Preparation of 177Lu-PSMA-617 in Hospital Radiopharmacy: Convenient Formulation of a Clinical Dose Using a Single-Vial Freeze-Dried PSMA-617 Kit Developed In-House.

OBJECTIVE: In the recent time, endoradionuclide therapy for metastatic castration-resistant prostate carcinoma employing 177Lu-PSMA-617 has yielded encouraging results and several clinical trials with the agent are currently ongoing. Routine preparation of 177Lu-PSMA-617 patient doses can be made simpler and convenient, if the ingredients essential for radiolabeling are made available in a ready-to-use lyophilized form. METHODS: PSMA-617 freeze-dried kit was formulated and used for the preparation of 177Lu-PSMA-617 clinical dose with high radiochemical purity using low/medium specific activity 177Lu. Detailed radiochemical studies were performed to determine the maximum activity and volume of 177LuCl3, which can be added in the kit for the formulation of 177Lu-PSMA-617. Studies were also performed to determine the shelf life of the kit to ensure its long-term usage. Studies were performed in buffer as well as human serum medium to determine the stability of the 177Lu-PSMA-617 complex after storing in respective media up to 7 days postpreparation. About ten patient doses of 177Lu-PSMA-617 were administered, and posttherapy scans were acquired. RESULTS: The formulated freeze-dried kit of PSMA-617 could be radiolabeled with an average percentage radiochemical purity > 98.53 ± 0.38. The freeze-dried kit was found suitable for tolerating up to 0.5 mL of 177LuCl3 (in 0.01 N HCl) and specific activity of 555 MBq/µg (15 mCi/µg) for the preparation of the patient dose of 177Lu-PSMA-617. The 177Lu-PSMA-617 complex prepared using the freeze-dried kit of PSMA-617 was observed to maintain % radiochemical purity (RCP) of 96.74 ± 0.87 and 94.81 ± 2.66, respectively, even after storing up to 7 days in buffer and human serum, respectively. 177Lu-PSMA-617 prepared using the in-house formulated freeze-dried kit of PSMA-617 exhibited accumulation in metastatic lesions picked up in a pretherapy PET scan. Reduction in number as well as size of lesions was observed in posttherapy scans acquired after two months of administering the first therapeutic dose of 177Lu-PSMA-617. CONCLUSIONS: The freeze-dried kit of PSMA-617 could be used for the preparation of 177Lu-PSMA-617 with high radiochemical purity (>98%) in a reproducible manner. 177Lu-PSMA-617 prepared using the developed kit was successfully evaluated in patients suffering from metastatic prostate cancer.

Lu-177 preparation for radiotherapy application.

A separation study using a (176)Yb target for the preparation of nca (177)Lu, which is a beta-emitting nuclide used not only in radioimmunotherapy applications but also in the treatment of various lesions, has been performed. A material having a better selectivity and separation efficiency for Lu than Yb was developed, and the separation conditions of (177)Lu were derived using this from a neutron irradiated (176)Yb target. The separation material was an organo-ceramic hybrid material containing a phosphate group. Adsorption behavior was determined through batch experiments, and (177)Lu separation from the Yb target was evaluated through column experiments. The Yb target, with a 99.72% in (176)Yb, was irradiated in the irradiation hole of HANARO, which has a thermal neutron flux of 1.6E+14ncm(-2)s(-1). The batch experiments revealed that the organo-ceramic hybrid material (Sol-POS) had a separation factor of 1.6 at 0.5M HCl. Separation was performed through extraction chromatography using a 5mg enriched Yb target, and the separation yield of the NCA (177)Lu was about 78%. If the amount of Yb target is increased to produce curies level (177)Lu, additional purification will be needed.

The low-energy ß(-) and electron emitter (161)Tb as an alternative to (177)Lu for targeted radionuclide therapy.

