The Zentralklinik Bad Berka is a privately financed hospital, and it is not a university hospital. Since it is not located in the immediate vicinity of a large city, one could assume that it is rather an unspectacular clinic on the edge of a forest. Nevertheless, for many years, this hospital has been generating high-quality scientific publications [1,2,3,4,5,6,7].

Since the establishment of nuclear medicine in this hospital, thousands of patients have been treated with innovative radiopharmaceuticals. One has to ask oneself how such a hospital can examine so many patients with innovative radiopharmaceuticals that so many different scientific results are generated and published?

To answer these questions, one should look at the starting point of every nuclear medical examination or therapy: the production of drugs in a radiopharmacy.

If you look at the job descriptions for the position of radiochemists/pharmacists, often one finds a fully packed field of activity. Additionally, a wide range of radiotracers and its production is desired (Fig. 24.1).

Fig. 24.1
An illustration of the natural scientist in a department of nuclear medicine. The job profile involves the head of production, qualified person, head of quality control, G M P documentation, microbiological monitoring, R S O, medical physicist, and order of radiopharmaceuticals.

Job descriptions for scientists in nuclear medicine flooded with tasks

Full size image

It can partly be seen that neither the hot cells for the radiopharmaceutical production, nor the synthesis modules and analytical equipment, and also no budget is available. Only a few lead shields and shielded syringes. One asks again oneself how these tasks are to be fulfilled?

Very often both the personnel requirements, the financial and technical necessities are completely underestimated.

For example, the cost of synthesis of a new radiopharmaceutical is often incorrectly calculated, since the descriptions of the radiolabeling in the scientific papers are usually reduced to the essentials. A short sentence in the experimental part of the publication can therefore conceal an equipment requirement of more than 100,000 euros. A misinterpretation of these data leads very quickly to the failure of the project.

As an example, Fig. 24.2 lists the personnel requirements for routine production of innovative drugs. The more technology is required, the more personnel is required to maintain the technology.

Fig. 24.2
A chart on the production of innovative radiopharmaceuticals. The personnel and financial costs are often underestimated. It includes head of production, head of quality control, qualified person, G M P documentation, quality assurance, microbiological and environmental monitoring.

Personal requirements for the radiopharmaceutical production of innovative radiotracers

Full size image

Since the last decades, the role of nuclear medicine in precision oncology has been growing. More and more radiolabeled target-seeking drugs are basically available for use in clinical practice. The requirements for this is that a corresponding radiopharmacy can provide these innovative radiotracers. Thus, the radiopharmacy plays an important role in the application of modern radiopharmaceuticals to patients.

Let us get back to the question why so many innovative tracers can be routinely used in our hospital?

It is thanks to the farsightedness, the vision and understanding of the clinic management and above all to the Director of Nuclear Medicine, Professor Richard Baum, that the basic requirements for the production of radiopharmaceuticals were consistently created both technically and in terms of personnel.

This can be illustrated with a historical review. The radiopharmacy was completed in 1998.

The laboratory was equipped with 11 MeV Cyclotron, six hot cells, analytical equipment (analytical HPLCs, GC), and synthesis modules (Fig. 24.3).

Fig. 24.3
6 photos of a nuclear medicine laboratory with a container to store radioactive material. The workstations with various equipments.

Technical equipment in the Bad Berka Radiopharmacy (1998–2017)

Full size image

In 1999, 18F-FDG production and distribution started. Starting from 2000 18F-FDG was produced with a manufacturing authorization, and since 2003, 18F-FDG was produced regularly during the night shift. At this time, two engineers, two chemists, and three medical technical assistants were working in our radiopharmacy. In 2004, the production of 68Ga-DOTA-peptides and 177Lu-DOTA-peptides started.

Figure 24.4 shows the production bench for the manual routine synthesis of 68Ga-DOTA-peptides. The manual module has been slightly modified to reduce the radiation exposure of the hands of our staff.

Fig. 24.4
2 photos of metallic containers in 2004 with Ga DOTATOC's first routine production. A C 18 column pipeline is present as well.

Manual synthesis module for the production of 68Ga-labeled DOTA-peptides

Full size image

The 68Ga-labeling was carried out using the acetone-based labeling procedure which was created by Professor Frank Rösch, Dr. Tschernosekov et al. This method was the workhorse at this time [8].

In 2010, two synthesis runs were performed daily to care for our patients.

During this time, some synthesis processes have been developed and optimized.

