**6.1 Traditional: 68Ge/68Ga-generator**

One of the reasons of the emerging application of gallium-68 in nuclear medicine is its cyclotron-independency and availability via radionuclide generator. Since the application of gallium-68 was a long time limited to research, advancements in generator design facilitated research on new 68Ga-radiopharmaceuticals as well as clinical use of the known.

Physical basis for radionuclide generators is the existence of the radioactive equilibria. The differentiation between radionuclide generations is based on the half-lives of the parent (1) and its daughter (2). Depending on the ratio between the two half-lives, three principal cases can be distinguished:


The basis for the 68Ge/68Ga-generator is the secular equilibrium between the parent radionuclide germanium-68 and its daughter gallium-68. Germanium-68 decays with T1/2 = 270.95 days via electron capture to gallium-68. This transition is subsequently followed by decay of gallium-68 to stable zinc-68. At equilibrium, the quantity of gallium-68 produced is equal to the quantity of gallium-68 decaying, while the parent activity does not significantly decrease over many half-lives of the daughter. The theoretical maximum activity or equilibrium state for a certain generator system can be obtained at the time t (**Figure 3**): *<sup>t</sup>* <sup>=</sup> \_1

$$t = \frac{1}{\lambda\_2 - \lambda\_1} \ln \frac{\lambda\_2}{\lambda\_1} \tag{1}$$

**Figure 3.** *Build-up kinetics of gallium-68 on the generator column after initial elution.*

For the 68Ge/68Ga system, equilibrium is reached after 14.1 h, representing maximum obtainable activity. Even if idle times of 12.5 half-lives are necessary to obtain maximum activities, the generators can be used more frequently. Within two halflives of gallium-68 already 75% of the maximum value is build-up and could be used.

The 68Ge/68Ga-generator system introduced in the 1960s by Gleason [10] underwent a lot of changes until today. From the first gallium cow providing gallium-68 after liquid–liquid extraction [10], nowadays the generators, based on a solid matrix (inorganic or organic) providing "ionic" 68Ga3+ eluates. The first commercially available generator of this type was developed by Cyclotron Ltd., Obninsk, Russian Federation [25] eluting gallium-68 with 0.1 M HCl with initial elution yields of ~80% and 68Ge breakthrough of 0.001% [26]. Since the introduction of this generator in 1996 [26], a lot has happened on the market. Today several manufacturers produce 68Ge/68Ga-generators, including ones with GMP grade (e.g. Isotopen Technologien Garching (ITG)) or with approval (e.g. GalliPharm® Eckert & Ziegler in the EU with marketing authorization, in the USA with type II drug master file (DMF) on file with FDA).

Even though these generators represent considerable improvements in 68Ga-production, there are still some obstacles to direct radiolabeling with gallium-68. Beside the low radioactive and high [H+ ] concentration and 68Ge breakthrough, especially the presence of other trivalent metal ions is an inconvenience. As 1 GBq gallium-68 is equal to 9.73 pmol (9.73×10<sup>−</sup>12 mol), these metallic impurities, even present at low levels (<ppm), can be a serious problem as they can compete with gallium-68 for the chelating function of the precursor. In addition to the IAEA recommendations on externally introduced metallic contaminations [21], several procedures are available to reduce those metallic impurities, either intrinsic or externally introduced. These post-elution purification methods, so called post-processing's, aim to improve the radioactive and [H+ ] concentration and the radionuclidic as well as chemical purity of the 68Ga-eluate. Beside fractionation of the eluate [11], anion-exchange (AEX) [13], cation-exchange (CEX) [27–29] and a combination thereof [30, 31] found to be suitable but only for fractionation but also are commercially used for cation-exchange.

#### **6.2 Work in progress: cyclotron**

Although 68Ge/68Ga-generators represent a convenient possibility for persistent patient care with 68Ga-radiopharmaceuticals, their 68Ga-activity available for

**29**

*Gallium-68: Radiolabeling of Radiopharmaceuticals for PET Imaging - A Lot to Consider*

radiolabeling underlies several restrictions resulting from generator design and physics. In conjunction with the sharp increase in demand in recent years, alternative production routes, preferably realizable with existing medical cyclotrons,

