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Parus J.L.,Radioisotope Center | Mikolajczak R.,Radioisotope Center
Current Topics in Medicinal Chemistry | Year: 2012

The paper focuses on the β-emitting radionuclides which might be useful for peptide receptor radionuclide therapy, PRRT. For the effective design of the radiopharmaceutical, the choice of radionuclide will depend on the purpose for which the radioligand is being used and on the physicochemical properties of the radionuclide. The important factor is also the availability and the cost of production. The physical characteristics of several radionuclides which are currently used or can be considered as potential candidates for PRRT is provided, followed by short description of production methods and chemical aspects of their use in preparation of peptide-based radiopharmaceuticals. Somatostatin analogues labeled with radionuclides have been a successful example of PRRT. For treatment of patients with inoperable or metastasized neuroendocrine tumors, somatostatin analogues labeled with the radioisotopes 111In, 90Y and 177Lu have been used so far. Labeling with 111In, mainly an Auger electron emitter, resulted in no reduction of tumor size while somatostatin analogues labeled with 90Y and 177Lu gave overall positive response and improved the patients' quality of life. These promising results together with the increasing availability of other β-emitting radionuclides are a good basis for further studies. © 2012 Bentham Science Publishers.


Pawlak D.,Radioisotope Center | Rangger C.,Innsbruck Medical University | Kolenc Peitl P.,University of Ljubljana | Garnuszek P.,Radioisotope Center | And 11 more authors.
European Journal of Pharmaceutical Sciences | Year: 2016

Introduction A variety of radiolabelled minigastrin analogues targeting the cholecystokinin 2 (CCK2) receptor were developed and compared in a concerted preclinical testing to select the most promising radiotracer for diagnosis and treatment of medullary thyroid carcinoma (MTC). DOTA-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (CP04) after labelling with 111In displayed excellent characteristics, such as high stability, receptor affinity, specific and persistent tumour uptake and low kidney retention in animal models. Therefore, it was selected for further clinical evaluation within the ERA-NET project GRAN-T-MTC. Here we report on the development of a pharmaceutical freeze-dried formulation of the precursor CP04 for a first multi-centre clinical trial with 111In-CP04 in MTC patients. Materials and methods The kit formulation was optimised by adjustment of buffer, additives and radiolabelling conditions. Three clinical grade batches of a final kit formulation with two different amounts of peptide (10 or 50 μg) were prepared and radiolabelled with 111In. Quality control and stability assays of both the kits and the resulting radiolabelled compound were performed by HPLC analysis. Results Use of ascorbic acid buffer (pH 4.5) allowed freeze-drying of the kit formulation with satisfactory pellet-formation. Addition of methionine and gentisic acid as well as careful selection of radiolabelling temperature was required to avoid extensive oxidation of the Met11-residue. Trace metal contamination, in particular Zn, was found to be a major challenge during the pharmaceutical filling process in particular for the 10 μg formulation. The final formulations contained 10 or 50 μg CP04, 25 mg ascorbic acid, 0.5 mg gentisic acid and 5 mg l-methionine. The radiolabelling performed by incubation of 200-250 MBq 111InCl3 at 90°C for 15 min resulted in reproducible radiochemical purity (RCP) > 94%. Kit-stability was proven for > 6 months at + 5°C and at + 25°C. The radiolabelled product was stable for > 4 h at + 25°C. Conclusion A kit formulation to prepare 111In-CP04 for clinical application was developed, showing high stability of the kit as well as high RCP of the final product. © 2016 The Authors. Published by Elsevier B.V.


