68Ga-PET: a powerful generator-based alternative to cyclotron-based PET radiopharmaceuticals

PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short-lived positron emitting isotopes. The most commonly used are accelerator-produced 11C and 18F. An alternative is the use of metallic positron emitters. Among them 68Ga deserves special attention because of its availability from long-lived 68Ge/68Ga generator systems which render 68Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga3+ is dominated by its hard acid character. A variety of mono- and bifunctional chelators have been developed which allow the formation of stable 68 Ga3+ complexes and convenient coupling to biomolecules. 68Ga coupling to small biomolecules is potentially an alternative to 18F- and 11C-based radiopharmacy. In particular, peptides targeting G-protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit-formulated precursors along with the generator may be provided, similar to the 99Mo/99mTc-based radiopharmacy, still the mainstay of nuclear medicine

Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy

Purpose: Targeting of tumours positive for somatostatin receptors (sst) with radiolabelled peptides is of interest for tumour localization, staging, therapy follow-up and targeted radionuclide therapy. The peptides used clinically are exclusively agonists, but recently we have shown that the radiolabelled somatostatin-based antagonist 111In-DOTA-sst2-ANT may be preferable to agonists. However, a comprehensive study of this radiolabelled antagonist to determine its significance was lacking. The present report describes the evaluation of this novel antagonist labelled with 111In and 177Lu in three different tumour models. Methods: Radiopeptide binding, internalization and dissociation studies were performed using cells expressing HEK293-rsst2. Biodistribution studies were performed in HEK293-rsst2, HEK293-hsst2 and HEK293-rsst3 xenografted mice. Results: Saturation binding analysis confirmed earlier IC50 data for 111/natIn-DOTA-sst2-ANT and showed similar affinity of 177/natLu-DOTA-sst2-ANT for the sst2. Only low internalization was found in cell culture (6.68 ± 0.06% at 4h), which was not unexpected for an antagonist, and this could be further reduced by the addition of sucrose. No internalization was observed in HEK293 cells not expressing sst. Both results indicate that the internalization was specific. 111In-DOTA-sst2-ANT and 177Lu-DOTA-sst2-ANT were shown to target tumour xenografts expressing the rat and the human sst2 receptor with no differences in their uptake or pharmacokinetics. The uptake in rsst2 and hsst2 was high (about 30 %IA/g 4h after injection) and surprisingly long-lasting (about 20-23 %IA/g 24h after injection). Kidney uptake was blocked by approximately 50% by lysine or Gelofusine. Conclusion: These results indicate that radiolabelled somatostatin-based antagonists may be superior to corresponding agonists. The long tumour retention time of 177Lu-DOTA-sst2-ANT indicates that this new class of compounds is of relevance not only in diagnostic imaging but also in targeted radionuclide therapy of sst-positive tumour

Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates

Purpose: A number of 111In- and 99mTc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A 68Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of 68Ga from a generator. The aim of the study was to develop a new 68Ga-folate-based PET radiotracer. Methods: Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with 67/68Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule 111In-DTPA-folate (111In-P3139). Results: The Kd values of 67/68Ga-P3026 (4.65 ± 0.82 nM) and 67/68Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order 67/68Ga-P3026 > 67/68Ga-P1254 > 111In-P3139, while almost double cellular retention was found for 67/68Ga-P3026 and 67/68Ga-P1254, compared to 111In-P3139. The biodistribution data of 67/68Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to 111In-P3139. PET/CT images, performed with 68Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours. Conclusion: The DOTA-folate conjugates can be efficiently labelled with 68Ga in labelling yields and specific activities which allow clinical application. The characteristics of the 67/68Ga-DOTA-folates are comparable to 111In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers for FR-positive tumour

In vitro characterization of 177Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study

Purpose: 131I- and 90Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin's lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (<20min) with either 177Lu or 90Y. Materials and methods: Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. Results: The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 105 times excess of diethylenetriaminepentaacetic acid (DTPA, 37°C, 7days). Two patients with relapsed NHL were treated with 740MBq/m2 body surface 177Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314mGy. The administration of 177Lu-DOTA-rituximab was tolerated well. Conclusion: Our results show that DOTA-rituximab (4:1) can be labelled with 177Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. 177Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NH

