Abstract: A novel PSMA targeting molecule ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA with high uptake and long retention in prostate cancer was developed, in which DOTA was used as the bifunctional chelator, glutamic acid-urea-lysine(Glu-Urea-Lys) was used as the targeting group, and 4-(p-tolyl)butyric acid(CP) group together with quinoline ring were introduced at the linker of this molecule. The precursor DOTA-CPN-PSMA was synthesized using solid-phase peptide synthesis method. DOTA-CPN-PSMA was labeled with carrier-free ¹⁷⁷Lu. The influences of pH, reaction time, temperature, and ratio of ¹⁷⁷Lu/PSMA on the radiolabeling were investigated respectively, and the optimal labeling condition was determined accordingly. The lipid water partition coefficient and in vitro stability of ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA were also measured. Preliminary SPECT/CT imaging study of ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA was performed in nude mice bearing 22RV1 tumor and compared with ［¹⁷⁷Lu］Lu-PSMA-I&T. The optimization of the labeling condition shows that the addition of gentisic acid is essential, and the reaction pH is at the range of 3.5-5.5, the reaction temperature and time is 60.94 ℃ and 5.15 min respectively, the ratio of ¹⁷⁷Lu/PSMA(mCi/μg, 1 Ci=3.7×10¹⁰ Bq) is controlled at 1∶1-2∶1. The radiochemical purity reaches over 95%, and even up to 99%. The results of in vitro stability study show that the radiochemical purity is remained ≥95% after being incubated in saline and bovine serum at 37 ℃ for 24 h. So that the solution of ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA is used for imaging study directly without further purification. The lipid-water partition coefficient of ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA is -2.02, indicate that it is more lipophilic than ［¹⁷⁷Lu］Lu-PSMA-I&T. Preliminary SPECT/CT studies reveal that ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA is mainly metabolized through kidneys. Compared with images of ［¹⁷⁷Lu］Lu-PSMA-I&T, higher uptake in prostate tumors and lower uptake in the kidneys are displayed. After 72 h, ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA demonstrates longer retension in tumor than ［¹⁷⁷Lu］-PSMA-I&T, but also displays longer retention in the body. These results demonstrate the potential of ［¹⁷⁷Lu］Lu-DOTA-CPN-PSMA as a candidate for the treatment of prostate cancer and it is worth further study.