Cadmium, an extremely toxic heavy metal, poses significant health risks to humans. Despite persistent research efforts, the development of effective treatments for cadmium intoxication remains a challenge. This study aims to establish the chemical groundwork for improved chelation therapy options against cadmium poisoning. Herein, the coordination chemistry of a series of sulfur-rich macrocycles featuring different polyamine backbones (NO3S, TACD3S, DO4S, TRI4S, and TE4S) was investigated. Our results demonstrate that DO4S exhibits exceptional Cd2+ scavenging ability, forming the most thermodynamically stable complex among the studied chelators. The stability of the Cd2+ complexes decreases in the following order: DO4S (pCd = 19.8) >> NO3S (pCd = 11.0) similar to TRI4S (pCd = 10.9) >> TE4S (pCd = 7.8) > TACD3S (pCd = 7.3). DFT calculations demonstrated that the backbone polarization properties dictate the observed reduced stability when shifting from DO4S to the other ligands. DO4S showed superior affinity when compared to the state-of-the-art Cd2+ chelators such as EDTA (pCd = 16.7), DTPA (pCd = 17.4), and DMSA (pCd = 13.2). The findings from this study underscore the potential of the examined chelating agents, with particular reference to DO4S, paving the way for the development of advanced chelation therapies to combat cadmium poisoning.

The Cu2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV–vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV–vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+–Cu2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+ complexes in aqueous solution were investigated by UV–vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+ to Cu+ on the CV time scale. The Cu+ complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+ and Cu+ complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+.

Die diffusible Radiopeptid-Brachytherapie mit Betastrahlern ist effektiv, aber mit einer beträchtlichen Spät-Neurotoxizität behaftet. Durch die Verwendung von Alphastrahlern kann diese wesentlich vermindert werden.

Imaging plays an important role in prostate cancer (PC), including accurate evaluation of the extent of disease, assessment of sites of recurrent disease, and monitoring of response to treatment. Molecular imaging techniques are among the novel developments related to the imaging of PC, and various SPECT and PET radiopharmaceuticals are now available in clinical trials or commercially. Here we describe the preclinical and clinical use of gastrin-releasing peptide receptors as targets for the imaging of PC, with a focus on the development of PET tracers for the imaging of gastrin-releasing peptide receptor-positive tumors.

Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor.

PURPOSE:Glucagon-like peptide-1 receptor (GLP-1R) is a molecular target for imaging of pancreatic beta cells. We compared the ability of [Nle(14),Lys(40)(Ahx-NODAGA-(64)Cu)NH2]-exendin-4 ([(64)Cu]NODAGA-exendin-4) and [Nle(14),Lys(40)(Ahx-NODAGA-(68)Ga)NH2]-exendin-4 ([(68)Ga]NODAGA-exendin-4) to detect native pancreatic islets in rodents.PROCEDURES:The stability, lipophilicity and affinity of the radiotracers to the GLP-1R were determined in vitro. The biodistribution of the tracers was assessed using autoradiography, ex vivo biodistribution and PET imaging. Estimates for human radiation dosimetry were calculated.RESULTS:We found GLP-1R-specific labelling of pancreatic islets. However, the pancreas could not be visualised in PET images. The highest uptake of the tracers was observed in the kidneys. Effective dose estimates for [(64)Cu]NODAGA-exendin-4 and [(68)Ga]NODAGA-exendin-4 were 0.144 and 0.012 mSv/MBq, respectively.CONCLUSION:[(64)Cu]NODAGA-exendin-4 might be more effective for labelling islets than [(68)Ga]NODAGA-exendin-4. This is probably due to the lower specific radioactivity of [(68)Ga]NODAGA-exendin-4 compared to [(64)Cu]NODAGA-exendin-4. The radiation dose in the kidneys may limit the use of [(64)Cu]NODAGA-exendin-4 as a clinical tracer.

Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors (pNET), we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy.