INTRODUCTION: The low-energy ß(-) emitter (161)Tb is very similar to (177)Lu with respect to half-life, beta energy and chemical properties. However, (161)Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to (177)Lu. It also emits low-energy photons that are useful for gamma camera imaging. METHODS: The (160)Gd(n,γ)(161)Gd→(161)Tb production route was used to produce (161)Tb by neutron irradiation of massive (160)Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) (161)Tb from the bulk of the (160)Gd target and from its stable decay product (161)Dy. (161)Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. (177)Lu. A (161)Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. RESULTS: Up to 15 GBq of (161)Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%-90% of the available (161)Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The (161)Tb obtained was of the quality required to prepare (161)Tb-DOTA-Tyr3-octreotate. CONCLUSIONS: We were able to produce (161)Tb in n.c.a. form by irradiating highly enriched (160)Gd targets; it can be obtained in the quantity and quality required for the preparation of (161)Tb-labeled therapeutic agents.

Extraction of lutetium(III) from aqueous solutions by employing a single fibre-supported liquid membrane.

Transport behaviour of Lu(III) across a polypropylene hollow fibre-supported liquid membrane containing di(2-ethylhexyl)phosphoric acid (DEHPA) in dihexyl ether as a carrier has been studied. The donor phase was LuCl(3) in the buffer solution consisting of 0.2 M sodium acetate at pH 2.5-5.0. A miniaturised system with a single hollow fibre has been operated in a batch mode. The concentration of Lu(III) was determined by indirect voltammetric method using Zn-EDTA complex. The effect of pH and volume of the donor phase, DEHPA concentration in the organic (liquid membrane) phase, the time of extraction and the content of the acceptor phase on the Lu(III) extraction and stripping behaviour was investigated. The results were discussed in terms of the pertraction and removal efficiency, the memory effect and the mean flux of Lu(III). The optimal conditions for the removal of (177)Lu(III) from labelled (177)Lu-radiopharmaceuticals were discussed and identified. The removal efficiency of Lu(III) greater than 99% was achieved at pH of the donor phase between 3.5 and 5.0 using DEHPA concentration in the organic phase of 0.47 M and the ratio of the donor to the acceptor phase of 182.

Reversibility of La and Lu sorption onto smectites: implications for the design of engineered barriers in deep geological repositories.

The sorption reversibility of La and Lu (considered as actinide analogues) onto a set of smectites (bentonite FEBEX; hectorite, HEC; MX80; saponite, SAP; Otay montmorillonite, SCa-3; and Texas montmorillonite, STx-1) was studied to estimate actinide retention by smectites that are candidates for use as engineered barriers in deep geological repositories. The sorption distribution coefficients (K(d)) and the reversibility parameters (desorption distribution coefficients (K(d,des)), adjusted distribution coefficients (K(d,adj)), and desorption rates (R(des))) were determined from batch tests in two ionic media: deionized water and Ca 0.02 mol L(-1). The latter simulates possible conditions due to the presence of concrete leachates. The results varied greatly depending on the ionic medium, the lanthanide concentration and the clay structure. The high values of K(d,des) obtained (up to 1.1 x 10(5) and 9.2 x 10(4) L kg(-1) for La and Lu in water, and 2.8 x 10(4) and 4.1 x 10(4)L kg(-1) for La and Lu in the Ca medium) indicate the suitability of the tested smectites for lanthanide (and therefore, actinide) retention. Based on all the data, SCa-3, HEC and FEBEX clays are considered the best choices for water environments, whereas in Ca environments the suitable clays depended on the lanthanide considered.

Production of 177Lu at the new research reactor FRM-II: Irradiation yield of 176Lu(n,gamma)177Lu.

Due to its physical and chemical characteristics, 177Lu is a very attractive radionuclide for use in nuclear medicine. This paper introduces a method for a precise calculation of the irradiation yield of 177Lu produced by neutron activation of 176Lu in a nuclear reactor. The calculation is based on the Westcott convention which requires the knowledge of the neutron flux parameters. In this work, the neutron flux parameters of the new research reactor FRM-II (Garching, Germany) were determined and the stability of thermal neutron flux and thermal neutron flux temperature was monitored. The comparison of theoretically calculated and experimentally determined yield for Lu176(n,gamma)Lu177 reaction is presented.

