Somatostatin Derivatives Research Articles

225Ac-Labeled Somatostatin Analogs in the Management of Neuroendocrine Tumors: From Radiochemistry to Clinic.

The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225Ac, its physical and radiochemical properties, as well as the place of 225Ac-DOTATOC and 225Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.

225Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with 177Lu-DOTATATE (DOTA-octreotate), a β-particle-emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted α-particle therapy has been shown to kill tumors that are resistant to targeted β-particle therapy, suggesting that targeted α-particle therapy may offer a promising treatment option for patients with 177Lu-DOTATATE-resistant disease. Although DOTATATE can chelate the clinically relevant α-particle-emitting radionuclide 225Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating 225Ac at room temperature, and assessed its invitro and invivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. 225Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with 225Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of 225Ac-MACROPATATE than of 225Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that 225Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of 225Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 225Ac-DOTATATE. Conclusion: 225Ac-MACROPATATE and 225Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of 225Ac-MACROPATATE, 225Ac-DOTATATE was deemed the superior agent for targeted α-particle peptide receptor radionuclide therapy.

Synthesis, Cytotoxicity and Antioxidant Activity of New Analogs of RC-121 Synthetic Derivatives of Somatostatin.

Based on the structure of RC-121 (D-Phe-c (Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2, - synthetic derivatives of somatostatin), some analogs were synthesized and tested for in vitro cytotoxic and antioxidant activity. The new analogs were modifyed at position 5 with Dap (diaminopropanoic acid), Dab (diaminobutanoic acid) and Orn and at position 6 with the unnatural amino acids Tle (t-leucine). The in vitro cytotoxic effects of the substances were investigated against a panel of human tumor cell lines HT-29 (Human Colorectal Cancer Cell Line), MDA-MB-23 (Human Breast Cancer Cell Line), Hep G-2 (Human Hepatocellular Carcinoma Cell Line) and HeLa (cervical cancer cell line). The antioxidant capacities were tested by ORAC (Oxygen Radical Antioxidant Capacity) and HORAC (Hydroxyl Radical Averting Capacity) methods. All substances expressed significantly higher antioxidant capacity by comparison with galic acid and Trolox. All substances showed considerable antioxidant capacity as well. Compound 2T (D-Phe-c(Cys-Tyr-DTrp- Dap-Tle-Cys)-Thr-NH2)had the highest antioxidant effect. The compound 4T (D-Phe-c(Cys-Tyr-D-Trp- Orn-Tle-Cys)-Thr-NH2) displayed antiproliferative effect on HeLa cells with IC50 30 µM. The peptide analog 3T (D-Phe-c(Cys-Tyr-D-Trp-Lys-Tle-Cys)-Thr-NH2) exerted the most pronounced inhibition on the cell vitality up to 53%, 56% and 65% resp. against MDA-MB-23, Hep G-2, HeLa in the higher tested concentration. The somatostatin analogs showed moderate influence on the vitality of different tumor cells and could be used in changing their pathology.

Structural characterization of octreotide impurities by on-line electrochemistry-tandem mass spectrometry

Octreotide, an octapeptide derivative of natural somatostatin, is widely used in the treatment of the secretion of gastrointestinal cancers, pituitary tumors, and acromegaly. To prolong the drug release, octreotide is extensively encapsulated with poly (D, L-lactic-co-glycolic acid) (PLGA) microspheres. While peptide impurities may be generated during fabrication of peptide-loaded microspheres and drug delivery processes, making the identification of peptide impurities a challenging task. For structural characterization of octreotide impurities, a new method based on mass spectrometry coupled with electrochemistry (EC-MS) was developed in this study. An electrospray ionization source with a grounded needle design was chosen as the coupling interface between electrochemistry and mass spectrometry, which simplifies instrument configuration and thus operation. Without any special sample preparation and any chemical reduction agents, disulfide bond in peptides was cleaved rapidly. The de novo sequencing octreotide and three acylated octreotides were easily obtained with followed tandem mass spectrometry. The results demonstrate that this method is suitable for fast evaluation and characterization of peptide containing disulfide bonds.

Somatostatin derivative (smsDX) targets cellular metabolism in prostate cancer cells after androgen deprivation therapy.