Gastrin releasing peptide (GRP) is a regulatory peptide that acts through its receptor (GRPR) to regulate physiological functions in various organs. GRPR is overexpressed in neoplastic cells of most prostate cancers and some renal cell cancers and in the tumoral vessels of urinary tract cancers. Thus, targeting these tumours with specifically designed GRP analogues has potential clinical application. Potent and specific radioactive, cytotoxic or nonradioactive GRP analogues have been designed and tested in various animal tumour models with the aim of receptor targeting for tumour diagnosis or therapy. All three categories of compound were found suitable for tumour targeting in animal models. The cytotoxic and nonradioactive GRP analogues have not yet shown convincing tumour-reducing effects in human trials; however, the first clinical studies of radioactive GRP analogues--both agonists and antagonists--suggest promising opportunities for both diagnostic tumour imaging and radiotherapy of prostate and other GRPR-expressing cancers.

The objective of this article is to present a new method for the diagnosis of insulinoma with the use of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4.

PURPOSE:Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 (111)In-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides.METHODS:Two CCK8-based peptides and ten gastrin-based peptide analogues were tested. All peptides were conjugated with DOTA and labelled with (111)In. Biodistribution studies were performed in mice with subcutaneous CCK2/gastrin receptor-expressing tumours and with receptor-negative tumours contralaterally. Biodistribution was studied by counting dissected tissues at 1 and 4 h after injection.RESULTS:Both the CCK analogues displayed relatively low tumour uptake (approximately 2.5%ID/g) as compared to minigastrin analogues. Two linear minigastrin peptides (MG0 and sargastrin) displayed moderate tumour uptake at both 1 and 4 h after injection, but also very high kidney uptake (both higher than 48%ID/g). The linear MG11, lacking the penta-Glu sequence, showed lower tumour uptake and also low kidney uptake. Varying the N-terminal Glu residues in the minigastrin analogues led to improved tumour targeting properties, with PP-F11 displaying the optimal biodistribution. Besides the monomeric linear peptides, a cyclized peptide and a divalent peptide were tested.CONCLUSION:Based on these studies, optimal peptides for peptide receptor radionuclide targeting of CCK2/gastrin receptor-expressing tumours were the linear minigastrin analogue with six D-Glu residues (PP-F11), the divalent analogue MGD5 and the cyclic peptide cyclo-MG1. These peptides combined high tumour uptake with low kidney retention, and may therefore be good candidates for future clinical studies.

Complete surgical resection beyond tumor margins cannot be achieved in glioblastoma multiforme (GBM) because of infiltrative nature. In several cancers, neoadjuvant treatment has been implemented to reduce the risk of tumor cell spreading during resection. In GBM, the objective of a neoadjuvant approach is reduction of tumor cells within the main tumor mass and beyond in the infiltration zone. Such an approach can only be performed if elevated intracranial pressure can be medically controlled. In a previous study with recurrent gliomas, we showed that local intratumoral injection of radiolabeled DOTAGA–substance P substantially inhibited further growth and led to radionecrotic transformation of the tumor (CCR 2006). We have now examined this modality as neoadjuvant treatment for GBM, primarily assessing feasibility, toxicity, the extent of resection, and functional outcome. After diagnosis of GBM, 17 patients were included in a prospective phase I study. Repetitive intratumoral injections of radiolabeled DOTAGA–substance P were performed, followed by surgical resection. Chemical synthesis, radiolabeling, and local injection of the peptidic vector [90Yttrium]-DOTAGA–substance P were described previously. Neoadjuvant injection of [90Y]-DOTAGA–substance P was feasible without decompensation of intracranial pressure. Prolonged application of corticosteroids was identified as the main risk factor for side effects. Fifteen patients stabilized or improved their functional status. The mean extent of resection in subsequent surgery was 96%. Neoadjuvant therapy of GBM using locally injected radiolabeled DOTAGA–substance P was feasible and of low toxicity. The high extent of resection and concomitant irradiation of tumor cells in the infiltration zone may be prognostically relevant.

The precise localization of some insulinomas with the use of conventional imaging techniques is a challenging clinical problem. These findings indicate that GLP-1–receptor scanning may offer a new ...

