Radiochemical Quality Research Articles

Routine Radiochemical Quality Control of 99mTc eluate and 99mTc-Labeled Radiopharmaceuticals

Routine Radiochemical Quality Control of 99mTc eluate and 99mTc-Labeled Radiopharmaceuticals

Radiochemical quality control of the radiopharmaceutical, 89SrCl2 produced in FBTR

89SrCl2 radiopharmaceuticals is mainly used for bone pain palliation in the cancer patients, is being produced in FBTR via 89Y(n, p)89Sr using yttria target. The irradiated yttria target is chemically processed in high pure quartz distilled nitric acid medium in hot cell facility, to avoid the corrosion of components of hotcell due to chloride ions while using HCl medium. Being ionic species, the purified 89Sr(II) cation in aqueous solution containing bulk nitrate and other trace anions, exists as SrXn species where X: F−, Cl−, Br−, NO3−, PO43− and SO42−, n: stoichiometric anion content. The aim of the manuscript is to standardise an efficient ultra-low level anion purification method (ppb range) for the conversion of SrXn to SrCl2 and estimate the residual anionic impurities as recommended by the appropriate source specifications for its medical application. Various methods were standardised for the removal of anions in the SrCl2 source produced by the above process which include evaporation, calcination, anion exchange column, cation exchange column as well as its combination with pre-concentration column of ion chromatography (IC) technique using 89Sr tracers as well as FBTR produced 89Sr solution. Assay of 89Sr and other anions including nitrate for the above study were accomplished using Cerenkov counting and ion chromatography respectively. Thus evaporation-calcination-column chromatography mode was finalised to obtain pure SrCl2 source free from nitrate and other anionic impurities. This is the first ever systematic study for the Radiochemical quality control of nca 89SrCl2 radiopharmaceutical produced in a fast reactor. This study also finds its application to any analytical lab as well as industry where there is a requirement of anion purification in the ppb level.

Radiochemical Quality Control Methods for Radium-223 and Thorium-227 Radiotherapies.

Background: The majority of radiopharmaceuticals for use in disease detection and targeted treatment undergo a single radioactive transition (decay) to reach a stable ground state. Complex emitters, which produce a series of daughter radionuclides, are emerging as novel radiopharmaceuticals. The need for validation of chemical and radiopurity with such agents using common quality control instrumentation is an area of active investigation. Here, we demonstrate novel methods to characterize 227Th and 223Ra. Materials and Methods: A radio-TLC scanner and a γ-counter, two common and widely accessible technologies, as well as a solid-state α-particle spectral imaging camera were evaluated for their ability to characterize and distinguish 227Th and 223Ra. We verified these results through purity evaluation of a novel 227Th-labeled protein construct. Results: The γ-counter and α-camera distinguished 227Th from 223Ra, enabling rapid and quantitative determination of radionuclidic purity. The radio-TLC showed limited ability to describe purity, although use under α-particle-specific settings enhanced resolution. All three methods were able to distinguish a pure from impure 227Th-labeled protein. Conclusions: The presented quality control evaluation for 227Th and 223Ra on three different instruments can be applied to both research and clinical settings as new alpha particle therapies are developed.

Optimization of Automatic Synthesis and Separation of [18F] AV-45 and Quality Control.

Objective: Based on the Tracerlab FXF-N platform, a synthesis program and preparative high-performance liquid chromatography (HPLC) purification program edited by us can stably and repeatedly produce [18F] AV-45 without changing the process. The [18F] AV-45 produced meets the main indexes of radiopharmaceutical intravenous preparations. Methods: The O-toluene sulfonated precursor (1 mg) was subjected to nucleophilic radiofluorination at 115°C in anhydrous dimethyl sulfoxide (DMSO), then the protective group was hydrolyzed by acid. The neutralized reaction mixture was purified through a preparative HPLC then formulated for injection using a C18 purification cartridge. This method yielded a relatively pure [18F] AV-45 product with high specific activity. Results: Four consecutive radiochemical synthesis operations were carried out in this experiment; the average production time of [18F] AV-45 preparation was 60 min, the radiochemical yield was 14.8 ± 2.1% (n = 4), the radiochemical purity was greater than 95%, and the other important quality control indexes met the requirements of radioactive drugs for intravenous administration. Conclusion: This experiment was based on the Tracerlab FXF-N platform with the synthesis program and preparative HPLC purification program edited by us. Through screening and optimization of the separation and purification system and the separation and analysis system, as well as automatic radiochemical synthesis and preparation quality control, intravenous [18F] AV-45 was successfully prepared.

