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The use of an albumin binder has been shown to improve tumor uptake of prostate-specific membrane antigen (PSMA)-targeting radiotherapeutic agents. The aim of this study was to develop improved radiotherapeutic agents that combine an optimized affinity-modifying group and optimized albumin binders to maximize the tumor-to-kidney absorbed dose ratio. Methods:  68 Ga-labeled DOTA-conjugated lysine-ureido-glutamate-based PSMA-targeting agents bearing various affinity-modifying groups or albumin binders were synthesized and evaluated by PET/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. The optimized affinity-modifying group and albumin binders were combined, and the resulting derivatives were radiolabeled with 177 Lu and evaluated by SPECT/CT imaging and biodistribution studies in LNCaP tumor-bearing mice. Radiation dosimetry was calculated using the OLINDA/EXM software. Results: Affinity-modifying group optimization revealed that 68 Ga-HTK03041 bearing a tranexamic acid-9-anthrylalanine affinity-modifying group had the highest tumor uptake (23.1 ± 6.11 percentage injected dose [%ID]/g at 1 h after injection). Albumin binder optimization showed that 68 Ga-HTK03055 and 68 Ga-HTK03086 bearing the N -(4-( p -chlorophenyl)butanoyl)-Gly and N -(4-( p -methoxyphenyl)butanoyl)-Gly motifs, respectively, had relatively faster tumor accumulation (∼30 %ID/g at 3 h after injection) and lower average kidney uptake (&lt;55 %ID/g at both 1 and 3 h after injection). Combining the tranexamic acid-9-anthrylalanine affinity-modifying group with N -(4-( p -chlorophenyl)butanoyl)-Gly and N -(4-( p -methoxyphenyl)butanoyl)-Gly albumin-binding motifs generated HTK03121 and HTK03123, respectively. 177 Lu-HTK03121 and 177 Lu-HTK03123 had extremely high peak uptake (104 ± 20.3 and 70.8 ± 23.7 %ID/g, respectively) in LNCaP tumor xenografts, and this peak was sustained up to 120 h after injection. Dosimetry calculation showed that compared with 177 Lu-PSMA-617, 177 Lu-HTK03121 and 177 Lu-HTK03123 delivered 18.7- and 12.7-fold higher absorbed dose to tumor but only 6.4- and 6.3-fold higher absorbed dose to kidneys, leading to 2.9- and 2.0-fold improvement in the tumor-to-kidney absorbed dose ratios. Conclusion: With greatly enhanced tumor uptake and tumor-to-kidney absorbed dose ratio, 177 Lu-HTK03121 and 177 Lu-HTK03123 have the potential to improve treatment efficacy using significantly lower quantities of 177 Lu and are promising candidates for clinical translation to treat metastatic castration-resistant prostate cancer.

the journal of nuclear medicine

<sup>177</sup>Lu-Labeled Albumin-Binder–Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio

177Lu-Labeled Albumin-Binder–Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio

¹⁷⁷Lu-Labeled Albumin-Binder–Conjugated PSMA-Targeting Agents with Extremely High Tumor Uptake and Enhanced Tumor-to-Kidney Absorbed Dose Ratio