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.

Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-68Ga-DOTAGA (68Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated. Methods Five patients with a history of prostate cancer were injected intravenously with 91–148 MBq of 68Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. Results Injection of 150 MBq of 68Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy). Conclusion 68Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by 18F-FDG.

Purpose: Based on the clinical relevance of the chemokine receptor 4 (CXCR4) as a molecular target in cancer and on the success of [68Ga]pentixafor as an imaging probe for high-contrast visualization of CXCR4-expression, the spectrum of clinical CXCR4-targeting was expanded towards peptide receptor radionuclide therapy (PRRT) by the development of [177Lu]pentixather.Experimental design: CXCR4 affinity, binding specificity, hCXCR4 selectivity and internalization efficiency of [177Lu]pentixather were evaluated using different human and murine cancer cell lines. Biodistribution studies (1, 6, 48, 96h and 7d p.i.) and in vivo metabolite analyses were performed using Daudi-lymphoma bearing SCID mice. Extrapolated organ doses were cross-validated with human dosimetry (pre-therapeutic and during [177Lu]pentixather PRRT) in a patient with multiple myeloma (MM).Results: [177Lu]pentixather binds with high affinity, specificity and selectivity to hCXCR4 and shows excellent in vivo stability. Consequently, and supported by >96% plasma protein binding and a logP=-1.76, delaying whole-body clearance of [177Lu]pentixather, tumor accumulation was high and persistent, both in the Daudi model and the MM patient. Tumor/background ratios (7d p.i.) in mice were 499±202, 33±7, 4.0±0.8 and 116±22 for blood, intestine, kidney and muscle, respectively. In the patient, high tumor/kidney and tumor/liver dose ratios of 3.1 and 6.4 were observed during [177Lu]pentixather PRRT (7.8 GBq), with the kidneys being the dose-limiting organs.Conclusions: [177Lu]pentixather shows excellent in vivo CXCR4-targeting characteristics and a suitable pharmacokinetic profile, leading to high tumor uptake and retention and thus high radiation doses to tumor tissue during PRRT, suggesting high clinical potential of this [68Ga]pentixafor/[177Lu]pentixather based CXCR4-targeted theranostic concept.

Preclinical and preliminary clinical evidence indicates that radiolabeled somatostatin (sst) receptor antagonists perform better than agonists in detecting neuroendocrine tumors (NETs). We performed a prospective phase I/II study to evaluate the sst receptor antagonist Ga-OPS202 (Ga-NODAGA-JR11; NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid and JR11 = Cpa-c(dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys)-dTyr-NH)) for PET imaging. Here, we report the results of phase I of the study. Patients received 2 single 150-MBq intravenous injections ofGa-OPS202 3-4 wk apart (15 μg of peptide at visit 1 and 50 μg at visit 2). At visit 1, a dynamic PET/CT scan over the kidney was obtained during the first 30 min after injection, and static whole-body scans were obtained at 0.5, 1, 2, and 4 h after injection; at visit 2, a static whole-body scan was obtained at 1 h. Blood samples and urine were collected at regular intervals to determine Ga-OPS202 pharmacokinetics. Safety, biodistribution, radiation dosimetry, and the most appropriate imaging time point forGa-OPS202 were assessed. Twelve patients with well-differentiated gastroenteropancreatic (GEP) NETs took part in the study.Ga-OPS202 cleared rapidly from the blood, with a mean residence time of 2.4 ± 1.1 min/L. The organs with the highest mean dose coefficients were the urinary bladder wall, kidneys, and spleen. The calculated effective dose was 2.4E-02 ± 0.2E-02 mSv/MBq, corresponding to 3.6 mSv, for a reference activity of 150 MBq. Based on total numbers of detected malignant lesions, the optimal time window for the scan was between 1 and 2 h. For malignant liver lesions, the time point at which most patients had the highest mean tumor contrast was 1 h. Ga-OPS202 was well tolerated; adverse events were grade 1 or 2, and there were no signals of concern from laboratory blood or urinalysis tests.Ga-OPS202 showed favorable biodistribution and imaging properties, with optimal tumor contrast between 1 and 2 h after injection. Dosimetry analysis revealed that the dose delivered by Ga-OPS202 to organs is similar to that delivered by otherGa-labeled sst analogs. Further evaluation of Ga-OPS202 for PET/CT imaging of NETs is therefore warranted.

Purpose The aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined. Methods Several conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed. Results Quantitative labeling yields could be achieved with >97 % radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv. Conclusion 18F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible.