Development and Preclinical Evaluation of 99m Tc- and 186 Re-Labeled NOTA and NODAGA Bioconjugates Demonstrating Matched
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RESEARCH ARTICLE
Development and Preclinical Evaluation of 99mTc- and 186Re-Labeled NOTA and NODAGA Bioconjugates Demonstrating Matched Pair Targeting of GRPR-Expressing Tumors George Makris,1 Rajendra P. Bandari,2 Marina Kuchuk,1 Silvia S. Jurisson,3 Charles J. Smith,1,2,4 Heather M. Hennkens 1,3 1
Research Reactor Center, University of Missouri, Columbia, MO, 65211, USA Research Service, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, 65201, USA 3 Department of Chemistry, University of Missouri, Columbia, MO, 65211, USA 4 Department of Radiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA 2
Abstract Purpose: The goal of this work was to develop hydrophilic gastrin-releasing peptide receptor (GRPR)-targeting complexes of the general formula fac-[M(CO)3(L)]+ [M = natRe, 99mTc, 186Re; L: NOTA for 1, NODAGA for 2] conjugated to a powerful GRPR peptide antagonist (DPhe-Gln-TrpAla-Val-Gly-His-Sta-Leu-NH2) via a 6-aminohexanoic acid linker. Procedures: Metallated-peptides were prepared employing the [M(OH2)3(CO)3]+ [M = Re, 99mTc, 186 Re] precursors. Re-1/2 complexes were characterized with HR-MS. IC50 studies were performed for peptides 1/2 and their respective Re-1/2 complexes in a binding assay utilizing GRPR-expressing human PC-3 prostate cancer cells and [125I]I-Tyr4-BBN as the competing ligand. The 99mTc/186Re-complexes were identified by HPLC co-injection with their Reanalogues. All tracers were challenged in vitro at 37 °C against cysteine/histidine (phosphatebuffered saline 10 mM, pH 7.4) and rat serum. Biodistribution and micro-SPECT/CT imaging of [99mTc]Tc-1/2 and [186Re]Re-2 were performed in PC-3 tumor-bearing ICR SCID mice. Results: High in vitro receptor affinity (IC50 2–3 nM) was demonstrated for all compounds. The 99m Tc/186Re-tracers were found to be hydrophilic (log D7.4 ≤ − 1.35) and highly stable. Biodistribution in PC-3 xenografted mice revealed good tumor uptake (%ID/g at 1 h: 4.3 ± 0.7 for [99mTc]Tc-1, 8.3 ± 0.9 for [99mTc]Tc-2 and 4.2 ± 0.8 for [186Re]Re-2) with moderate retention over 24 h. Rapid renal clearance was observed for [99mTc]Tc-2 and [186Re]Re-2 (9 84 % at 4 h), indicating favorable pharmacokinetics. Micro-SPECT/CT images for the 99mTc-tracers clearly visualized PC-3 tumors in agreement with the biodistribution data and with superior imaging properties found for [99mTc]Tc-2. Conclusions: [99mTc]Tc-2 shows promise for further development as a GRPR-imaging agent. [186Re]Re-2 demonstrated very similar in vivo behavior to [99mTc]Tc-2, and further studies are therefore justified to explore the theranostic potential of our approach for targeting of GRPRpositive cancers.
Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01537-1) contains supplementary material, which is available to authorized users. Correspondence to: Heather Hennkens; e-mail: [email protected]
Makris G. et al.: Evaluation of GRPR-targeting
99m
Tc/186Re-Labeled Bioconjugates
Key words: Technetium-99m, Rhenium-186, Orga
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