RT Journal Article
SR Electronic
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
FD Society of Nuclear Medicine
SP 1169
OP 1176
DO 10.2967/jnumed.115.158550
VO 56
IS 8
A1 Martina Weineisen
A1 Margret Schottelius
A1 Jakub Simecek
A1 Richard P. Baum
A1 Akin Yildiz
A1 Seval Beykan
A1 Harshad R. Kulkarni
A1 Michael Lassmann
A1 Ingo Klette
A1 Matthias Eiber
A1 Markus Schwaiger
A1 Hans-Jürgen Wester
YR 2015
UL http://jnm.snmjournals.org/content/56/8/1169.abstract
AB 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.