Development and Preclinical Evaluation of 99mTc- and 186Re-Labeled NOTA and NODAGA Bioconjugates Demonstrating Matched Pair Targeting of GRPR-Expressing Tumors.

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-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.

• Authors: George Makris, Rajendra P Bandari, Marina Kuchuk, Silvia S Jurisson, Charles J Smith, Heather M Hennkens
• Journal: Molecular imaging and biology (Mol Imaging Biol) Vol. 23 Issue 1 Pg. 52-61 (02 2021) ISSN: 1860-2002 [Electronic] United States
• PMID: 32886303 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
• Acetates
• Heterocyclic Compounds, 1-Ring
• Ligands
• Peptides
• Radioisotopes
• Receptors, Bombesin
• Rhenium-186
• 1,4,7-triazacyclononane-N,N',N''-triacetic acid
• Rhenium
• Technetium

Topics

• Acetates (chemistry)
• Animals
• Heterocyclic Compounds, 1-Ring (chemistry)
• Inhibitory Concentration 50
• Ligands
• Mice, SCID
• Neoplasms (diagnostic imaging)
• Peptides (chemistry)
• Radioisotopes (chemistry)
• Receptors, Bombesin (metabolism)
• Rhenium (chemistry)
• Single Photon Emission Computed Tomography Computed Tomography
• Technetium (chemistry)
• Tissue Distribution
• Whole Body Imaging
• Mice