Maina T.,Greek National Center For Scientific Research | Konijnenberg M.W.,Erasmus University Rotterdam | KolencPeitl P.,University of Ljubljana | Garnuszek P.,Radioisotope Center | And 11 more authors.
European Journal of Pharmaceutical Sciences | Year: 2016

Introduction From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial. Materials and methods Acute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing double A431-CCK2R(±) xenografts at 1, 4 and 24 h pi. Further 4-h animal groups were either additionally treated with the plasma expander gelofusine or injected with 111In-CP04 prepared by wet-labelling. Pharmacokinetics in healthy mice included the 30 min, 1, 4, 24, 48 and 72 h time points pi. Dosimetric calculations were based on extrapolation of mice data to humans adopting two scaling models. Results CP04 was well-tolerated by both mice and rats, with an LD50 > 178.5 μg/kg body weight for mice and a NOAEL (no-observed-adverse-effect-level) of 89 μg/kg body weight for rats. After labelling, 111In-CP04 remained > 70% intact in peripheral mouse blood at 5 min pi. The uptake of 111In-CP04 prepared from the freeze-dried kit and by wet-labelling were comparable in the A431-CCK2R(+)-xenografts (9.24 ± 1.35%ID/g and 8.49 ± 0.39%ID/g, respectively; P > 0.05). Gelofusine-treated mice exhibited significantly reduced kidneys values (1.69 ± 0.15%ID/g vs. 5.55 ± 0.94%ID/g in controls, P < 0.001). Dosimetry data revealed very comparable effective tumour doses for the two scaling models applied, of 0.045 and 0.044 mSv/MBq. Conclusion The present study has provided convincing toxicology, biodistribution and dosimetry data for prompt implementation of the freeze-dried kit formulation without or with gelofusine administration in a multicentre clinical trial in MTC patients. © 2016 The Authors


PubMed | Innsbruck Medical University, Azienda Ospedaliero Universitaria Pisana, Radioisotope Center, Greek National Center For Scientific Research and 4 more.
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, (111)In-CP04 ((111)In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of (111)In-CP04 in animal models, essential for the regulatory approval of the clinical trial.Acute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of (111)In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of (111)In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing double A431-CCK2R() xenografts at 1, 4 and 24h pi. Further 4-h animal groups were either additionally treated with the plasma expander gelofusine or injected with (111)In-CP04 prepared by wet-labelling. Pharmacokinetics in healthy mice included the 30min, 1, 4, 24, 48 and 72h time points pi. Dosimetric calculations were based on extrapolation of mice data to humans adopting two scaling models.CP04 was well-tolerated by both mice and rats, with an LD50>178.5g/kg body weight for mice and a NOAEL (no-observed-adverse-effect-level) of 89g/kg body weight for rats. After labelling, (111)In-CP04 remained >70% intact in peripheral mouse blood at 5min pi. The uptake of (111)In-CP04 prepared from the freeze-dried kit and by wet-labelling were comparable in the A431-CCK2R(+)-xenografts (9.241.35%ID/g and 8.490.39%ID/g, respectively; P>0.05). Gelofusine-treated mice exhibited significantly reduced kidneys values (1.690.15%ID/g vs. 5.550.94%ID/g in controls, P<0.001). Dosimetry data revealed very comparable effective tumour doses for the two scaling models applied, of 0.045 and 0.044mSv/MBq.The present study has provided convincing toxicology, biodistribution and dosimetry data for prompt implementation of the freeze-dried kit formulation without or with gelofusine administration in a multicentre clinical trial in MTC patients.


PubMed | Innsbruck Medical University, Azienda Ospedaliero Universitaria Pisana, Radioisotope Center, Greek National Center For Scientific Research and 3 more.
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

