Seizure Outcome After Surgery for MRI-Diagnosed Focal Cortical Dysplasia
Anna Willard, Ana Antonic‐Baker, Zhibin Chen, Terence J. O’Brien, Patrick Kwan, Piero Perucca
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 <sup>68</sup>Ga-based PET and <sup>177</sup>Lu-based endoradiotherapeutic treatment in patients with metastatic and castration-resistant disease. <b>Methods:</b> PSMA I&T was synthesized in a combined solid phase and solution chemistry strategy. The PSMA affinity of <sup>nat</sup>Ga-/<sup>nat</sup>Lu-PSMA I&T was determined in a competitive binding assay using LNCaP cells. Internalization kinetics of <sup>68</sup>Ga- and <sup>177</sup>Lu-PSMA I&T were investigated using the same cell line, and biodistribution studies were performed in LNCaP tumor–bearing CD-1 <i>nu/nu</i> mice. Initial human PET imaging studies using <sup>68</sup>Ga-PSMA I&T, as well as endoradiotherapeutic treatment of 2 patients with metastatic PC using <sup>177</sup>Lu-PSMA I&T, were performed. <b>Results:</b> 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 <sup>68</sup>Ga<sup>III</sup> and <sup>177</sup>Lu<sup>III</sup>. Uptake of <sup>68</sup>Ga-/<sup>177</sup>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 <sup>68</sup>Ga-PSMA I&T PET imaging allowed high-contrast detection of bone lesions, lymph node, and liver metastases. Endoradiotherapy with <sup>177</sup>Lu-PSMA I&T in 2 patients was found to be effective and safe with no detectable side effects. <b>Conclusion:</b><sup>68</sup>Ga-PSMA I&T shows potential for high-contrast PET imaging of metastatic PC, whereas its <sup>177</sup>Lu-labeled counterpart exhibits suitable targeting and retention characteristics for successful endoradiotherapeutic treatment. Prospective studies on larger cohorts of patients are warranted and planned.