The aim of this study was to determine the inter- and intrapatient variability of absorbed dose to the whole body, kidneys, and tumor, as well as the question of whether the first therapy could serve as a guide for future therapies. Fifty (50) (90)Y-DOTATOC therapies were given to 30 patients diagnosed with refractory stage IV neuroendocrine tumors (20 patients received two therapies, 10 patients received one therapy). The first and second therapies were delivered at standard intervals. (90)Y-activity was prescribed by surface area (3.7 GBq/m(2)), and approximately 100 MBq (111)In-DOTATOC was administered concurrently for imaging purposes. Amino acid coadministration for renal protection was performed. Measurements of activity in whole-body and single-photon emission computed tomography images were acquired at various time points after the administration of the radiopharmaceutical. The dosimetry for whole body, kidneys, and tumor was based on these data. The interpatient variability (the ratio of the maximum absorbed dose per injected activity for all patients) was larger than the intrapatient variability (the ratio of absorbed dose per injected activity for subsequent therapies in the same patient for whole body, kidneys, and tumor. These results imply that the first therapy could serve as a guide for future therapies. This approach might allow for targeted radionuclide therapy to be delivered by prescribed absorbed dose, rather than by administered activity.

Substance P is the main ligand of neurokinin type 1 (NK-1) receptors, which are consistently overexpressed in malignant gliomas. The peptidic vector 111In/90Y-DOTAGA-substance P binds to these receptors and can be used for local treatment of brain tumours. Dosimetry for this interstitial brachytherapy has mainly been done using geometrical models; however, they often do not faithfully reproduce the in vivo biodistribution of radiopharmaceuticals, which is indispensable to correlate the deposited energy with clinical response. The aim of this study was to establish a reproducible dosimetry protocol for intratumoural radiopeptide therapy.

Targeting neuroendocrine tumors expressing somatostatin receptor subtypes (sst) with radiolabeled somatostatin agonists is an established diagnostic and therapeutic approach in oncology. While agonists readily internalize into tumor cells, permitting accumulation of radioactivity, radiolabeled antagonists do not, and they have not been considered for tumor targeting. The macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was coupled to two potent somatostatin receptor-selective peptide antagonists [NH 2 -CO-c(DCys-Phe-Tyr-DAgl 8 (Me,2-naphthoyl)-Lys-Thr-Phe-Cys)-OH (sst 3 -ODN-8) and a sst 2 -selective antagonist (sst 2 -ANT)], for labeling with 111/nat In. 111/nat In-DOTA-sst 3 -ODN-8 and 111/nat In-DOTA–[4-NO 2 -Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 ] ( 111/nat In-DOTA-sst 2 -ANT) showed high sst 3 - and sst 2 -binding affinity, respectively. They did not trigger sst 3 or sst 2 internalization but prevented agonist-stimulated internalization. 111 In-DOTA-sst 3 -ODN-8 and 111 In-DOTA-sst 2 -ANT were injected intravenously into mice bearing sst 3 - and sst 2 -expressing tumors, and their biodistribution was monitored. In the sst 3 -expressing tumors, strong accumulation of 111 In-DOTA-sst 3 -ODN-8 was observed, peaking at 1 h with 60% injected radioactivity per gram of tissue and remaining at a high level for >72 h. Excess of sst 3 -ODN-8 blocked uptake. As a control, the potent agonist 111 In-DOTA–[1-Nal 3 ]-octreotide, with strong sst 3 -binding and internalization properties showed a much lower and shorter-lasting uptake in sst 3 -expressing tumors. Similarly, 111 In-DOTA-sst 2 -ANT was injected into mice bearing sst 2 -expressing tumors. Tumor uptake was considerably higher than with the highly potent sst 2 -selective agonist 111 In-diethylenetriaminepentaacetic acid–[Tyr 3 ,Thr 8 ]-octreotide ( 111 In-DTPA-TATE). Scatchard plots showed that antagonists labeled many more sites than agonists. Somatostatin antagonist radiotracers therefore are preferable over agonists for the in vivo targeting of sst 3 - or sst 2 -expressing tumors. Antagonist radioligands for other peptide receptors need to be evaluated in nuclear oncology as a result of this paradigm shift.