Cancer cell metabolism responsive to androgen deprivation therapy (ADT) may be involved in the development and progression of prostate cancer and the ultimate failure of androgen-deprivation therapy. To investigate the metabolism regulation effects on androgen-independent growth of prostate cancer, an established LNCaP-s cell model that resembles the clinical scenario of castration-resistant prostate cancer (CRPC), was used in this current study. This cell line was cultured from androgen-sensitive LNCaP parental cells, in an androgen-reduced condition, resembling clinical androgen deprivation therapy. To assess the effects of smsDX on the invasiveness of prostate cancer cells we used wound healing assay and Matrigel™ invasion assay. We evaluated differentially expressed proteins of the parental LNCaP cells and LNCaP-s cells after ADT by means of two-dimensional gel electrophoresis (2-DE) followed by MALDI-TOF mass spectrometric analysis. The covered area in the wound and the number of cells invading through a Matrigel chamber were significantly smaller for cells treated with smsDX than they were for control cells treated with vehicle. 56 proteins were found differentially expressed in LNCaP-s cells compared to LNCaP cells, majority of them were down-regulated after ADT treatment. 104 proteins of LNCaP cells and 86 in LNCaP-s cells, separately, were found differentially expressed after treatment with smsDX, When we explored these protein functions within the website UniProtKB/Swiss-Prot, surprisingly, most of the proteins were found to be involved in the cellular metabolism and mitochondrial function regulation. LNCaP-s as potential metastatic androgen-independent cancer cells, its metabolism and mitochondrial functions could be altered by a new somatostatin derivative smsDX, the smsDX regulatory effects on metabolism in LNCaP-s deliver more therapeutic information with the treatment of CRPC.

Laser Heating of Gold Nanospheres Functionalized with Octreotide: In Vitro Effect on HeLa Cell Viability

The aim of this study was to assess the effect of laser heating a well-characterized gold nanoparticle (AuNP)-octreotide system on HeLa cell viability, to evaluate its potential as a suitable agent for plasmonic photothermal therapy. Octreotide is a synthetic peptide derivative of somatostatin with an effect on the survival of HeLa cells. Peptides bound to AuNPs are biocompatible and stable multimeric systems with target-specific molecular recognition. Octreotide was conjugated to AuNPs (∼20 nm) by spontaneous reaction with the thiol groups. The nanoconjugate was characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), ultraviolet visible spectroscopy (UV-Vis), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Irradiation experiments were conducted using an Nd:YAG laser pulsed for 5 ns at 532 nm with a repetition rate of 10 Hz for up to 6 min while delivering an average irradiance of 0.65 W/cm(2). HeLa cells were incubated at 37°C (1) with AuNP-citrate, (2) with AuNP-octreotide, or (3) without nanoparticles. After laser irradiation, the presence of AuNP caused a significant increase in the temperature of the medium (48°C vs. 38.3°C of that without AuNP). The AuNP-octreotide system resulted in a significant decrease in cell viability of up to 6 % compared with the AuNP-citrate system (15.8±2.1%). Two possible mechanisms could be at play: (1) octreotide alone exerts an effect on survival HeLa cells, or (2) the release of heat (∼727°C per nanoparticle) in the membranes or cytoplasm of the cells caused by the interaction between AuNP-octreotide and somatostatin receptors reduced viability. The AuNP-octreotide system exhibited properties suitable for plasmonic photothermal therapy in the treatment of cervical cancer.

Bioactive Unnatural Somatostatin Analogues through Bioorthogonal Iodo- and Ethynyl-Disulfide Intercalators

Iodo- and ethynyl-containing bisalkylating bioconjugation agents 5 and 8 were achieved and allow the introduction of reactive unnatural substituents into proteins and peptides whilst the bioactive 3D structure is retained. Derivatives of the peptide hormone somatostatin bearing a single iodo or ethynyl group were prepared through intercalation into the disulfide bridge. For the first time, the exact reaction mechanism of the intercalation was elucidated by applying 2D NMR experiments and it was shown that, during the reaction, somatostatin diastereomers were formed. Site-directed modification of the ethynyl-modified peptide with a coumarin chromophore was achieved through a [1,3] dipolar Huisgen cycloaddition reaction; this suggests that such a derivative could serve as an attractive platform to prepare artificial somatostatin compound libraries. The biological activity and specificity of a representative modified somatostatin derivative was demonstrated and efficient receptor-mediated cell uptake occurred in a dose-dependent manner into receptor positive cells only. The iodo and ethynyl bioconjugation reagents presented herein could be applied for introducing such substituents into alternative peptides and proteins and, in principle, could facilitate the efficient design of a broad variety of artificial protein and peptide analogues with previously unknown bioactivities.

