Refined Chelator Spacer Moieties Ameliorate the Pharmacokinetics of PSMA-617

Prostate-specific membrane antigen (PSMA) binding tracers are promising agents for the targeting of prostate tumors. To further optimize the clinically established radiopharmaceutical PSMA-617, novel PSMA ligands for prostate cancer endoradiotherapy were developed. A series of PSMA binding tracers that comprise a benzyl group at the chelator moiety were obtained by solid-phase synthesis. The compounds were labeled with (68)Ga or (177)Lu. Competitive cell-binding assays and internalization assays were performed using the cell line C4-2, a subline of the PSMA positive cell line LNCaP (human lymph node carcinoma of the prostate). Positron emission tomography (PET) imaging and biodistribution studies were conducted in a C4-2 tumor bearing BALB/c nu/nu mouse model. All (68)Ga-labeled ligands were stable in human serum over 2 h; (177)Lu-CA030 was stable over 72 h. The PSMA ligands revealed inhibition potencies [K(i)] (equilibrium inhibition constants) between 4.8 and 33.8 nM. The percentage of internalization of the injected activity/10(6) cells of (68)Ga-CA028, (68)Ga-CA029, and (68)Ga-CA030 was 41.2 ± 2.7, 44.3 ± 3.9, and 53.8 ± 5.4, respectively; for the comparator (68)Ga-PSMA-617, 15.5 ± 3.1 was determined. Small animal PET imaging of the compounds showed a high tumor-to-background contrast. Organ distribution studies revealed high specific uptake in the tumor, that is, approximately 34.4 ± 9.8% of injected dose per gram (%ID/g) at 1 h post injection for (68)Ga-CA028. At 1 h p.i., (68)Ga-CA028 and (68)Ga-CA030 demonstrated lower kidney uptake than (68)Ga-PSMA-617, but at later time points, kidney time–activity curves converge. In line with the preclinical data, first diagnostic PET imaging using (68)Ga-CA028 and (68)Ga-CA030 revealed high-contrast detection of bone and lymph node lesions in patients with metastatic prostate cancer. The novel PSMA ligands, in particular CA028 and CA030, are promising agents for targeting PSMA-positive tumor lesions as shown in the preclinical evaluation and in a first patient, respectively. Thus, clinical translation of (68)Ga-CA028 and (68)Ga/(177)Lu-CA030 for diagnostics and endoradiotherapy of prostate cancer in larger cohorts of patients is warranted.