Production of radiopharmaceuticals

Production of radiopharmaceuticals for preclinical and clinical research


Current spectrum of radiopharmaceuticals produced at the Max Planck Institute:

Tracer Target Enzyme/Target receptor Illustration of
[18F]FDG Hexokinase Glucose metabolism
[18F]FLT Thymidine kinase 1 Proliferation
[18F]FHBG Viral Thymidine kinase 1 Gene transfection
[18F]F-DOPA DOPA-Decarboxylase Dopamine status
[15O]H2O - Blood flow
[11C]PK11195 Peripheral Benzodiazepine receptor Activated microglia
[11C]Methionin Amino acid transporter Amino acid transport
[11C]Raclopride D2-Receptor D2-Receptor status
[11C]MP4A Acetylcholine esterase Activity of ACh-Esterase
[11C]Flumazenil Benzodiazepine receptor Benzodiazepine receptor status

Examples for the production of radiopharmaceuticals

[2-18F]-2-Fluor-2-desoxy-D-glucose ([18F]FDG)

 [18F]FDG is a glucose analogue well suited to measure glucose metabolism non-invasively in the human body. Many tumors show an increased activity of hexokinase and an increased glucose transporter level. This results in a high accumulation of [18F]FDG in tumor tissue. After cell uptake, FDG is phosphorylated by hexokinase to form FDG-6-phosphate. No further glycolysis of this metabolite takes place leading to tracer retention in the tumor, which can be visualized with very high sensitivity using positron emission tomography (PET). 

The [18F]FDG-synthesis scheme is shown below:

 

 

[18F]FDG-synthesis module in a hot cell

Using a cryptofix-mediated nucleophilic reaction, the cyclotron-produced [18F]fluoride is substituted for the triflate leaving-group of the protected precursor. Next, the protecting groups are cleaved using sodium hydroxide and the radiolabelled glucose analogue is purified by solid phase extraction. Finally, [18F]FDG is filled into multi-injection vials and sterilized.

 

 

 

Figure on the right:
[18F]FDG-synthesis module in a hot cell

 

The synthesis is carried out in a synthesis module which is remotely controlled via a PC in a lead-shielded hot cell. Shown below is the schematic diagram which allows to control the [18F]FDG-synthesis.

[18F]FDG synthesis: The diagram shows vessels for precursor and other reactants, main reaction vessel and the solid phase extraction column for final product purification

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[11C]PK11195

Microglia, a particular cell type in the brain, play an important role in the brain’s immune defence. Once activated, these macrophages destroy dead cells and thus help tissue regeneration. However, they are also thought to be involved in inflammatory processes often observed after brain lesions caused by stroke, Alzheimer’s disease, Multiple Sclerosis or other types of neurodegeneration.

The marker substance [11C]PK11195 can be used for to detect such neuroinflammatory processes. It addresses the peripheral benzodiazepine receptor which is expressed by activated microglia. Using [11C]PK11195-PET, binding of the radiotracer indicates regions of activated microglia and inflammatory processes. In this way, estimation of both size and location of an inflammatory process is possible.

Radiosynthesis of [11C]PK11195

 

The radiosynthesis of [11C]PK11195 starts with the preparation of [11C]methyl iodide. First, [11C]carbon dioxide is produced by irradiation of nitrogen gas with protons at the cyclotron. [11C]CO2 is converted to [11C]methyl iodide via [11C]methane by catalytic gas phase iodination at 760°C. The resulting [11C]methyl iodide is passed into a solution of desmethyl-PK11195 which is 11C-methylated at 70°C. The product is isolated by HPLC and purified by solid phase extraction. The synthesis is performed in a hot cell by means of a fully automated module (see below).

 

Synthesis module for 11C-compound
Synthesis module for 11C-compound

 

More about this topic:

The research and development group Radiochemistry/Cyclotron produces and develops radiopharmaceuticals.

At the beginning of tracer production, initial high radioactivities are required. Hence, remotely controlled radiosyntheses take place in lead-shielded hot cells to prevent exposition to radiation.