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Selection of an optimal macrocyclic chelator improves the imaging of prostate cancer using cobalt-labeled GRPR antagonist RM26
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.ORCID iD: 0000-0001-7921-3268
Odense Univ Hosp, Dept Nucl Med, PET & Cyclotron Unit, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.ORCID iD: 0000-0001-9492-448X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
Odense Univ Hosp, Dept Nucl Med, PET & Cyclotron Unit, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 17086Article in journal (Refereed) Published
Abstract [en]

Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. We have recently used 55Co (T1/2 = 17.5 h) as a label for next day PET imaging of GRPR expression obtaining high imaging contrast. The radionuclide-chelator combination can significantly influence the biodistribution of radiopeptides. Therefore, in this study, we hypothesized that the properties of 55Co-labeled PEG2-RM26 can be improved by identifying the optimal macrocyclic chelator. All analogues (X-PEG2-RM26, X = NOTA,NODAGA,DOTA,DOTAGA) were successfully labeled with radiocobalt with high yields and demonstrated high stability. The radiopeptides bound specifically and with picomolar affinity to GRPR and their cellular processing was characterized by low internalization. The best binding capacity was found for DOTA-PEG2-RM26. Ex vivo biodistribution in PC-3 xenografted mice was characterized by rapid blood clearance via renal excretion. Tumor uptake was similar for all conjugates at 3 h pi, exceeding the uptake in all other organs. Higher kidney uptake and longer retention were associated with N-terminal negative charge (DOTAGA-containing conjugate). Tumor-to-organ ratios increased over time for all constructs, although significant chelator-dependent differences were observed. Concordant with affinity measurements, DOTA-analog had the best retention of activity in tumors, resulting in the highest tumor-to-blood ratio 24 h pi, which translated into high contrast PET/CT imaging (using 55Co).

Place, publisher, year, edition, pages
2019. Vol. 9, article id 17086
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-398422DOI: 10.1038/s41598-019-52914-yISI: 000497701800043PubMedID: 31745219OAI: oai:DiVA.org:uu-398422DiVA, id: diva2:1376036
Funder
Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN 2018/436Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353
Note

De 2 första författarna delar förstaförfattarskapet. De 2 sista författarna delar sistaförfattarskapet.

Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2020-01-09Bibliographically approved

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