Receptor-mediated tumor targeting based on peptide hormones

Importance of the field: Tumor targeting with peptides is based on the discovery that receptors for many regulatory peptides are overexpressed in tumor cells, compared with their expression in normal tissues. Consequently, these peptides and their analogues can be used as carriers/targeting moieties for the preparation of diagnostic and therapeutic agents that have increased selectivity and decreased peripheral toxicity.Areas covered in this review: Here an overview is given of the most relevant gonadotropin-releasing hormone (GnRH) and somatostatin derivatives, as well as of their applications in cancer diagnosis and therapy. For this purpose, recently published data in these areas (mostly articles published from 2000 to 2009) were reviewed.What the reader will gain: In contrast to other regulatory peptides that stimulate the tumor growth, GnRH and somatostatin derivatives have inhibitory effect; therefore, they were used primarily for the preparation of various conjugates to be used in targeted chemotherapy, targeted radiotherapy, photodynamic therapy, boron neutron capture therapy and cancer diagnosis. Some of these conjugates have already found clinical applications, whereas others are now in preclinical and clinical trials.Take home message: Tumor targeting with hormone peptides provides a basis for the development of new diagnostic and therapeutic approaches for cancer.

Synthesis and in Vitro Evaluation of a Rhenium-Cyclized Somatostatin Derivative Series

The structure-activity relationships of a series of rhenium (Re)-cyclized octreotide derivatives are described. The effects of changes in the peptide sequence, N-terminus, and C-terminus on metal cyclization, as well as binding to the somatostatin receptor, were investigated. Each peptide complex was found to have an integrated Re(V) core with a single metal oxo group, two coordination sites filled by the cysteine sulfhydryls, and another by the amide nitrogen of Phe (3)/Tyr (3). The final coordination site was determined by the peptide N-terminus: the N-terminal amine coordinated for N-NH 2 peptides and the amide nitrogen of Thr (6) for peptides with acetylated N-termini. Re-cyclization of the octreotide derivatives led to structural perturbations of the somatostatin receptor-binding sequence relative to the Re-free disulfide analogues, resulting in reduced binding affinities. The findings presented herein demonstrate the importance of understanding the consequences of structural modifications when designing metal-peptide complexes for somatostatin receptor targeting.

Investigation of new bifunctional agents: D-Penicillamine

Somatostatin inhibits the release of growth hormone (somatotropin) from the Anterior Pituitary. The main use of derivatives of somatostatin is to diagnose growth hormone problems and to use against some forms of cancer which involve growth hormone. Also somatostatin suppresses gastric acid secretion, gallbladder contractions, and pancreatic enzyme secretion. The aim of the current study is to investigate new bifunctional agents for labeling with 99mTc. Therefore D-Penicillamine was used as a bifunctional agent and compared to DTPA in the labeling with 99mTc. Quality controls were established using thin layer radio chromatography (TLRC) and electrophoresis techniques. In addition, high performance liquid radio chromatography (HPLRC) was also performed for elimination of possible uncertainties. The radiolabeled complexes maintained their stabilities throughout the study. The results obtained showed that 99mTc-D-Penicillamine-somatostatin is a promising potential radiopharm aceutical and an alternative of 99mTc-DTPA-somatostatin for in vivo and in vitro applications.

Can somatostatin derivatives really be suggested in the treatment of chylothorax?

©2007The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Can somatostatin derivatives really be suggested in the treatment of chylothorax?

