Refined chelator spacer moieties ameliorate the pharmacokinetics of PSMA-617

• Verfasst von: Santos, José Carlos dos [VerfasserIn]
• Verfasst von: Schäfer, Martin [VerfasserIn]
• Verfasst von: Bauder-Wüst, Ulrike [VerfasserIn]
• Verfasst von: Beijer, Barbro [VerfasserIn]
• Verfasst von: Eder, Matthias [VerfasserIn]
• Verfasst von: Leotta, Karin [VerfasserIn]
• Verfasst von: Kleist, Christian [VerfasserIn]
• Verfasst von: Meyer, Jan-Philip [VerfasserIn]
• Verfasst von: Dilling, Thomas R. [VerfasserIn]
• Verfasst von: Lewis, Jason S. [VerfasserIn]
• Verfasst von: Kratochwil, Clemens [VerfasserIn]
• Verfasst von: Kopka, Klaus [VerfasserIn]
• Verfasst von: Haberkorn, Uwe [VerfasserIn]
• Verfasst von: Mier, Walter [VerfasserIn]
• Titel: Refined chelator spacer moieties ameliorate the pharmacokinetics of PSMA-617
• Verf.angabe: José Carlos dos Santos, Martin Schäfer, Ulrike Bauder-Wüst, Barbro Beijer, Matthias Eder, Karin Leotta, Christian Kleist, Jan-Philip Meyer, Thomas R. Dilling, Jason S. Lewis, Clemens Kratochwil, Klaus Kopka, Uwe Haberkorn and Walter Mier
• E-Jahr: 2022
• Jahr: 09 August 2022
• Umfang: 12 S.
• Fussnoten: Gesehen am 03.11.2022
• Titel Quelle: Enthalten in: Frontiers in Chemistry
• Ort Quelle: Lausanne : Frontiers Media, 2013
• Jahr Quelle: 2022
• Band/Heft Quelle: 10(2022), Artikel-ID 898692, Seite 1-12
• ISSN Quelle: 2296-2646
• DOI: doi:10.3389/fchem.2022.898692
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1820701417
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

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 was obtained by solid-phase synthesis. The compounds were labeled with 68Ga or 177Lu. 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). PET-imaging and biodistribution studies were conducted in a C4-2 tumor bearing BALB/c nu/nu mouse model. All 68Ga-labeled ligands were stable in human serum over 2 h; 177Lu-CA030 was stable over 72 h. The PSMA ligands revealed inhibition potencies [Ki] (equilibrium inhibition constants) between 4.8 and 33.8 nM. The percentage of internalization of the injected activity/106 cells of 68Ga-CA028, 68Ga-CA029 and 68Ga-CA030 was 41.2 ± 2.7, 44.3 ± 3.9 and 53.8 ± 5.4 respectively; for the comparator 68Ga-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, i.e. approximately 34.4 ± 9.8 percentage of injected dose per gram (%ID/g) at 1 h post injection for 68Ga-CA028. At 1 h p.i. 68Ga-CA028 and 68Ga-CA030 demonstrated lower kidney uptake than 68Ga-PSMA-617, but at later time-points kidney time-activity-curves converge. In line with the preclinical data, first diagnostic PET imaging using 68Ga-CA028 and 68Ga-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 68Ga-CA028 and 68Ga/177Lu-CA030 for diagnostics and endoradiotherapy of prostate cancer in larger cohorts of patients is warranted.