A variety of radiolabelled minigastrin analogues targeting the cholecystokinin 2 (CCK2) receptor were developed and compared in a concerted preclinical testing to select the most promising radiotracer for diagnosis and treatment of medullary thyroid carcinoma (MTC). DOTA-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (CP04) after labelling with (111)In displayed excellent characteristics, such as high stability, receptor affinity, specific and persistent tumour uptake and low kidney retention in animal models. Therefore, it was selected for further clinical evaluation within the ERA-NET project GRAN-T-MTC. Here we report on the development of a pharmaceutical freeze-dried formulation of the precursor CP04 for a first multi-centre clinical trial with (111)In-CP04 in MTC patients.The kit formulation was optimised by adjustment of buffer, additives and radiolabelling conditions. Three clinical grade batches of a final kit formulation with two different amounts of peptide (10 or 50 g) were prepared and radiolabelled with (111)In. Quality control and stability assays of both the kits and the resulting radiolabelled compound were performed by HPLC analysis.Use of ascorbic acid buffer (pH4.5) allowed freeze-drying of the kit formulation with satisfactory pellet-formation. Addition of methionine and gentisic acid as well as careful selection of radiolabelling temperature was required to avoid extensive oxidation of the Met(11)-residue. Trace metal contamination, in particular Zn, was found to be a major challenge during the pharmaceutical filling process in particular for the 10 g formulation. The final formulations contained 10 or 50 g CP04, 25mg ascorbic acid, 0.5mg gentisic acid and 5mg L-methionine. The radiolabelling performed by incubation of 200-250 MBq (111)InCl3 at 90 C for 15 min resulted in reproducible radiochemical purity (RCP) >94%. Kit-stability was proven for >6 months at +5 C and at +25 C. The radiolabelled product was stable for >4h at +25 C.A kit formulation to prepare (111)In-CP04 for clinical application was developed, showing high stability of the kit as well as high RCP of the final product.


Sowa-Staszczak A.,Jagiellonian University | Pach D.,Jagiellonian University | Mikolajczak R.,Radioisotope Center | Macke H.,University Hospital Freiburg | And 12 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2013

Purpose: 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. Methods: Studies were performed in 11 patients with negative results of all available non-isotopic diagnostic methods (8 with symptoms of insulinoma, 2 with malignant insulinoma and 1 with nesidioblastosis). In all patients glucagon-like peptide-1 (GLP-1) receptor imaging (whole-body and single photon emission computed tomography/CT examinations) after the injection of 740 MBq of the tracer was performed. Results: Both sensitivity and specificity of GLP-1 receptor imaging were assessed to be 100 % in patients with benign insulinoma. In all eight cases with suspicion of insulinoma a focal uptake in the pancreas was found. In six patients surgical excision of the tumour was performed (type G1 tumours were confirmed histopathologically). In one patient surgical treatment is planned. One patient was disqualified from surgery. In one case with malignant insulinoma pathological accumulation of the tracer was found only in the region of local recurrence. The GLP-1 study was negative in the other malignant insulinoma patient. In one case with suspicion of nesidioblastosis, a focal accumulation of the tracer was observed and histopathology revealed coexistence of insulinoma and nesidioblastosis. Conclusion: [Lys40(Ahx-HYNIC- 99mTc/EDDA)NH2]-exendin-4 seems to be a promising diagnostic tool in the localization of small insulinoma tumours, but requires verification in a larger series of patients. © 2012 The Author(s).


Parus J.L.,Radioisotope Center | Pawlak D.,Radioisotope Center | Mikolajczak R.,Radioisotope Center | Duatti A.,University of Ferrara
Current Radiopharmaceuticals | Year: 2015

A short overview of fundamental chemistry of lutetium and of structural characteristics of lutetium coordination complexes, as relevant for understanding the properties of lutetium-177 radiopharmaceuticals, is presented. This includes basic concepts on lutetium electronic structure, lanthanide contraction, coordination geometries, behavior in aqueous solution and thermodynamic stability. An illustration of the structure and binding properties of the most important chelating agents for the Lu3+ ion in aqueous solution is also reported with specific focus on coordination complexes formed with linear and macrocyclic polydentate amino-carboxylate donor ligands. © 2015 Bentham Science Publishers.


