Refined chelator spacer moieties ameliorate the pharmacokinetics of PSMA-617
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 were 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). Positron emission tomography (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, that is, approximately 34.4 ± 9.8% 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
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Anmerkungen
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Frontiers in chemistry. - 10 (2022) , 898692, ISSN: 2296-2646
- Ereignis
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Veröffentlichung
- (wo)
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Freiburg
- (wer)
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Universität
- (wann)
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2022
- Urheber
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Santos, José Carlos dos
Schäfer, Martin
Bauder-Wüst, Ulrike
Beijer, Barbro
Eder, Matthias
Leotta, Karin
Kleist, Christian
Meyer, Jan-Philip
Dilling, Thomas R.
Lewis, Jason S.
Kratochwil, Clemens
Kopka, Klaus
Haberkorn, Uwe
Mier, Walter
- DOI
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10.3389/fchem.2022.898692
- URN
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urn:nbn:de:bsz:25-freidok-2291260
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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25.03.2025, 13:52 MEZ
Datenpartner
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Beteiligte
- Santos, José Carlos dos
- Schäfer, Martin
- Bauder-Wüst, Ulrike
- Beijer, Barbro
- Eder, Matthias
- Leotta, Karin
- Kleist, Christian
- Meyer, Jan-Philip
- Dilling, Thomas R.
- Lewis, Jason S.
- Kratochwil, Clemens
- Kopka, Klaus
- Haberkorn, Uwe
- Mier, Walter
- Universität
Entstanden
- 2022