - Ntziachristos, Vasilis
AU - Schwaiger, Markus
AU - van Leeuwen, Fijs W.B.
AU - Wester, Hans Jürgen
PY - 2018
DA - 2018/09/20 00:00:00
PB - Society of Nuclear Medicine and Molecular Imaging
SP - 71-78
IS - 1
VL - 60
PMID - 30237214
SN - 0161-5505
SN - 2159-662X
ER -
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@article{2018_Schottelius,
author = {M. Schottelius and Alexander Wurzer and Katharina Wissmiller and Roswitha Beck and Maximilian Koch and Dimitrios Gorpas and Johannes Notni and Tessa Buckle and Matthias van Oosterom and Katja Steiger and Vasilis Ntziachristos and Markus Schwaiger and Fijs W.B. van Leeuwen and Hans Jürgen Wester},
title = {Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer},
journal = {Journal of Nuclear Medicine},
year = {2018},
volume = {60},
publisher = {Society of Nuclear Medicine and Molecular Imaging},
month = {sep},
url = {https://doi.org/10.2967%2Fjnumed.118.212720},
number = {1},
pages = {71--78},
doi = {10.2967/jnumed.118.212720}
}
Cite this
MLA
Copy
Schottelius, M., et al. “Synthesis and Preclinical Characterization of the PSMA-Targeted Hybrid Tracer PSMA-I&F for Nuclear and Fluorescence Imaging of Prostate Cancer.” Journal of Nuclear Medicine, vol. 60, no. 1, Sep. 2018, pp. 71-78. https://doi.org/10.2967%2Fjnumed.118.212720.
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