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.

After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life. OBJECTIVE AND INTERVENTION: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) 131I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured. The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 +/- 7 vs. 18 +/- 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group. This study demonstrates comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.

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