Abstract
<div>Abstract<p>We developed a novel therapeutic radioligand, [<sup>177</sup>Lu]<b>1h</b>, with an albumin binding motif and evaluated it in a prostate-specific membrane antigen (PSMA)-expressing tumor xenograft mouse model. Fourteen PSMA target candidates were synthesized, and binding affinity was evaluated with an <i>in vitro</i> competitive binding assay. First, four compound candidates were selected depending on binding affinity results. Next, we selected four compounds ([<sup>68</sup>Ga]<b>1e</b>, [<sup>68</sup>Ga]<b>1g</b>, [<sup>68</sup>Ga]<b>1h</b>, and [<sup>68</sup>Ga]<b>1k</b>) were screened for tumor targeting efficiency by micro–positron emission tomography/computed tomography (micro-PET/CT) imaging. Finally, [<sup>177</sup>Lu]<b>1h</b> compound was evaluated the tumor targeting efficiency and therapeutic efficiency by micro–single-photon emission computed tomography/computed tomography (micro-SPECT/CT), biodistribution, and radiotherapy studies. Estimated human effective dose was calculated by biodistribution data. Compound <b>1h</b> showed a high binding affinity (<i>K<sub>i</sub></i> value = 4.08 ± 0.08 nmol/L), and [<sup>177</sup>Lu]<b>1h</b> showed extended blood circulation (1 hour = 10.32 ± 0.31, 6 hours = 2.68 ± 1.07%ID/g) compared to [<sup>177</sup>Lu]PSMA-617 (1 h = 0.17 ± 0.10%ID/g). [<sup>177</sup>Lu]<b>1h</b> was excreted via the renal pathway and showed high tumor uptake (24.43 ± 3.36%ID/g) after 1 hour, which increased over 72 hours (72 hours = 51.39 ± 9.26%ID/g). Mice treated with 4 and 6 MBq of [<sup>177</sup>Lu]<b>1h</b> showed a median survival rate of >61 days. In particular, all mice treated with 6 MBq of [<sup>177</sup>Lu]<b>1h</b> survived for the entire monitoring period. The estimated human effective dose of [<sup>177</sup>Lu]<b>1h</b> was 0.07 ± 0.01 and 0.03 ± 0.00 mSv/MBq in total body and kidney, respectively. The current study indicates that [<sup>177</sup>Lu]<b>1h</b> has the potential for further investigation of metastatic castration-resistant prostate cancer (mCRPC) therapy in clinical trials.</p></div>
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