On the basis of the high and consistent expression of prostatespecific 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. Methods: 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. Results: 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. Conclusion: 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.

Chemokine ligand-receptor interactions play a pivotal role in cell attraction and cellular trafficking, both in normal tissue homeostasis and in disease. In cancer, chemokine receptor-4 (CXCR4) expression is an adverse prognostic factor. Early clinical studies suggest that targeting CXCR4 with suitable high-affinity antagonists might be a novel means for therapy. In addition to the preclinical evaluation of [68Ga]Pentixafor in mice bearing human lymphoma xenografts as an exemplary CXCR4-expressing tumor entity, we report on the first clinical applications of [68Ga]Pentixafor-Positron Emission Tomography as a powerful method for CXCR4 imaging in cancer patients. [68Ga]Pentixafor binds with high affinity and selectivity to human CXCR4 and exhibits a favorable dosimetry. [68Ga]Pentixafor-PET provides images with excellent specificity and contrast. This non-invasive imaging technology for quantitative assessment of CXCR4 expression allows to further elucidate the role of CXCR4/CXCL12 ligand interaction in the pathogenesis and treatment of cancer, cardiovascular diseases and autoimmune and inflammatory disorders.

A veritable gallium TRAP: Triazacyclononane‐phosphinic acid chelators (TRAP) form highly stable complexes with Ga3+ (see figure) extremely efficiently over a wide pH range. Homo‐ and heteromultimeric bioconjugates can be synthesized in a straightforward manner, all of which renders TRAP a chelator with ideal properties for 68Ga positron emission tomography (PET) imaging agent elaboration.