Development and Preclinical Evaluation of 99mTc- and 186Re-Labeled NOTA and NODAGA Bioconjugates Demonstrating Matched Pair Targeting of GRPR-Expressing Tumors
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-Trp-Ala-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, 186Re] 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 Re-analogues. All tracers were challenged in vitro at 37 °C against cysteine/histidine (phosphate-buffered 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 99mTc/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 (> 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 GRPR-positive cancers.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
Molecular imaging and biology - 23(2021), 1 vom: 18. Feb., Seite 52-61 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Makris, George [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.08.2021 Date Revised 26.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s11307-020-01537-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM314591303 |
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| 100 | 1 | |a Makris, George |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Development and Preclinical Evaluation of 99mTc- and 186Re-Labeled NOTA and NODAGA Bioconjugates Demonstrating Matched Pair Targeting of GRPR-Expressing Tumors |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 25.08.2021 | ||
| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) via a 6-aminohexanoic acid linker | ||
| 520 | |a PROCEDURES: Metallated-peptides were prepared employing the [M(OH2)3(CO)3]+ [M = Re, 99mTc, 186Re] 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 Re-analogues. All tracers were challenged in vitro at 37 °C against cysteine/histidine (phosphate-buffered 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 | ||
| 520 | |a RESULTS: High in vitro receptor affinity (IC50 2-3 nM) was demonstrated for all compounds. The 99mTc/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 (> 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 | ||
| 520 | |a 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 GRPR-positive cancers | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Gastrin-releasing peptide receptor | |
| 650 | 4 | |a Micro-SPECT/CT imaging | |
| 650 | 4 | |a Organometallic complexes | |
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| 700 | 1 | |a Jurisson, Silvia S |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Charles J |e verfasserin |4 aut | |
| 700 | 1 | |a Hennkens, Heather M |e verfasserin |4 aut | |
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