Incorporation Monitoring of Staff using I-131 and Lu-177 in a Nuclear Medicine Ward

In addition to the well-established therapy with iodine-131, treatments with lutetium-177 are increasingly being performed on an inpatient basis in Germany. All of these treatments have be taken into account when assessing the potential internal dose and for incorporation monitoring of personnel. This article describes the experience with and the results of incorporation monitoring of staff of a nuclear medicine ward of a university hospital in Germany. Personnel working in a nuclear medicine ward was regularly measured using a whole body counter. In total, 234 measurements were performed over a period of 12 months. Incorporation factors were determined considering activities handled or applied to patients in the respective time period. In approx. 74 % of measurements, no incorporations was found. In the remaining measurements, activity was detected. Assuming incorporation, the maximum effective dose would be less than 0.15 mSv per measurement. The incorporation factors determined in this work were in the order of magnitude of 10-7 for all groups except for personnel performing radiochemical quality control. For this group, only an upper limit of the incorporation factor of 10-5 can be specified. The risk of incorporating radiactivity can be considered low for personnel working in a nuclear medicine ward. An incorporation factor of 10-7 is appropriate for medical, nursing, and cleaning staff and personnel performing radiochemical syntheses.

Towards Facile Radiolabeling and Preparation of Gallium-68-/Bismuth-213-DOTA-[Thi8, Met(O2)11]-Substance P for Future Clinical Application: First Experiences.

Substance P (SP) is a small peptide commonly known as a preferential endogenous ligand for the transmembrane neurokinin-1 receptor. Nuclear Medicine procedures currently involve radiolabeled SP derivatives in peptide radioligand endotherapy of inoperable glioblastoma. Promising clinical results sparked the demand for facile production strategies for a functionalized 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8, Met(O2)11]-SP to allow for rapid Gallium-68 or Bismuth-213 complexation. Therefore, we provide a simple kit-like radiotracer preparation method that caters for the gallium-68 activity eluted from a SnO2 generator matrix as well as preliminary results on the adaptability to produce [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP from the same vials containing the same starting material. Following a phase of radioanalysis for complexation of gallium-68 to DOTA-[Thi8, Met(O2)11]SP and assessing the radiolabeling parameters, the vials containing appropriate kit-prototype material were produced in freeze-dried batches. The facile radiolabeling performance was tested and parameters for future human application were calculated to meet the criteria for theranostic loco-regional co-administration of activity doses comprising [68Ga]Ga-DOTA-[Thi8, Met(O2)11]SP mixed with [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP. [68Ga]Ga-DOTA-[Thi8, Met(O2)11]SP was prepared quantitatively from lyophilized starting material within 25 min providing the required molar activity (18 ± 4 GBq/µmol) and activity concentration (98 ± 24 MBq/mL), radiochemical purity (>95%) and sustained radiolabeling performance (4 months at >95% LE) as well as acceptable product quality (>95% for 120 min). Additionally, vials of the same starting materials were successfully adapted to a labeling strategy available for preparation of [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP providing sufficient activity for 1–2 human doses. The resultant formulation of [68Ga]Ga-/[213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP activity doses was considered of adequate radiochemical quality for administration. This investigation proposes a simple kit-like formulation of DOTA-[Thi8, Met(O2)11]SP—a first-line investigation into a user friendly, straightforward tracer preparation that would warrant efficient clinical investigations in the future. Quantitative radiolabeling was accomplished for [68Ga]Ga-DOTA-[Thi8, Met(O2)11]SP and [213Bi]Bi-DOTA-[Thi8, Met(O2)11]SP preparations; a key requirement when addressing the specific route of catheter-assisted co-injection directly into the intratumoral cavities.