Examples are:

  • The combined cationic/anionic purification and labeling procedure for the labeling of fragile compounds with 68Ga [9].

  • The one-pot synthesis of 18F-FEC [10].

  • The cartridge-based purification of 18F-FET [11].

In 2011, the NaCl-based 68Ga-labeling method was discovered in our radiopharmacy and was subsequently used for the routine production of 68Ga-labeled tracers as well as for the labeling of experimental peptides and other compounds. These results have been also published [12]. The 68Ga-labeling procedure is shown schematically in Fig. 24.5. This scheme shows also the anionic labeling and the acetone-based 68Ga-labeling procedure.

Fig. 24.5
A flowchart on the 2011 development of the sodium chloride-based labeling method. Elution by gallium generator and mixed with hydrochloric acid further elution of 500 microliters with H C l, N a C l, and 400 microliters with cation exchanger resin is eluted, after which gallium is obtained.

Scheme of different 68Ga-labeling procedures

Full size image

Furthermore, this method was immediately transferred to various automatic synthesis modules and was used for thousands of synthesis runs in our hospital for the radiopharmaceutical production of 68Ga-DOTA-TOC and 68Ga-PSMA [13] (Fig. 24.6).

Fig. 24.6
3 methods for sodium chloride based labeling procedure used for the production of gallium 68 peptides that are adapted to different synthesis modules.

Different automated synthesis modules for the production of 68Ga compounds using the NaCl-based labeling procedure. This procedure was developed at the hospital Bad Berka by the author Dirk Müller

Full size image

Table 24.1 exemplarily shows an overview of some innovative radiotracers produced in the radiopharmacy for application to patients.

Table 24.1 A selection of experimentally applied radiotracers, which were used in the context of compassionate trials in the Zentralklinik Bad Berka
Full size table

With this list of experimental tracers, the authors would like to highlight the outstanding pioneering work that Professor Richard Baum has done for the Nuclear Medicine Society.

The new radiopharmacy was built between 2014 and 2017. A new cyclotron with a solid target, an alpha laboratory, and new analytical equipment has been installed (Fig. 24.7).

Fig. 24.7
8 photos of the establishment of a new nuclear medicine laboratory with the latest equipment.

The new radiopharmacy was built between 2014 and 2017

Full size image

At the same time, the routine production of alpha-emitting therapeutics in our radiopharmacy, the 225Ac-labeled peptides, began. Additionally, first results from experimental data on the cyclotron-based production of 68Ga could be collected and has been presented in 2019.

One of the most important topics is the fibroblast activation protein FAP which is expressed on cancer-associated fibroblasts. The concentration in normal tissue is usually low. FAP is therefore a highly interesting target for radio-molecular imaging and therapy, and this could be a milestone in the history of nuclear medicine. A few quinoline-based PET tracers have been developed which act as FAP inhibitors (FAPIs). The study of the biodistribution of 68Ga-labeled FAPIs showed an uptake which is comparable with 18F-FDG but also a significant washout effect between 1–3 h after injection [14].

Another approach, namely, the use of FAP-affine peptides such as the peptide FAP-2286, opens the opportunity for radio-molecular therapy due to significantly longer residence times. Furthermore, the PET tracers based on FAP-2286 seem to show a higher tumor uptake compared to 18F-FDG. FAP-2286 is a new and innovative compound of the company 3B-Pharma.

The following Figs. 24.8 and 24.9 show some HPLC results of the radiolabeling and synthesis of the radiopharmaceutical production of FAP tracers for the diagnosis and therapy for patients with different tumor diseases. Fig. 24.8 shows the HPLCs of the compound FAP-2286 labeled with 68Ga, immediately after the labeling and 2 h later. Figure 24.9 shows the HPLCs of the 177Lu-labeled peptide FAP-2286, again immediately after the labeling and after 2 and 24 h.

Fig. 24.8
A graph on intensity versus time for stability of gallium 68 FAP with 2 peaks seen at 10 minutes.

Stability of 68Ga-FAP-2286: HPLC of the final product, immediately after the labeling and after 2 h

Full size image
Fig. 24.9
A graph on intensity versus time for stability of Lutetium 177 FAP with 3 peaks observed at 10 minutes.

Stability of 177Lu-FAP-2286: HPLC of the final product, immediately after the labeling, after 2 and 24 h

Full size image

Finally the authors would like to thank Professor Baum for many, many years of close cooperation.