Pach D.,Jagiellonian University | Sowa-Staszczak A.,Jagiellonian University | Kunikowska J.,Medical University of Warsaw | Krolicki L.,Medical University of Warsaw | And 8 more authors.
Radiotherapy and Oncology | Year: 2012

Purpose: PRRT is a known tool in the management of patients with disseminated and inoperable NETs. The aim of study was to assess the effectiveness of the repeated cycles of PRRT in patients with disseminated and inoperable NETs. Material and methods: Eighty nine patients were included in the PRRT. Among them 16 patients (18%) were qualified for a repeated PRRT cycle due to progression of the disease. In one of the patients qualified for the repeated cycle, PRRT was used as neoadjuvant therapy. The results and side-effects of the repeated cycles of PRRT were analyzed. Results: Disease stabilization was observed in 10 patients 6 months after the repeated PRRT cycle and in 5 patients after 12 and 18 months. Ten of the patients who had received repeated PRRT cycles died. In the case of neoadjuvant therapy, further reduction of the tumor size was observed, enabling qualification for surgery. Clinically significant reduction in the mean values of morphological parameters was not observed. Only after 12 and 18 months the mean values of creatinine levels were higher than the normal range (only in 2 patients). Conclusions: The repeated cycles of PRRT did not cause a clinically significant increase of the toxicity of PRRT. The changes in kidney and blood morphology parameters were transient. The repeated cycles of PRRT enabled stabilization of the disease. © 2011 Elsevier Ireland Ltd. All rights reserved.


Sowa-Staszczak A.,Jagiellonian University | Pach D.,Jagiellonian University | Chrzan R.,Jagiellonian University | Trofimiuk M.,Jagiellonian University | And 6 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2011

Purpose: Neuroendocrine tumours (NET) are a heterogeneous group of neoplasms of diffuse neuroendocrine cells. Surgery is the main aim in the treatment of NETs, which becomes impossible in the case of large tumours or infiltration into other tissues and/or important blood vessels. Neoadjuvant therapy might be helpful in decreasing NET size also, leading us to the point where a tumour, previously considered inoperable, becomes operable. The aim of the study was to assess the usage of peptide receptor radionuclide therapy (PRRT) as a neoadjuvant treatment, enabling surgical intervention in primary inoperable NET. Methods Among 47 patients treated with PRRT, 6 patients were chosen with large, inoperable tumours, for whom enabling of complete surgical excision of the lesions might offer the prospect for a cure. Response to the therapy was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST). Results: The mean tumour size decreased from 6.9 (min. 3.1 cm, max. 9.6 cm) before therapy to 5.4 cm (min. 3.1 cm, max. 9.5 cm) after the treatment. According to RECIST, stabilization of the disease was observed in four and partial responses in two patients. In two patients, reduction of the tumour size enabled surgical intervention. Conclusion: (1) PRRT might be considered a neoadjuvant therapy in primary inoperable NETs. (2) According to RECIST, stabilization of the disease was observed in the majority of patients. (3) We suggest that not only tumour diameter changes, but also tumour volume and contrast enhancement changes in computed tomography should be taken into consideration in assessment of the response to the therapy. (4) Somatostatin receptor scintigraphy is an important tool for qualification of the radioisotope therapy and also for the assessment of the response to PRRT. © Springer-Verlag 2011.


Pawlak D.W.,Radioisotope Center
Talanta | Year: 2013

A new analytical procedure for (90)Sr determination in freshly milked (90)Y from a (90)Sr/(90)Y generator is described. To a solution containing 125 mg of Sr a 200 to 400 MBq sample of (90)Y is added and strontium is separated from (90)Y using DGA column of 1 mL volume. (90)Sr is recovered in a yield close to 100% and counted in a liquid scintillation spectrometer (LSC). The separated strontium is slightly contaminated with (90)Y in the range from 7 to 19% of (90)Sr activity. The separation and counting can be completed within 30 min. The detection limit in 900 s counting time is equal to about 0.2 Bq. This corresponds to (90)Sr/(90)Y activity ratio of 10(-8) level. Copyright © 2013 Elsevier B.V. All rights reserved.

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