Pediatric Critical Care Medicine: May 2007 - Volume 8 - Issue 3 - p 308 doi: 10.1097/01.PCC.0000262799.34181.80

Somatostatin Receptor-Binding Peptides Suitable for Tumor Radiotherapy with Re-188 or Re-186. Chemistry and Initial Biological Studies

Somatostatin derivative peptides previously designed for radiodiagnostic purposes (99mTc P829 or 99mTc depreotide) were reoptimized for radiotherapy of tumors with rhenium radioisotopes. An optimized pharmacophore peptide P1839 was derived by in vitro binding affinity assay to AR42J rat pancreatic tumor cell membranes. Peptides with chelating domains and their oxorhenium(V) complexes were tested in vitro for binding to NCI H69 human SCLC tumor membranes. Further optimization entailed radiolabeling with 99mTc and biodistribution in an AR42J xenograft mouse model. Kidney uptake was decreased substantially by removing positively charged residues. Neutral N3S diamide amine thiol chelators with no adjacent positive charges had the best overall properties. Substituting an aromatic amino acid into the chelator approximately doubled the tumor uptake. The final optimized peptide P2045 (39) radiolabeled with 99mTc exhibited increased tumor uptake ( approximately 25 %ID/g at 1.5 h), lower kidney uptake ( approximately 4.8 %ID/g at 1.5 h), and extensive urinary excretion (59 %ID at 1.5 h). Finally, comparison biodistribution studies between 99mTc and 188Re (39) showed a good correlation between the two metal complexes and demonstrated prolonged tumor retention (> or =24 h).

Design, Synthesis, and Biological Evaluation of Somatostatin-Based Radiopeptides

The prototypes for tumor targeting with radiolabeled peptides are derivatives of somatostatin. Usually, they primarily have high affinity for somatostatin receptor subtype 2 (sst2), and they have moderate affinity for sst5. We aimed at developing analogs that recognize different somatostatin receptor subtypes for internal radiotherapy in order to extend the present range of accessible tumors. We synthesized DOTA-octapeptides based on octreotide by replacing Phe3 mainly with unnatural amino acids. The affinity profile was determined by using cell lines transfected with sst1-5. Internalization was determined by using AR42J, HEK-sst3, and HEK-sst5 cell lines, and biodistribution was studied in rat tumor models. Two of the derivatives thus obtained showed an improved binding affinity profile, enhanced internalization into cells expressing sst2 and sst3, respectively, and better tumor:kidney ratios in animals.

From scinti-mammography and metabolic imaging to receptor targeted PET-new principles of breast cancer detection

Early detection of breast cancer is a prerequisite for treatment success and improvement of survival. In tumors under 10mm diameter the standard morphological methods of imaging such as sonography, mammography and MRI imaging are of lesser specificity and loose sensitivity. Under 5mm detection of breast cancer remains a chalenge. Since recent years scinti-mammography using perfusion weighted enrichment of 99m-Tc-MIBI for imaging has become a standard technique indetection of breast cancer. It is superior when ever small lesions with increased perfusion are to be expected. it is used specially in dense breast patients. Other functional methods such as F-18-FDG-PET, C-11-Methionine-PET and the use of Ga-68-Somatostatin- or Ga-68-Bombesin-PET have been discussed for the early detection and therapy control of breast cancer patents. Especially the high specific low background receptor-PET imaging exels over the standard methods because of its ability to detect lesions even below 2 mm, as it has been shown for the Ga-68-DOTA-somatostatins. Because simple exchange of the diagnostic PET isotope against a therapeutical isotope like Lu-177, Y-90, Ga-67 or Cu-67 the receptor PET is directly linked to radio-peptide therapy. As the studies of J. C. Reubi et alii have been shown several peptide receptors are expressed in breast cancer, like the sms receptors and the gastrin releasing peptide receptors (bombesin receptors). One of the most widely expressed receptors expressed in breast cancer, which tends to be relatively selective, is NPY1 receptor. Intensive work had been done on the development of peptide ligands by A. Beck-Sicklinger and her group. These new developed peptides are very promising in combination with somatostatin and bombesin derivatives. Dedicated breast pet devices in combination with these high specific tracers have great potential to open and entire new quality in early detection of breast cancer and may lead to its radiopeptide therapy.

Synthesis of trifunctional somatostatin based derivatives for improved cellular and subcellular uptake

It is now well established that the biological effects of Auger-emitting radionuclides are critically dependent on their subcellular location. Therefore, for their use in molecular imaging and targeted radionuclide therapy, attempts should be made to increase the nuclear specificity of the carriers. In the present paper the synthesis of novel trifunctional somatostatin derivatives containing a nuclear localization motif is described. These derivatives of [DOTA 0, Tyr 3]-octreotide (DOTATOC, DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) were obtained in high yields using Fmoc peptide synthesis in solid and in solution phase.

