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 ⁶⁸Ga-based PET and ¹⁷⁷Lu-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 ^natGa-/^natLu-PSMA I&T was determined in a competitive binding assay using LNCaP cells. Internalization kinetics of ⁶⁸Ga- and ¹⁷⁷Lu-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 ⁶⁸Ga-PSMA I&T, as well as endoradiotherapeutic treatment of 2 patients with metastatic PC using ¹⁷⁷Lu-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 ⁶⁸Ga^III and ¹⁷⁷Lu^III. Uptake of ⁶⁸Ga-/¹⁷⁷Lu-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 ⁶⁸Ga-PSMA I&T PET imaging allowed high-contrast detection of bone lesions, lymph node, and liver metastases. Endoradiotherapy with ¹⁷⁷Lu-PSMA I&T in 2 patients was found to be effective and safe with no detectable side effects. Conclusion: ⁶⁸Ga-PSMA I&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.

Aim: The objective of this study was to analyze the safety and efficacy of ¹⁷⁷Lu-labeled DOTAGA-based prostate specific membrane antigen (PSMA) ligand ¹⁷⁷Lu-DOTAGA-(I-y)fk(Sub-KuE) (¹⁷⁷Lu-PSMA) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Fifty-six mCRPC patients underwent PSMA radioligand therapy (RLT) with ¹⁷⁷Lu-PSMA. ⁶⁸Ga-PSMA-HBED-CC (⁶⁸Ga-PSMA) PET/CT was used for patient selection and follow-up after PSMA-RLT. Hematological status, renal function and serum prostate specific antigen (PSA) levels were documented before and after therapy. Dosimetry was performed in 30 patients. Results: ¹⁷⁷Lu-PSMA demonstrated high absorbed tumor doses (median, 3.3 mGy/MBq) as compared to normal organs. Parotid glands received higher doses (1.3 mGy/MBq) than kidneys (0.8 mGy/MBq). All patients tolerated the therapy without any acute adverse effects. Except mild reversible xerostomia in two patients, no long-term side effect was observed. There was a small, but statistically significant reduction in erythrocyte and leukocyte counts, of which only the erythrocytes decreased slightly below the normal range. No thrombocytopenia occurred. The severity of pain significantly reduced in 2/6 (33.33%) patients. Decrease in PSA was noted in 45/56 (80.3%) patients. In 25 patients, followed up at least 6 months after ≥2 PSMA-RLT cycles, molecular response evaluation (⁶⁸Ga-PSMA PET/CT) revealed partial remission (PR) in 14, stable disease (SD) in 2 and progressive disease (PD) in 9 patients. Contrast-enhanced CT exhibited PR in 5, SD in 13, and PD in 7 patients. The median progression-free survival was 13.7 months, and the median overall survival was not reached at follow-up of 28 months. Conclusion: PSMA-RLT with ¹⁷⁷Lu-PSMA is feasible, safe and effective in end-stage progressive mCRPC with appropriate selection and follow-up of patients by ⁶⁸Ga-PSMA PET/CT applying the concept of Theranostics.

The chemokine receptor CXCR4 is a key factor for tumor growth and metastasis in several types of human cancer. Based on promising experiences with a radio-labelled CXCR4 ligand (⁶⁸Ga-pentixafor) for diagnostic receptor targeting, ¹⁷⁷Lu-/⁹⁰Ypentixather were recently developed as endoradiotherapeutic vectors. Here, we summarize the first–in-man experience in three heavily pretreated patients with intra- and extensive extramedullary manifestations of multiple myeloma undergoing CXCR4-directed endoradiotherapy. CXCR4-target expression was demonstrated by baseline ⁶⁸Ga-pentixafor-PET. Each treatment was approved by the clinical ethics committee. Pre-therapeutic ¹⁷⁷Lu-pentixather dosimetry was performed prior to ¹⁷⁷Lu-pentixather-/⁹⁰Y-pentixather-treatment. Subsequently, patients underwent additional chemotherapy and autologous stem cell transplantation (SCT) for bone marrow rescue. Remarkable therapeutic effect was visualized in two patients showing significant reduction of ¹⁸F-FDG-uptake. CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous SCT, especially for patients with advanced multiple myeloma

The overexpression of the chemokine receptor CXCR4 plays an important role in oncology, since together with its endogenous ligand, the stromal cell–derived factor (SDF1-α), CXCR4 is involved in tumor development, growth, and organ-specific metastasis. As part of our ongoing efforts to develop highly specific CXCR4-targeted imaging probes and with the aim to assess the suitability of this ligand for first proof-of-concept studies in humans, we further evaluated the new ⁶⁸Ga-labeled high-affinity cyclic CXCR4 ligand, ⁶⁸Ga-CPCR4-2 (cyclo(D-Tyr¹-[NMe]-D-Orn²-[4-(aminomethyl) benzoic acid,⁶⁸Ga-DOTA]-Arg³-2-Nal⁴-Gly⁵)). Methods: Additional biodistribution and competitions studies in vivo, dynamic PET studies, and investigations on the metabolic stability and plasma protein binding were performed in nude mice bearing metastasizing OH1 human small cell lung cancer xenografts. CXCR4 expression on OH1 tumor sections was determined by immunohistochemical staining. Results: ^natGa-CPCR4-2 exhibits high CXCR4 affinity with a half maximum inhibitory concentration of 4.99 ± 0.72 nM. ⁶⁸Ga-CPCR4-2 showed high in vivo stability and high and specific tumor accumulation, which was reduced by approximately 80% in competition studies with AMD3100. High CXCR4 expression in tumors was confirmed by immunohistochemical staining. ⁶⁸Ga-CPCR4-2 showed low uptake in nontumor tissue and particularly low kidney accumulation despite predominant renal excretion, leading to high-contrast delineation of tumors in small-animal PET studies. Conclusion: The small and optimized cyclic peptide CPCR4-2 labeled with ⁶⁸Ga is a suitable tracer for targeting and imaging of human CXCR4 receptor expression in vivo. The high affinity for CXCR4, its in vivo stability, and the excellent pharmacokinetics recommend the further evaluation of ⁶⁸Ga-CPCR4-2 in a proof-of-concept study in humans.