Selection of the first 99m^{99m} Tc-Labelled somatostatin receptor subtype 2 antagonist for clinical translation : preclinical assessment of two optimized candidates

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project &ldquo;TECANT&rdquo; two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (&gt;50%, at 2 h/37 &deg;C) and lower dissociation rate (&lt;30%, at 2 h/37 &deg;C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 &micro;Sv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist

Labeling of the monoclonal antibody ant-CEA with Sm-153: radiochemical and radiobiological evaluation

In the present study the labeling of the monoclonal antibody anti-CEA and of the polyclonal human immunoglobulin Sandoglobuline with the radioisotope 153Sm has been investigated. Samarium-153 (t1/2 = 46.75 h) is mainly a beta emitter (Eβ = 227 keV), which can be used for therapeutic purposes, while its γ-ray (Eγ = 103 keV, 28%) facilitates scintigraphic imaging. Thus, monoclonal antibodies labeled with 153Sm can be used for combined radioimmunoscintigraphy and radioimmunotherapy. Labeling can be achieved using the bicyclic anhydride of DTPA (cDTPAa) as the bifunctional chelating agent, which, when conjugated to antibody molecules, can bind 153Sm. Labeling was performed with the addition of 153Sm, in the form of 153SmCl3 solution, to the Ab-DTPA immunoconjugate solution, at a pH range of 5.0-5.5. The reaction mixture was incubated at room temperature and free 153Sm was eliminated by gel filtration, in a Bio Gel P30 column. The labeling control was performed using a combination of radiochemical techniques (gel filtration, HPLC, ITLC-SG and SDS-PAGE). The factors, which possibly affect the labeling yield, have been investigated, in order to find out those which lead to a final product, obtainable in high yield and with high radiochemical purity. Optimization of factors (pH, Ab, Ab-DTPA concentration etc) leads to a labeling yield > 90%. The final product was obtained in radiochemical purity > 98%, which allows its use for in vivo studies. The anti-CEA-DTPA immunoconjugate was prepared using different concentrations of anti-CEA (3 to 15 mg/ml) and different molar ratios of anti-CEA:cDTPAa (1:3.5 to 1:45). The number of DTPA molecules attached per anti-CEA molecule (DTPA/anti-CEA) was determined and the effect of DTPA conjugation on the antibody molecule was studied with HPLC and SDS-PAGE. The number of DTPA/anti-CEA increases by increasing both the anti-CEA:cDTPAa molar ratio and the antibody concentration. It is obvious that this leads to an increase in labeling yield and in higher specific activity of the final product. However as a consequence, polymer formation takes place. The effect of DTPA conjugation on the in vivo distribution of the labeled antibody was evaluated in normal mice, where the differences in biodistribution were obvious, in cases of polymer species existence. The limitary number of DTPA/anti-CEA, in order to avoid polymer formation, is 1.5 and it corresponds to an anti-CEA concentration of 3 mg/ml and an anti-CEA:cDTPAa molar ratio of 1:10. In order to achieve a final product with high specific activity it is preferable to use 153SmCl3 solution with high specific activity. In the above maximum tolerated conditions the specific activity of the final product reached a maximum value of 1.2 mCi/mg, using 153SmCl3 solution with specific activity of 763 mCi/mg. The in vivo distribution of [153Sm]DTPA-anti-CEA