imprint:
Springer Science and Business Media LLC, 2023
Published in:EJNMMI Research
Language:
English
DOI:
10.1186/s13550-022-00942-7
ISSN:
2191-219X
Origination:
Footnote:
Description:
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>Radioguided surgery (RGS) has recently emerged as a valuable new tool in the management of recurrent prostate cancer (PCa). After preoperative injection of a <jats:sup>99m</jats:sup>Tc-labeled prostate-specific membrane antigen (PSMA) inhibitor, radioguided intraoperative identification and resection of lesions is facilitated by means of suitable γ-probes. First clinical experiences show the feasibility of RGS and suggest superiority over conventional lymph node dissection in recurrent PCa. However, commonly used [<jats:sup>99m</jats:sup>Tc]Tc-PSMA-I&S exhibits slow whole-body clearance, thus hampering optimal tumor-to-background ratios (TBR) during surgery. We therefore aimed to develop novel <jats:sup>99m</jats:sup>Tc-labeled, PSMA-targeted radioligands with optimized pharmacokinetic profile to increase TBR at the time of surgery.
</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>Three <jats:sup>99m</jats:sup>Tc-labeled N4-PSMA ligands were preclinically evaluated and compared to [<jats:sup>99m</jats:sup>Tc]Tc-PSMA-I&S. PSMA affinity (IC<jats:sub>50</jats:sub>) and internalization were determined on LNCaP cells. Lipophilicity was assessed by means of the distribution coefficient log<jats:italic>D</jats:italic><jats:sub>7.4</jats:sub> and an ultrafiltration method was used to determine binding to human plasma proteins. Biodistribution studies and static <jats:italic>µ</jats:italic>SPECT/CT-imaging were performed at 6 h p.i. on LNCaP tumor-bearing CB17-SCID mice.
</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>The novel N4-PSMA tracers were readily labeled with [<jats:sup>99m</jats:sup>Tc]TcO<jats:sub>4</jats:sub><jats:sup>−</jats:sup> with RCP > 95%. Comparable and high PSMA affinity was observed for all [<jats:sup>99m</jats:sup>Tc]Tc-N4-PSMA-ligands. The ligands showed variable binding to human plasma and medium to low lipophilicity (log<jats:italic>D</jats:italic><jats:sub>7.4</jats:sub> − 2.6 to − 3.4), both consistently decreased compared to [<jats:sup>99m</jats:sup>Tc]Tc-PSMA-I&S. Biodistribution studies revealed comparable tumor uptake among all [<jats:sup>99m</jats:sup>Tc]Tc-N4-PSMA-ligands and [<jats:sup>99m</jats:sup>Tc]Tc-PSMA-I&S, while clearance from most organs was superior for the novel tracers. Accordingly, increased TBR were achieved. [<jats:sup>99m</jats:sup>Tc]Tc-N4-PSMA-12 showed higher TBR than [<jats:sup>99m</jats:sup>Tc]Tc-PSMA-I&S for blood and all evaluated tissue. In addition, a procedure suitable for routine clinical production of [<jats:sup>99m</jats:sup>Tc]Tc-N4-PSMA-12 was established. Labeling with 553 ± 187 MBq was achieved with RCP of 98.5 ± 0.6% (<jats:italic>n</jats:italic> = 10).
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</jats:sec><jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>High tumor accumulation and favorable clearance from blood and non-target tissue make [<jats:sup>99m</jats:sup>Tc]Tc-N4-PSMA-12 an attractive tracer for RGS, possibly superior to currently established [<jats:sup>99m</jats:sup>Tc]Tc-PSMA-I&S. Its GMP-production according to a method presented here and first clinical investigations with this novel radioligand is highly recommended.</jats:p>
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