Preliminary evaluation of the radiotherapeutic efficacy of 131I-atorvastatin in rats with hepatocellular carcinoma

As one of the most critical types of cancer, hepatocellular carcinoma (HCC) affects many people worldwide. This study demonstrated the prospective use of atorvastatin, a drug that inhibits the mevalonate pathway, causing hypolipidemia, as a carrier to deliver the iodine-131 (131I) isotope to liver tissues for HCC radiotherapy. The atorvastatin radioiodination method was optimized for utilizing the 131I isotope. The radiochemical quality and the in vitro stability of the generated [131I]atorvastatin were investigated. In addition, the biodistribution experiments of [131I]atorvastatin were evaluated in both normal and HCC-induced rat models. [131I]atorvastatin was produced at a maximum radiochemical yield of 86.7 ± 0.49%. The [131I]atorvastatin solution purified via high-performance liquid chromatography showed good in vitro stability for 12 h after tagging. Biodistribution analyses revealed remarkable liver targeting capacity of [131I]atorvastatin and good localization of 131I in liver tissues. Overall, the encouraging biochemical profile and histopathological findings have been reported, and preliminary investigations on the possible use of [131I]atorvastatin as a radiotracer and its impact on HCC radiotherapy in rats show promise.

Construction and Preclinical Evaluation of a 124/131I-Labeled Radiotracer for the Detection of Mesothelin-Overexpressing Cancer

Mesothelin is a molecular biomarker of many types of solid cancers, which may represent a highly promising new target in the development of cancer-targeted diagnostic agents. A human anti-mesothelin antibody with a low molecular weight, ET210sc, was applied; this antibody has potent affinity and can penetrate tissue quickly and stably without causing immunoreactions. We developed a new 124/131I-labeled radiotracer of ET210sc. The 124/131I-labeled ET210sc radiotracer showed excellent radiochemical quality (with over 99% radiolabeling yield, 0.07 GBq/μmol specific activity) and remarkable stability in phosphate-buffered saline (>95% at 3 days). The radiotracer retained its potent affinity (dissociation constant, Kd = 0.101 nM). The radiotracer specifically bound to mesothelin-positive cells in vitro. Interestingly, the radiotracer exhibited significant positive-to-negative tumor uptake ratios (1.5:1) 3 days postinjection. The estimated absorbed doses of each organ (e.g., 0.704 mGy/MBq for the rectum; 0.341 mGy/MBq for the spleen) met the medical safety standards for further clinical applications. Our findings provide an initial proof of concept for the potential use of 124/131I-labeled ET210sc radiotracers to detect mesothelin-overexpressing cancer. 124I-ET210sc is proposed to be an ideal imaging agent for further clinical applications.

Improved production of 76Br, 77Br and 80mBr via CoSe cyclotron targets and vertical dry distillation

IntroductionThe radioisotopes of bromine are uniquely suitable radiolabels for small molecule theranostic radiopharmaceuticals but are of limited availability due to production challenges. Significantly improved methods were developed for the production and radiochemical isolation of clinical quality 76Br, 77Br, and 80mBr. The radiochemical quality of the radiobromine produced using these methods was tested through the synthesis of a novel 77Br-labeled inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1), a DNA damage response protein. Methods76Br, 77Br, and 80mBr were produced in high radionuclidic purity via the proton irradiation of novel isotopically-enriched Co76Se, Co77Se, and Co80Se intermetallic targets, respectively. Radiobromine was isolated through thermal chromatographic distillation in a vertical furnace assembly. The 77Br-labeled PARP inhibitor was synthesized via copper-mediated aryl boronic ester radiobromination. ResultsCyclotron production yields were 103 ± 10 MBq∙μA−1∙h−1 for 76Br, 88 ± 10 MBq∙μA−1∙h−1 for 80mBr at 16 MeV and 17 ± 1 MBq∙μA−1∙h−1 for 77Br at 13 MeV. Radiobromide isolation yields were 76 ± 11% in a small volume of aqueous solution. The synthesized 77Br-labeled PARP-1 inhibitor had a measured apparent molar activity up to 700 GBq/μmol at end of synthesis. ConclusionsA novel selenium alloy target enabled clinical-scale production of 76Br, 77Br, and 80mBr with high apparent molar activities, which was used to for the production of a new 77Br-labeled inhibitor of PARP-1. Advances in knowledgeNew methods for the cyclotron production and isolation of radiobromine improved the production capacity of 77Br by a factor of three and 76Br by a factor of six compared with previous methods. Implications for patient carePreclinical translational research of 77Br-based Auger electron radiotherapeutics, such as those targeting PARP-1, will require the production of GBq-scale 77Br, which necessitates next-generation, high-yielding, isotopically-enriched cyclotron targets, such as the novel intermetallic Co77Se.