was evaluated in nude mice, bearing experimental tumors, with anatomic and imaging techniques. The tumor was developed after local implantation of Colo 205 cancer cells, expressing carcinoembryonic antigen (CEA). The apparent association constant Ka of [153Sm]DTPA-anti-CEA for this cell line, as determined by Scatchard analysis, is 2 / 107 M-1. A comparative to nude mice biodistribution study was also performed in normal mice, in order to evaluate the effect of tumor existence in the antibody distribution. [153Sm]DTPA-anti-CEA showed slow blood clearance, it was concentrated mainly into the liver, spleen and lungs, while it was excreted through the kidneys. The comparative biodistribution study in normal and nude mice showed no significant differences in the radioactivity concentration levels in healthy tissues, for 4 hours to 2 days post injection. Differences were obvious from 3-5 days post injection, where the values in the above tissues where higher in nude mice compared to normal. An increase in radioactivity concentration in bones with time was also observed, where it was at the same level for the two kind of animals. [153Sm]DTPA-anti-CEA was evaluated in nude mice bearing tumors weighing 0.5 to 2.5 g. Focusing on tumor radioactivity concentration, higher concentration was observed in 0.5-0.8 g tumors compared to those of 1.5-2.5 g, 24 hours post injection. In nude mice bearing tumors of about the same weight tumor uptake increased with time, reaching a maximum value 2 days post injection. The biodistribution results agreed with scintigraphic studies performed on gamma camera. The tumor can be visualized 4-24 hours post injection, but due to the high background, it can be clearly distinguished from the other tissues 2 days post injection.Στην παρούσα εργασία μελετήθηκε η επισήμανση του μονοκλωνικού αντισώματος anti-CEA και της πολυκλωνικής ανθρώπειου ανοσοσφαιρίνης Sandoglobuline, με το ραδιοϊσότοπο 153Sm. Το σαμάριο-153 (t1/2 = 46.75 h) εκπέμπει κυρίως σωματίδια β- (Eβ = 227 keV) και μπορεί να χρησιμοποιηθεί για θεραπευτικούς σκοπούς, ενώ η ταυτόχρονη εκπομπή ακτινοβολίας-γ (Eγ = 103 keV, 28%) διευκολύνει στη λήψη σπινθηρογραφικής απεικόνισης. Γι’ αυτό, τα επισημασμένα με 153Sm μονοκλωνικά αντισώματα μπορούν να βρουν συνδυασμένη εφαρμογή στη ραδιοανοσοσπινθηρογράφηση και ραδιοανοσοθεραπεία. Για την επισήμανση χρησιμοποιείται ο δικυκλικός ανυδρίτης του DTPA (cDTPAa) ως το χηλικό μέσο διπλής δράσης, το οποίο συνδεδεμένο στα μόρια του αντισώματος, δύναται να δεσμεύσει το 153Sm. Η επισήμανση λαμβάνει χώρα με την προσθήκη του 153Sm, με τη μορφή διαλύματος 153SmCl3, στο διάλυμα του ανοσοσυμπλέγματος Ab-DTPA, σε pH στην περιοχή 5.0-5.5. Το μίγμα της αντίδρασης επωάζεται σε θερμοκρασία περιβάλλοντος και το ελεύθερο 153Sm απομακρύνεται με χρωματογραφία μοριακής διήθησης σε πηκτή, σε στήλη Bio Gel P30. Ο έλεγχος της επισήμανσης γίνεται με ένα συνδυασμό ραδιοχημικών τεχνικών (χρωματογραφία μοριακής διήθησης σε πηκτή, HPLC, ITLC-SG και SDS-PAGE). Μελετώνται οι παράγοντες οι οποίοι πιθανόν επηρεάζουν την απόδοση της επισήμανσης, ώστε να βρεθούν εκείνοι που οδηγούν σε ένα τελικό προϊόν, με μεγάλη απόδοση και υψηλή ραδιοχημική καθαρότητα. Η κατάλληλη επιλογή των παραγόντων (pH, συγκέντρωση Ab και Ab-DTPA κ.