Purpose: Nectin-4 is an emerging biomarker for cancer diagnosis and therapy. Recently, enfortumab vedotin (EV) was approved by the FDA as the first nectin-4 targeting antibody–drug conjugate for treating advanced urothelial carcinoma (UC). A PET imaging method to noninvasively quantify nectin-4 expression level would potentially help to select patients most likely to respond to EV and predict the response. Experimental Design: In this study, we designed a bicyclic peptide-based nectin-4 targeting radiotracer 68Ga-N188. Initially, we performed preclinical evaluations of 68Ga-N188 in UC cell lines and xenograft mouse models. Next, we performed the translational study in healthy volunteers and a pilot cohort of patients with advanced UC on uEXPLORER total-body PET/CT. Results: In the preclinical study, 68Ga-N188 showed high affinity to nectin-4, specific uptake in a nectin-4(+) xenograft mouse model, and suitable pharmacokinetic and safety profiles. In the translational study, 2 healthy volunteers and 14 patients with advanced UC were enrolled. The pharmacokinetic profile was determined for 68Ga-N188, and the nectin-4 relative expression level in different organs was quantitatively imaged. Conclusions: A clear correlation between PET SUV value and nectin-4 expression was observed, supporting the application of 68Ga-N188 PET as a companion diagnostic tool for optimizing treatments that target nectin-4. See related commentary by Jiang et al., p. 3259

Prostate-specific membrane antigen (PSMA) is a well-established biological target that is overexpressed on the surface of prostate cancer lesions. Radionuclide-labeled small-molecule PSMA inhibitors have been shown to be promising PSMA-specific agents for the diagnosis and therapy of prostate cancer. In this study, a glutamate-urea-based PSMA-targeted ligand containing an isonitrile (CNGU) was synthesized and labeled with ^99mTc to prepare [^99mTc]Tc-CNGU with a high radiochemical purity (RCP). The CNGU ligand showed a high affinity toward PSMA (K_i value is 8.79 nM) in LNCaP cells. The [^99mTc]Tc-CNGU exhibited a good stability in vitro and hydrophilicity (log P = −1.97 ± 0.03). In biodistribution studies, BALB/c nude mice bearing LNCaP xenografts showed that the complex had a high tumor uptake with 4.86 ± 1.19% ID/g, which decreased to 1.74 ± 0.90% ID/g after a pre-injection of the selective PSMA inhibitor ZJ-43, suggesting that it was a PSMA-specific agent. Micro-SPECT imaging demonstrated that the [^99mTc]Tc-CNGU had a tumor uptake and that the uptake was reduced in the image after blocking with ZJ-43, further confirming its PSMA specificity. All of the results in this work indicated that [^99mTc]Tc-CNGU is a promising PSMA-specific tracer for the imaging of prostate cancer.

Clinical trials have shown the significant efficacy of [¹⁷⁷Lu]Lu-PSMA-617 for treating prostate cancer. However, the pharmacokinetic characteristics and therapeutic performance of [¹⁷⁷Lu]Lu-PSMA-617 still need further improvement to meet clinical expectations. The aim of this study was to evaluate the feasibility and therapeutic potential of three novel ¹⁷⁷Lu-labeled ligands for the treatment of prostate cancer. The novel ligands were efficiently synthesized and radiolabeled with non-carrier added ¹⁷⁷Lu; the radiochemical purity of the final products was determined by Radio-HPLC. The specific cell-binding affinity to PSMA was evaluated in vitro using prostate cancer cell lines 22Rv1and PC-3. Blood pharmacokinetic analysis, biodistribution experiments, small animal SPCET imaging and treatment experiments were performed on normal and tumor-bearing mice. Among all the novel ligands developed in this study, [¹⁷⁷Lu]Lu-PSMA-Q showed the highest uptake in 22Rv1 cells, while there was almost no uptake in PC-3 cells. As the SPECT imaging tracer, [¹⁷⁷Lu]Lu-PSMA-Q is highly specific in delineating PSMA-positive tumors, with a shorter clearance half-life and higher tumor-to-background ratio than [¹⁷⁷Lu]Lu-PSMA-617. Biodistribution studies verified the SPECT imaging results. Furthermore, [¹⁷⁷Lu]Lu-PSMA-Q serves well as an effective therapeutic ligand to suppress tumor growth and improve the survival rate of tumor-bearing mice. All the results strongly demonstrate that [¹⁷⁷Lu]Lu-PSMA-Q is a PSMA-specific ligand with significant anti-tumor effect in preclinical models, and further clinical evaluation is worth conducting.