Production logistics of 177Lu for radionuclide therapy.

Owing to its favourable decay characteristics 177Lu [T(1/2)=6.71 d, Ebeta(max)=497 keV] is an attractive radionuclide for various therapeutic applications. Production of 177Lu using [176Lu (n,gamma)177Lu] reaction by thermal neutron bombardment on natural as well as enriched lutetium oxide target is described. In all, approximately 4 TBq/g (108 Ci/g) of 177Lu was obtained using natural Lu target after 7 d irradiation at 3 x 10(13) n/cm2/s thermal neutron flux while it was approximately 110 TBq/g (3000 Ci/g) of 177Lu when 60.6% enriched 176Lu target was used. In both the cases, radionuclidic purity was approximately 100%, only insignificant quantity of 177mLu [T(1/2)=160.5 d, Ebeta(max)=200 keV] could be detected as the radionuclidic impurity. Production logistics using different routes of production is compared. Possible therapeutic applications of 177Lu are discussed and its merits highlighted by comparison with other therapeutic radionuclides.

Radiochemical separation of no-carrier-added 177Lu as produced via the 176Yb(n,gamma)177Yb-->177Lu process.

The 176Yb(n,gamma)177Yb-beta(-)-->177Lu process was investigated to provide no-carrier-added (nca) 177Lu. The radiochemical separation of the 177Lu from the macro-amounts of the ytterbium target based on the cementation process, i.e. the selective extraction of Yb by Na(Hg) amalgam from Cl-/CH3COO- electrolytes, followed by a final cation exchange purification. The cementation separation process provides a decontamination factor of Yb(III) of 10(4), the cation exchange purification adding a decontamination factor of > 10(2). The nca 177Lu is available in radiochemically pure form despite the chemical similarity of the lanthanides with 75 +/- 5% overall separation yield within 4-5 h. It can be used to synthesise nca 177Lu labelled radiotherapeuticals.

Separation of carrier-free hafnium and lutetium radionuclides produced in 16O activated terbium metal target.

Charged particle activation with approximately 88 MeV 16O7+ beam on natural terbium metal foil leads to the production of the short lived carrier-free radioisotopes 170,171Ta and their corresponding daughter products 170,171Hf and 170,171Lu in the target matrix. Liquid-liquid extraction with HDEHP diluted in cyclohexane was carried out for the separation of 170,171Hf and 170,171Lu from the bulk terbium in an aqueous HCl medium.

Separation of rare earth elements by high-speed counter-current chromatography.

Besides being widely used in electronic and glass industries, rare earth elements have recently been found to have important biological effects including the ability to stabilize and enhance interferon activity [J.J. Sedmak and S.E. Grossberg, J. Gen. Virol, 52 (1981) 195]. In this paper, the rare earth elements have been separated using a high-speed counter-current chromatography (HSCCC) centrifuge equipped with three multilayer coils connected in series. Two-phase solvent systems were composed of n-heptane containing di-(2-ethylhexyl)phosphoric acid (stationary phase) and dilute hydrochloric acid (mobile phase) where the partition coefficient of each can be optimized by selecting the proper hydrochloric acid concentration. The mobile phase was eluted through the column at a flow-rate of 5 ml/min, while the apparatus was rotated at 900 rpm. Continuous detection of the rare earth elements was effected by means of a post-column reaction with arsenazo III and the elution curve was obtained by on-line monitoring at 650 nm. Excellent isocratic separations of closely related rare earth elements were achieved at high partition efficiencies up to several thousand theoretical plates. Versatility of the present method was demonstrated in an exponential gradient elution of hydrochloric acid concentration where fourteen rare earth elements were all resolved in about 4.5 h.