ά) οδηγεί σε απόδοση επισήμανσης > 90%. Το τελικό προϊόν παραλαμβάνεται με ραδιοχημική καθαρότητα > 98%, ποσοστό που επιτρέπει τη χρήση του σε in vivo μελέτες. Το ανοσοσύμπλεγμα anti-CEA-DTPA παρασκευάστηκε χρησιμοποιώντας διαφορετικές συγκεντρώσεις anti-CEA (3 έως 15 mg/ml) και διαφορετικές γραμμομοριακές αναλογίες anti-CEA:cDTPAa (1:3.5 έως 1:45). Προσδιορίστηκε ο αριθμός των μορίων του DTPA που συνδέονται ανά μόριο anti-CEA (DTPA/anti-CEA) και μελετήθηκε η επίδραση της σύμπλεξης του DTPA στο μόριο του αντισώματος με HPLC και SDS-PAGE. Ο αριθμός DTPA/anti-CEA αυξάνεται με την αύξηση είτε της γραμμομοριακής αναλογίας anti-CEA:cDTPAa είτε της συγκέντρωσης του αντισώματος. Είναι προφανές ότι αυτό οδηγεί σε αύξηση του ποσοστού της επισήμανσης και σε υψηλότερη ειδική ραδιενέργεια του τελικού προϊόντος. Εντούτοις, έχει ως συνέπεια το σχηματισμό πολυμερών. Η επίδραση της σύμπλεξης του DTPA στην in vivo κατανομή του επισημασμένου αντισώματος αξιολογήθηκε σε φυσιολογικούς μυς, όπου οι διαφορές στην βιοκατανομή ήταν εμφανείς, στις περιπτώσεις της παρουσίας πολυμερών. Ο οριακός αριθμός DTPA/anti-CEA, ώστε να αποφευχθεί ο σχηματισμός πολυμερών, είναι 1.5 και αντιστοιχεί σε συγκέντρωση anti-CEA 3 mg/ml και γραμμομοριακή αναλογία anti-CEA:cDTPAa 1:10. Για την παραλαβή του επισημασμένου αντισώματος με υψηλή ειδική ραδιενέργεια είναι προτιμότερο να χρησιμοποιηθεί διάλυμα 153SmCl3 με υψηλή ειδική ραδιενέργεια. Στις παραπάνω οριακές συνθήκες η ειδική ραδιενέργεια του τελικού προϊόντος φτάνει μια μέγιστη τιμή ίση με 1.2 mCi/mg, με την χρήση διαλύματος 153SmCl3 ειδικής ραδιενέργειας 763 mCi/mg. Η in vivo κατανομή του [153Sm]DTPA-anti-CEA αξιολογήθηκε με ανατομικές και απεικονιστικές τεχνικές σε άθυμους μυς, στους οποίους είχε προκληθεί πειραματικός όγκος. Ο όγκος αναπτύχθηκε μετά από τοπική εμφύτευση των καρκινικών κυττάρων Colo 205 που εκφράζουν το καρκινοεμβρυϊκό αντιγόνο (CEA). Η φαινομένη σταθερά σύνδεσης Ka του [153Sm]DTPA-anti-CEA για τη συγκεκριμένη κυτταρική σειρά, όπως αυτή υπολογίστηκε βάση της ανάλυσης Scatchard, είναι ίση με 2 / 107 M-1. Παράλληλα, με τη μελέτη βιοκατανομής στους άθυμους μυς πραγματοποιήθηκε μια συγκριτική μελέτη σε φυσιολογικούς μυς, ώστε να εκτιμηθεί η επίδραση της ύπαρξης του όγκου στην κατανομή του αντισώματος μέσα στον οργανισμό. Το [153Sm]DTPA-anti-CEA παρουσιάζει βραδεία αιματική κάθαρση, συγκεντρώνεται κυρίως στο ήπαρ, τον σπλήνα και τους πνεύμονες, ενώ απεκκρίνεται μέσω των νεφρών. Η συγκριτική μελέτη βιοκατανομής σε φυσιολογικούς και άθυμους μυς δεν έδειξε σημαντικές διαφορές στη συγκέντρωση της ραδιενέργειας στους υγιείς ιστούς, για το χρονικό διάστημα από 4 ώρες έως 2 ημέρες μετά τη χορήγηση. Διαφορές ήταν εμφανείς 3-5 ημέρες μετά τη χορήγηση, όπου οι τιμές στους προαναφερόμενους ιστούς ήταν αυξημένες στους άθυμους μυς σε σύγκριση με τους φυσιολογικούς. Παρατηρήθηκε επίσης μια σταδιακή αύξηση της ραδιενεργού συγκέντρωσης στα οστά με την πάροδο του χρόνου, η οποία βρισκόταν στα ίδια επίπεδα και για δύο είδη πειραματόζωων. Το [153Sm]DTPA-anti-CEA αξιολογήθηκε σε άθυμους μυς με όγκους από 0.5 έως 2.5 g. Εστιάζοντας στην συγκέντρωση της ραδιενέργειας στον όγκο, η υψηλότερη συγκέντρωση παρατηρήθηκε στους όγκους με βάρος 0.5-0.8 g, σε σύγκριση με τους αντίστοιχους βάρους 1.5-2.5 g, 24 ώρες μετά τη χορήγηση. Στους άθυμους μυς με όγκους περίπου ίδιου μεγέθους η πρόσληψη από τον όγκο αυξάνεται με το χρόνο, φτάνοντας μια μέγιστη τιμή 2 ημέρες μετά την χορήγηση. Τα αποτελέσματα συμφωνούν με τις σπινθηρογραφικές μελέτες σε γ-κάμερα. Ο όγκος μπορεί να διακριθεί 4-24 ώρες μετά τη χορήγηση, αλλά λόγω του υψηλού υπόβαθρου, μπορεί να διαχωριστεί ευκρινώς από τους υπόλοιπους ιστούς 2 ημέρες μετά τη χορήγηση

Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms

Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors

Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [177Lu]Lu-OPS201 Compared to the Agonist [177Lu]Lu-DOTA-TATE

Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST2) peptide agonist [177Lu]Lu-DOTA-TATE is effective and well-established. Recent studies suggest improved therapeutic efficacy using the SST2 peptide antagonist [177Lu]Lu-OPS201. However, little is known about the cellular mechanisms that lead to the observed differences. In the present in vitro study, we compared kinetic binding, saturation binding, competition binding, cellular uptake and release of [177Lu]Lu-OPS201 versus [177Lu]Lu-DOTA-TATE using HEK cells stably transfected with the human SST2. While [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE exhibited comparable affinity (KD, 0.15 &plusmn; 0.003 and 0.08 &plusmn; 0.02 nM, respectively), [177Lu]Lu-OPS201 recognized four times more binding sites than [177Lu]Lu-DOTA-TATE. Competition assays demonstrated that a high concentration of the agonist displaced only 30% of [177Lu]Lu-OPS201 bound to HEK-SST2 cell membranes; an indication that the antagonist binds to additional sites that are not recognized by the agonist. [177Lu]Lu-OPS201 showed faster association and slower dissociation than [177Lu]Lu-DOTA-TATE. Whereas most of [177Lu]Lu-OPS201 remained at the cell surface, [177Lu]Lu-DOTA-TATE was almost completely internalised inside the cell. The present data identified distinct differences between [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE regarding the recognition of receptor binding sites (higher for [177Lu]Lu-OPS201) and their kinetics (faster association and slower dissociation of [177Lu]Lu-OPS201) that explain, to a great extent, the improved therapeutic efficacy of [177Lu]Lu-OPS201 compared to [177Lu]Lu-DOTA-TATE

Evaluation of 177Lu-DOTA-sst2 antagonist versus 177Lu-DOTA-sst2 agonist binding in human cancers in vitro

Somatostatin receptor targeting of neuroendocrine tumors using radiolabeled somatostatin agonists is today an established method to image and treat cancer patients. However, in a study using an animal tumor model, somatostatin receptor antagonists were shown to label sst(2)- and sst(3)-expressing tumors in vivo better than agonists, with comparable affinity even though they are not internalized into the tumor cell. In the present study, we evaluated the in vitro binding of the antagonist (177)Lu-DOTA-pNO(2)-Phe-c (DCys-Tyr-DTrp-Lys-Thr-Cys) DTyrNH(2) ((177)Lu-DOTA-BASS) or the (177)Lu-DOTATATE agonist to sst(2)-expressing human tumor samples

New Developments in Peptide Receptor Radionuclide Therapy

Peptide Receptor Radionuclide Therapy (PRRT) is an established treatment for non-operable or metastatic neuroendocrine neoplasms that express highly and frequently somatostatin receptors. More generally, PRRT is an attractive therapy option for delivering cytotoxic radiation to tumor cells through specific binding of a radiolabeled peptide to a molecular target. The development of imaging companions gave rise to the concept of radiotheranostics, important for in vivo tumor detection, characterization, staging but also, and more importantly, for individual patient selection and treatment. The success of somatostatin receptor targeting paved the way for the clinical translation of other peptide-based radiopharmaceuticals targeting, e.g. the receptors Cholecystokinin 2 (CCK2), Gastrin Releasing Peptide (GRPR), Neurokinin-1 (NK-1) and C-X-C motif chemokine 4 (CXCR4). While historically the Auger-emitter 111In and the high-energy β--emitter 90Y were used, the vast majority of PRRT are currently performed with the medium-energy β--emitter 177Lu, while α-emitters are increasingly studied in various clinical applications.JRC.G.I.5-Advanced Nuclear Knowledg