TY - JOUR T1 - <sup>68</sup>Ga- and <sup>177</sup>Lu-Labeled PSMA I&amp;T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1169 LP - 1176 DO - 10.2967/jnumed.115.158550 VL - 56 IS - 8 AU - Martina Weineisen AU - Margret Schottelius AU - Jakub Simecek AU - Richard P. Baum AU - Akin Yildiz AU - Seval Beykan AU - Harshad R. Kulkarni AU - Michael Lassmann AU - Ingo Klette AU - Matthias Eiber AU - Markus Schwaiger AU - Hans-Jürgen Wester Y1 - 2015/08/01 UR - http://jnm.snmjournals.org/content/56/8/1169.abstract N2 - 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&amp;T) for 68Ga-based PET and 177Lu-based endoradiotherapeutic treatment in patients with metastatic and castration-resistant disease. Methods: PSMA I&amp;T was synthesized in a combined solid phase and solution chemistry strategy. The PSMA affinity of natGa-/natLu-PSMA I&amp;T was determined in a competitive binding assay using LNCaP cells. Internalization kinetics of 68Ga- and 177Lu-PSMA I&amp;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 68Ga-PSMA I&amp;T, as well as endoradiotherapeutic treatment of 2 patients with metastatic PC using 177Lu-PSMA I&amp;T, were performed. Results: PSMA I&amp;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&amp;T allowed fast and high-yield labeling with 68GaIII and 177LuIII. Uptake of 68Ga-/177Lu-PSMA I&amp;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 68Ga-PSMA I&amp;T PET imaging allowed high-contrast detection of bone lesions, lymph node, and liver metastases. Endoradiotherapy with 177Lu-PSMA I&amp;T in 2 patients was found to be effective and safe with no detectable side effects. Conclusion: 68Ga-PSMA I&amp;T shows potential for high-contrast PET imaging of metastatic PC, whereas its 177Lu-labeled counterpart exhibits suitable targeting and retention characteristics for successful endoradiotherapeutic treatment. Prospective studies on larger cohorts of patients are warranted and planned. ER -