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Automated synthesis of PET-tracers

The steadily growing clinical interest in molecular imaging methods such as positron emission tomography (PET) is also leading to an increasing demand for new, easily reproducible and, above all, very high levels of radioactivity (> 50 GBq) achievable synthesis processes for the production of beta+-emitter-bearing radioactive drugs (PET tracers). At the same time, these synthesis processes in their entirety must meet the high demands and requirements of "Good Manufacturing Practice" (GMP). In order to take into account the official regulations, in particular with regard to sterility and purity of the products, as well as the protection of the manufacturing operators against ionizing radiation, the synthesis of radiopharmaceuticals is carried out using synthesis modules located in lead-shielded cells (so-called hot cells). The latter, of course, presupposes that such synthesis processes and devices can be automated and remotely controlled by computer. Currently, the most common models can be divided into two main categories: systems with a fixed pre-defined tube design, and systems using disposable cartridges. Depending on the requirements, one or the other can be advantageous or disadvantageous. For this reason, both systems are also used in the radio pharmacological production of the INM-5. The models with a fixed design, including all necessary software, were completely constructed, developed and built in the workshops of the FZJ by the INM-5.

Kommerziell erhältliches Kassettensynthesemodul GE FastLabKommerziell erhältliches Kassettensynthesemodul GE FastLab

The following figure shows an example of such a synthesis apparatus (right in the picture) including the associated R&I flow chart (left in the picture).

Modell einer am INM-5 konstruierten Syntheseeinheit.Modell einer am INM-5 konstruierten Syntheseeinheit.

Process of the automated synthesis using the example of [18F]FET

After the synthesis unit has been cleaned, it is filled with all the raw materials required for the production of [18F]FET, according to a predefined standard working procedure (SOP). After completion of all further synthesis preparations, the lead box of the "hot cell" is closed manually. Simultaneously with the preparation, the required 18F- is produced by irradiation of approx. 1.5 mL H218O with 16 MeV proton energy at the internal baby cyclotron by the nuclear reaction 18O(p, n)18F. [18F]Fluoride is then transported into the synthesis apparatus by means of a helium stream.

Synthesis of O-(2-[18F]Fluorethyl)-l-tyrosin

After starting the synthesis, [18F]fluoride is first fixed on an anion exchange cartridge, then eluted with an aqueous K2CO3 solution and transferred into the reactor of the synthesis apparatus. The resulting fluoride ion is a weak nucleophile due to its high degree of solvency owing to its high charge density. To increase the reactivity of 18F- to such an extent that nucleophilic substitutions are possible, phase transfer catalysts (e. g.: Cryptofix-2.2.2) must be added and water removed.

Gitter­modell der Komplexierung eines Kaliumkations (violett) durch Kryptofix-2.2.2Gitter­modell der Komplexierung eines Kaliumkations (violett) durch Kryptofix-2.2.2

To remove the water, acetonitrile is added and the solution is azeotropically dried several times.

Synthese der geschützten Vorstufe von [18F]FETSynthese der geschützten Vorstufe von [18F]FET

Subsequently, the addition of triphenylmethylamino-3- (4- (2- (toluene-4-sulfonyloxy)ethoxy)phenyl)propionic acid tert-butyl ester leads to the protected precursor of the desired product within 5 min at 85 °C. The letter is converted into the crude product solution of [18F]FET in the presence of HCl at 100 °C by cleavage of the protecting groups (shown in green).

Abspaltung der SchutzgruppenAbspaltung der Schutzgruppen

Chromatographic purification and filling

After the separation of the protective groups, the crude product solution is cooled down to room temperature, neutralized with aqueous caustic soda solution and purified by means of preparative HPLC.   

The fraction containing the product is then transferred into a collection vessel, the final activity and volume are determined and transferred to sterile vials via a sterile membrane filter using automatic dispensing. The manufactured product is divided into four portions (quality control sample, patient sample, sterile test sample, reserve sample). Sterile test and retention samples are first stored in a lead-shielded safe and later further processed. The patient sample is packed by the radiation protection commissioner in a suitable transport box, sealed and sent to the predetermined recipient.

Quality control and batch release of the radiopharmaceutical at INM-5

Simultaneously with the handover and transport process, the quality control sample is examined in accordance with the inspection instructions. Various analytical methods are used here. For example, the residual solvents are tested by means of gas chromatography, the HPLC provides information on radiochemical and chemical purity, and the content of endotoxins can be determined by the Lumulus test.

The results of the analyses carried out are transferred to an analysis protocol and checked by the head of quality control. The manufacturing protocol and the analysis protocol are then handed over to the qualified person together with all raw data. The latter performs a document check. If all specification requirements are met and there are no quality-relevant deviations, the approval for the application of the product batch is given by the signature of the qualified person on the analysis report.