18F-Alfatide II automated preparation based on 18F-minireactor and microPET/CT imaging in tumor

Objective To develop the automated preparation of 18F-Alfatide Ⅱ using newly-designed 18F-minireactor and perform 18F-Alfatide Ⅱ microPET/CT imaging in tumor. Methods The automated preparation of 18F-Alfatide Ⅱ was developed by using 18F-microreactor and water phase Al18F-chelating method, and the radiochemical yield and quality analysis were measured. The nude mice bearing breast tumor ZR-75-1 and nasopharyngeal tumor CNE1 were established (n=3 respectively). MicroPET/CT imaging was performed at 0.5, 1.0 and 2.0 h after the injection of 18F-Alfatide Ⅱ. The region of interest (ROI) was depicted and the tumor/muscle (T/M) ratio was calculated. Results 18F-Alfatide Ⅱ was automatically prepared with the total synthesis time of 40 min, the radiochemical yield of (28±6)% (no decay corrected, n=11), and the radiochemical purity >97%. All quality analysis indexes accorded with the radiopharmaceutical requirements. 18F-Alfatide Ⅱ microPET/CT images of ZR-75-1 and CNE1 tumors were clear due to the high radioactivity uptake of tumor lesions (T/M ratio was greater than 4.0 at 1.0 h after injection). Conclusion Based on the 18F-minireactor, the 18F-Alfatide Ⅱ can be prepared successfully with short synthesis time and high radiochemical yield, which can help the application studies in 18F-Alfatide Ⅱ microPET/CT imaging. Key words: Peptides, cyclic; Arg-Gly-Asp; Fluorine radioisotopes; Chemistry techniques, synthetic; Breast neoplasms; Nasopharyngeal neoplasms; Neoplasm transplantation; Mice, nude

Current Approach in Radiochemical Quality Control of the 99mTc-Radiopharmaceuticals: a mini-review

Abstract To present optimized chromatographic systems for radiochemical purity (RCP) evaluation of 99mTc-eluate and 99mTc-radiopharmaceuticals, as well as to assess doses calibrator reliability for routine purposes in hospital radiopharmacies. RCP was determined by different systems and radioactivity was quantified by TLC-scanner, doses calibrator and gamma-counter. Suitable and optimized systems were presented for RCP analyses. No significant differences were observed between radioactivity counting devices and, thus, doses calibrator showed reliability for RCP determination in hospital radiopharmacies.

The effect of chelator type on in vitro receptor binding and stability in 177Lu-labeled cetuximab and panitumumab.

Monoclonal antibodies are used in the therapy of various diseases. Thanks to their high specific uptake in target tissues, these antibodies can be utilized in targeted radioimmunotherapy as carriers of radioisotopes to tumors. However, important characteristics of antibodies such as target binding and stability in the organism may be affected by various structural parameters. This study has focused on the potential influence of selected chelators on radiochemical quality and in vitro receptor binding capacity in two modified monoclonal antibodies-cetuximab and panitumumab, both ligands of the epidermal growth factor receptor (EGFR). These two antibodies were each coupled with three macrocyclic chelators (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, and 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-4-(S)-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid) and labeled with lutetium-177. The stability of the preparations was checked, and the cell binding to EGFR-expressing cell lines was examined. The used method led to very stable radiolabeled preparations. The results showed that binding to the target cells was not affected by the type of chelator. All three chelators may be useful for the labeling of cetuximab and panitumumab with lutetium-177 in future preclinical or clinical studies. Our study revealed previously unpublished fact that the type of chelator selected does not affect binding of EGFR-targeted antibodies labeled with lutetium-177.

Specific Radioactivity of Neutron Induced Radioisotopes: Assessment Methods and Application for Medically Useful 177Lu Production as a Case

The conventional reaction yield evaluation for radioisotope production is not sufficient to set up the optimal conditions for producing radionuclide products of the desired radiochemical quality. Alternatively, the specific radioactivity (SA) assessment, dealing with the relationship between the affecting factors and the inherent properties of the target and impurities, offers a way to optimally perform the irradiation for production of the best quality radioisotopes for various applications, especially for targeting radiopharmaceutical preparation. Neutron-capture characteristics, target impurity, side nuclear reactions, target burn-up and post-irradiation processing/cooling time are the main parameters affecting the SA of the radioisotope product. These parameters have been incorporated into the format of mathematical equations for the reaction yield and SA assessment. As a method demonstration, the SA assessment of 177Lu produced based on two different reactions, 176Lu (n,γ)177Lu and 176Yb (n,γ) 177Yb (β- decay) 177Lu, were performed. The irradiation time required for achieving a maximum yield and maximum SA value was evaluated for production based on the 176Lu (n,γ)177Lu reaction. The effect of several factors (such as elemental Lu and isotopic impurities) on the 177Lu SA degradation was evaluated for production based on the 176Yb (n,γ) 177Yb (β- decay) 177Lu reaction. The method of SA assessment of a mixture of several radioactive sources was developed for the radioisotope produced in a reactor from different targets.