Phase I Trial on sms‐D70 Somatostatin Analogue in Advanced Prostate and Renal Cell Cancer

Plasma concentrations and tolerability of a novel somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to somatostatin receptor subtypes 2 and 5, HRPC expressing mainly somatostatin receptors 1 and 4, a somatostatin derivative based on the natural somatostatin having affinity to all five somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated derivative, somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 131I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

Antitumor activity and pharmacology of TT-232 (a novel somatostatin structural derivative) in malignant melanoma patients

3151 Background: TT-232 (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) is a structural derivative of natural signal inhibitory peptide somatostatin. It has been shown to bind to SSTR1 and 4 (somatostatin receptors) and pyruvate kinase M2 receptor, with selective anti-proliferative and anti-inflammatory properties. Methods: Patients with histologically proven metastatic malignant melanoma had been treated with 480 μg/kg TT-232, daily 4-hour infusion on days 1–7, every second week. Serum level of TT-232 has been measured with an enzyme immunoassay (ELISA) method. On days 1, 7, and 56. the following hormones were measured: FSH, LH, prolactine, TSH, fT4, oestradiole, progesterone, and testosterone Results:. Between August 2001 and September 2002 twelve patients (male:6, female:6) were enrolled in the study. The median age was 52 yrs. (range 27–72). The primary tumour localization was the following: trunk:7, head:1, ocular:1, upper extremity:1, lower extremity:2. All pts had previous surgery, 8 had radiotherapy, all received chemotherapy and 11 had immunotherapy as well. Altogether 49 cycles had been given (range 2–8, median 4). One patient had partial remission (lymphnodes) and 3 pts had stable disease (hepatic, mediastinal, rertoperitoneal lymphnodes and pulmonary metastases).Out of 343 days of treatment fever (gr.1–2) has been observed on 8 days. No other significant side effect occurred. The mean steady state concentration was 3.42 μg/mL, the mean elimination half-life was 1.71 hours and the clearence was 2.91 hours/L. The TSH level has doubled by day 7 and remained high on day 56 as well (p>0,05). Other hormones have showed no significant changes. Conclusion: TT-232 seems to be a promising new agent in the treatment of malignant melanoma with no obvious toxicity. No significant financial relationships to disclose.

Antitumor activity and pharmacology of TT-232 (a novel somatostatin structural derivative) in malignant melanoma patients

3151 Background: TT-232 (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) is a structural derivative of natural signal inhibitory peptide somatostatin. It has been shown to bind to SSTR1 and 4 (somatostatin receptors) and pyruvate kinase M2 receptor, with selective anti-proliferative and anti-inflammatory properties. Methods: Patients with histologically proven metastatic malignant melanoma had been treated with 480 μg/kg TT-232, daily 4-hour infusion on days 1–7, every second week. Serum level of TT-232 has been measured with an enzyme immunoassay (ELISA) method. On days 1, 7, and 56. the following hormones were measured: FSH, LH, prolactine, TSH, fT4, oestradiole, progesterone, and testosterone Results:. Between August 2001 and September 2002 twelve patients (male:6, female:6) were enrolled in the study. The median age was 52 yrs. (range 27–72). The primary tumour localization was the following: trunk:7, head:1, ocular:1, upper extremity:1, lower extremity:2. All pts had previous surgery, 8 had radiotherapy, all re...

Renal toxicity after radionuclide therapy.

During the past 10 years, a variety of radiolabeled monoclonal antibodies, antibody fragments, and low-molecular- weight oncophilic peptides have been used to deliver radioactivity to target cells for therapeutic purposes. The high and persistent localization of several of these radiolabeled molecules in the kidneys raised concern about potential renal radiation toxicity compromising therapeutic effectiveness. In particular, radiolabeled peptides, such as yttrium-90-labeled synthetic somatostatin analogues, have initiated a discussion on the safety profiles of the various somatostatin derivatives in recent clinical trials. In general, the toxicity risk seems to depend on the characteristics of the oncophilic molecule, such as the molecular weight, electric charges and clearance pathways as well as the chemical and physical characteristics of the applied radionuclide. Encouraging results for the prevention of radiation-induced renal damage by radiolabeled peptides have been obtained by co-infusion of positively charged amino acids. The available literature on nephrotoxicity after radiolabeled peptide therapy is reviewed, and therapeutic options that have become available as a result of greater insights into putative pathogenic mechanisms are discussed.