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- Document type:
- Journal Article; Research Support, Non-U.S. Gov't
- Author(s):
- Weineisen, Martina; Schottelius, Margret; Simecek, Jakub; Baum, Richard P; Yildiz, Akin; Beykan, Seval; Kulkarni, Harshad R; Lassmann, Michael; Klette, Ingo; Eiber, Matthias; Schwaiger, Markus; Wester, Hans-Jürgen
- Title:
- 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies.
- Abstract:
- On the basis of the high and consistent expression of prostate-specific membrane antigen (PSMA) in metastatic prostate cancer (PC), the goal of this study was the development, preclinical evaluation, and first proof-of-concept investigation of a PSMA inhibitor for imaging and therapy (PSMA I&T) for (68)Ga-based PET and (177)Lu-based endoradiotherapeutic treatment in patients with metastatic and castration-resistant disease.PSMA I&T was synthesized in a combined solid phase and solution chemistry strategy. The PSMA affinity of (nat)Ga-/(nat)Lu-PSMA I&T was determined in a competitive binding assay using LNCaP cells. Internalization kinetics of (68)Ga- and (177)Lu-PSMA I&T were investigated using the same cell line, and biodistribution studies were performed in LNCaP tumor-bearing CD-1 nu/nu mice. Initial human PET imaging studies using (68)Ga-PSMA I&T, as well as endoradiotherapeutic treatment of 2 patients with metastatic PC using (177)Lu-PSMA I&T, were performed.PSMA I&T and its cold gallium and lutetium analog revealed nanomolar affinity toward PSMA. The DOTAGA (1,4,7,10-tetraazacyclododecane-1-(glutamic acid)-4,7,10-triacetic acid) conjugate PSMA I&T allowed fast and high-yield labeling with (68)Ga(III) and (177)Lu(III). Uptake of (68)Ga-/(177)Lu-PSMA I&T in LNCaP tumor cells is highly efficient and PSMA-specific, as demonstrated by competition studies both in vitro and in vivo. Tumor targeting and tracer kinetics in vivo were fast, with the highest uptake in tumor xenografts and kidneys (both PSMA-specific). First-in-human (68)Ga-PSMA I&T PET imaging allowed high-contrast detection of bone lesions, lymph node, and liver metastases. Endoradiotherapy with (177)Lu-PSMA I&T in 2 patients was found to be effective and safe with no detectable side effects.(68)Ga-PSMA I&T shows potential for high-contrast PET imaging of metastatic PC, whereas its (177)Lu-labeled counterpart exhibits suitable targeting and retention characteristics for successful endoradiotherapeutic treatment. Prospective studies on larger cohorts of patients are warranted and planned.
- Journal title abbreviation:
- J Nucl Med
- Year:
- 2015
- Journal volume:
- 56
- Journal issue:
- 8
- Pages contribution:
- 1169-76
- Language:
- eng
- Fulltext / DOI:
- doi:10.2967/jnumed.115.158550
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/26089548
- Print-ISSN:
- 0161-5505
- TUM Institution:
- Klinik und Poliklinik für Nuklearmedizin
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