Preparation and In Vivo Evaluation of 90Y-Meso-Dimercaptosuccinic Acid (90Y-DMSA) for Possible Therapeutic Use: Comparison with 99mTc-DMSA

The aim of this study was to find out if (90)Y could form a stabile complex with meso-2,3-dimercaptosuccinic acid (DMSA) and if (90)Y-DMSA may have potential for tumor therapy in the palliative treatment of bone metastases. The preparing of (90)Y-DMSA was carried out by varying experimental parameters, such as ligand concentration, pH, time, and temperature of the reaction, in order to maximize the labeling yield. Analysis of the complexes enclosed the radiochemical quality control (instant thin-layer chromatography, paper chromatography, and high-performance liquid chromatography), determination of pharmacokinetical parameters as well as biodistribution study in healthy male Wistar rats. In vitro stability of the complexes was tested too. (90)Y-DMSA could be prepared in high yields (>95%) under optimized conditions of reaction. Stability studies in saline and human serum in vitro showed no significant release of activity from the ligand over 24 hours and 10 days, respectively. The preliminary biodistribution results in rat at 2 hours indicated that (90)Y-DMSA, at both pH levels, was significantly retained into bone. The uptake in the kidneys was lower for (90)Y-DMSA at pH 8.0 then at pH 3.0. The retention in other organs was negligible. (90)Y complexes could be made with ease with DMSA. (90)Y-DMSA was obtained in good yield and was found to be very stable. A promising biodistribution result of this complex pointed at potential in the palliative treatment of bone metastases.

Guideline for radioimmunotherapy of CD20+ follicular B-cell non-Hodgkin's lymphoma

This guideline is a prerequisite for the quality management in the treatment of non-Hodgkon-lymphomas in patients with relapsed or refractory follicular lymphoma after rituximab therapy and as consolidation therapy after first remission following CHOP like treatment using radioimmunotherapy. It is based on an interdisciplinary consensus and contains background information and definitions as well as specified indications and detailed contraindications of treatment. Essential topics are the requirements for institutions performing the therapy. For instance, presence of an expert for medical physics, intense cooperation with all colleagues committed to treatment of lymphomas, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with those colleagues (hemato-oncologists) who propose, in general, radioimmunotherapy under consideration of the development of the disease.

Labeling, characterization, and in vivo localization of a new 90Y-based phosphonate chelate 2,3-dicarboxypropane-1,1-diphosphonic acid for the treatment of bone metastases: Comparison with 99mTc–DPD complex

The goal of this investigation was to examine the possibilities for yttrium-90-labeling of the 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), which is currently labeled with technetium-99m and as a 99mTc–DPD clinically used as bone imaging agent. Analysis of the complex enclosed the radiochemical quality control methods, biodistribution studies, as well as the determination of pharmacokinetic parameters. The biological behavior of complexes 90Y–DPD, 99mTc–DPD and 90Y-labeled DPD-kit formulation [ 90Y–(Sn)–DPD] in animal model was compared. The labeling conditions were standardized to give the maximum yield, which ranged between 93% and 98%. The examined 90Y complex could be easily prepared, with an outstanding yield and was also found to be very stable for at least 10 h after 90Y-labeling. Protein binding value was 4.6 ± 0.7% for 90Y–DPD complex and the complex possess a hydrophilic character. The satisfactory results of 90Y–DPD biodistribution in healthy test animals were obtained; the uptake in the bone was 11–13% ID/g after 24 h depending on the pH value during the preparation. With high skeletal uptake, a minimum uptake in soft tissues and rapid blood clearance the 90Y–DPD complex proved to be an excellent candidate for targeting tumor therapy.

