Details

Autor(en) / Beteiligte

• Makris, George
• Bandari, Rajendra P
• Kuchuk, Marina
• Jurisson, Silvia S
• Smith, Charles J
• Hennkens, Heather M

Titel

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

Ist Teil von

• Molecular imaging and biology, 2021-02, Vol.23 (1), p.52

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• The goal of this work was to develop hydrophilic gastrin-releasing peptide receptor (GRPR)-targeting complexes of the general formula fac-[M(CO) (L)] [M =  Re, Tc, Re; L: NOTA for 1, NODAGA for 2] conjugated to a powerful GRPR peptide antagonist ( Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH ) via a 6-aminohexanoic acid linker. Metallated-peptides were prepared employing the [M(OH ) (CO) ] [M = Re, Tc, Re] precursors. Re-1/2 complexes were characterized with HR-MS. IC 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 [ I]I-Tyr -BBN as the competing ligand. The Tc/ Re-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 [ Tc]Tc-1/2 and [ Re]Re-2 were performed in PC-3 tumor-bearing ICR SCID mice. High in vitro receptor affinity (IC 2-3 nM) was demonstrated for all compounds. The Tc/ Re-tracers were found to be hydrophilic (log D  ≤ - 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 [ Tc]Tc-1, 8.3 ± 0.9 for [ Tc]Tc-2 and 4.2 ± 0.8 for [ Re]Re-2) with moderate retention over 24 h. Rapid renal clearance was observed for [ Tc]Tc-2 and [ Re]Re-2 (> 84 % at 4 h), indicating favorable pharmacokinetics. Micro-SPECT/CT images for the Tc-tracers clearly visualized PC-3 tumors in agreement with the biodistribution data and with superior imaging properties found for [ Tc]Tc-2. [ Tc]Tc-2 shows promise for further development as a GRPR-imaging agent. [ Re]Re-2 demonstrated very similar in vivo behavior to [ Tc]Tc-2, and further studies are therefore justified to explore the theranostic potential of our approach for targeting of GRPR-positive cancers.