Evaluation of fresh and old eluate of 99Mo/99mTc generators used for labeling of different pharmaceutical kits

Sixty 99Mo/99mTc wet column generators, loaded with two different 99Mo activities, were analyzed in order to assess the quality of their eluates. Each elution was used for labeling of different radiopharmaceuticals, in order to evaluate whether “risky” elutions, namely those performed just after generator delivery and at 72 hours or more from the last elution, could be conveniently employed when fresh available radioactivity is not enough for the planned labeling or when shipping problems arise, or delay in delivery of a new generator occurs. Radiochemical quality control of all radiopharmaceuticals labeled with these elutions was performed. The elutions differed mainly in 99Tc ground state (99gTc) and amounts of oxidizing impurities. Radiolabeling procedures, however, were not affected, suggesting that these “risky” elutions might be appropriately used, in “emergency” conditions, for labeling radiopharmaceuticals although their radiochemical purity control is recommended prior to patient administration.

Preparation, radiochemical purity control and stability of99mTc-mertiatide (Mag-3)

Scintigraphic image analysis of 99mTc-mertiatide (Mag-3, mercaptoacetyltriglycine) clearance provides the determination of the blood flow, the tubular transit time and the excretion as well from both kidneys. Radiopharmaceutical routine recommends a radiochemical purity control before administration of the product to a patient. The main objective of this study is to develop a Mag-3 labeling procedure that fits better than the previous one in our daily routine production of radiopharmaceuticals. Increasing proportions of 99mTc-Mag-3 were measured during the heating and cooling steps of the Mag-3 labeling procedure. HPLC analysis was used to confirm the results of a rapid radiochemical quality control assay on standard ITLC-SG paper. The reconstitution time takes 20-25 minutes from the harvest of pertechnetate to a ready-for-use calibrated patient syringe. The HPLC profile of 99mTc-Mag-3 including its minor impurities remains unchanged for 24-48 hours after reconstitution. The application of a programmable Peltier-directed device for heating/cooling provides a better control of the temperature course. The procedure proposed fully meets the labeling criteria recommended by the supplier and can be performed with a minimum of attention within a time-span that we formerly needed for solely the radiochemical purity control assay. Moreover, 99mTc-Mag-3 prepared in this way seems to be considerably more stable than mentioned in the manufacturer's instructions.

Guideline for radioimmunotherapy of rituximab relapsed or refractory CD20+ follicular B-cell nonHodgkin´s lymphoma

Summary:This guideline is a prerequisite for the quality management in the treatment of non-Hodgkin-lymphomas using radioimmunotherapy. It is based on an interdisciplinary consensus and contains background information and definitions as well as specified indications and detailed contraindications of treatment. Essential topics are the requirements for institutions performing the therapy. For instance, presence of an expert for medical physics, intense cooperation with all colleagues committed to treatment of lymphomas, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how the treatment has to be carried out technically. Here, quality control and documentation of labelling are of greatest importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with those colleagues (haematology-oncology) who propose, in general, radioimmunotherapy under consideration of the development of the disease.

Synthesis of [99mTc]DTPA-Folate and Its Evaluation as a Folate-Receptor-Targeted Radiopharmaceutical

A DTPA-folate conjugate was radiolabeled with (99m)Tc by stannous chloride reduction of [(99m)Tc]sodium pertechnetate in an aqueous solution of DTPA-folate. The radiochemical purity of the product consistently exceeded 97%, as assessed by thin-layer chromatography employing conditions analogous to those for radiochemical quality control of the radiopharmaceutical [(99m)Tc]DTPA. HPLC demonstrated that the radiolabeled product resulted from the intact DTPA-folate conjugate and not unconjugated DTPA. The ability of [(99m)Tc]DTPA-folate to target folate receptors in vivo was assessed in biodistribution studies with athymic mice bearing subcutaneous folate-receptor-positive human KB cell tumors. As an internal control, previously studied [(111)In]DTPA-folate was coinjected with the [(99m)Tc]DTPA-folate, along with varying amounts of DTPA-folate (0.38 mg/kg, 1.6 mg/kg, or 14 mg/kg). At each DTPA-folate dose, [(99m)Tc]DTPA-folate exhibited tumor uptake comparable to that of the coadministered [(111)In]DTPA-folate, with radiotracer levels declining at the higher DTPA-folate doses due to competitive receptor binding of the unlabeled conjugate. Tumor uptake of both tracers was also competitively blocked by preadministered folic acid dihydrate (2.9 mg/kg). Tumor-to-background tissue contrast obtained with [(99m)Tc]DTPA-folate was generally similar to that obtained with [(111)In]DTPA-folate. The (99m)Tc-labeled DTPA-folate conjugate may have utility as a targeted radiopharmaceutical for imaging neoplastic tissues known to overexpress the folate receptor.