Small to medium energy medical cyclotrons are suitable for 68Ga-production via the 68Zn(p,n)68Ga reaction using either a solid or a liquid target. Among the possible nuclear reactions [32, 33], it is the most reasonable leading to large production yields. For optimal results, the starting material zinc-68 as well as the proton energy needs to be selected with care to reduce co-production of long-living radioisotopes of gallium. Nevertheless, co-production of gallium-66 and gallium-67 is unavoidable due to the starting material and the excitation function of the 68Zn(p,2n)67Ga reaction [32, 33]. This has to be taken into account when producing gallium-68 via cyclotron for radiopharmaceutical application as both radioisotopes cannot be

For production of gallium-68 via cyclotron, either a solid or a liquid target can be used. For both target types, a lot of options exist leading to a several considerations to be made. Solid targets, for example, can be pressed, electroplated, foil or fused, all types having their advantages and disadvantages which are not mentioned here. In a first instance, the choice of target will mostly be done due to the actual conditions of the site. An existing production site for 18F-compounds which want to implement gallium-68 would probably choose the liquid target route, as the preconditions for a solid target (target holder, cooling, target transfer and target processing) are expensive and likely not available. Compared with that, the liquid target is a quick and inexpensive option to obtain gallium-68 when a generator is not reasonable. A detailed overview about all possible alternatives and their advantages/disadvantages is given by

After irradiation, the gallium-68 needs to be purified from target material either

if a solid or liquid target was used. The quantity of zinc necessary for the target need to be removed as it and all other metal impurities may perturb the radiolabeling reaction of gallium-68. Intense research on this topic lead to several purification methods based on solvent extraction [34, 35], precipitation [36] and solid phase

Solid-phase extraction using a cation exchange resin or hydroxamate resin is most appropriate for an effective separation of gallium-68 from unwanted metals and can be easily combined with a second resin. This second purification step

] concentration to facilitate further processing

*DOI: http://dx.doi.org/10.5772/intechopen.90615*

separated from the desired gallium-68.

separation [37–44] and suitable for automation.

• Local conditions (expertise and equipment)

• Separation time (should be as short as possible)

• Possibility to recycle zinc-68 from target solution

allows an additional reduction of [H<sup>+</sup>

• Acids (concentration and volume)

• Availability of materials

• Robustness of technique

• Ease of automation

of the final product [21]:

moved into the focus.

the IAEA [21].

radiolabeling underlies several restrictions resulting from generator design and physics. In conjunction with the sharp increase in demand in recent years, alternative production routes, preferably realizable with existing medical cyclotrons, moved into the focus.

Small to medium energy medical cyclotrons are suitable for 68Ga-production via the 68Zn(p,n)68Ga reaction using either a solid or a liquid target. Among the possible nuclear reactions [32, 33], it is the most reasonable leading to large production yields. For optimal results, the starting material zinc-68 as well as the proton energy needs to be selected with care to reduce co-production of long-living radioisotopes of gallium. Nevertheless, co-production of gallium-66 and gallium-67 is unavoidable due to the starting material and the excitation function of the 68Zn(p,2n)67Ga reaction [32, 33]. This has to be taken into account when producing gallium-68 via cyclotron for radiopharmaceutical application as both radioisotopes cannot be separated from the desired gallium-68.

For production of gallium-68 via cyclotron, either a solid or a liquid target can be used. For both target types, a lot of options exist leading to a several considerations to be made. Solid targets, for example, can be pressed, electroplated, foil or fused, all types having their advantages and disadvantages which are not mentioned here. In a first instance, the choice of target will mostly be done due to the actual conditions of the site. An existing production site for 18F-compounds which want to implement gallium-68 would probably choose the liquid target route, as the preconditions for a solid target (target holder, cooling, target transfer and target processing) are expensive and likely not available. Compared with that, the liquid target is a quick and inexpensive option to obtain gallium-68 when a generator is not reasonable. A detailed overview about all possible alternatives and their advantages/disadvantages is given by the IAEA [21].

After irradiation, the gallium-68 needs to be purified from target material either if a solid or liquid target was used. The quantity of zinc necessary for the target need to be removed as it and all other metal impurities may perturb the radiolabeling reaction of gallium-68. Intense research on this topic lead to several purification methods based on solvent extraction [34, 35], precipitation [36] and solid phase separation [37–44] and suitable for automation.

Solid-phase extraction using a cation exchange resin or hydroxamate resin is most appropriate for an effective separation of gallium-68 from unwanted metals and can be easily combined with a second resin. This second purification step allows an additional reduction of [H<sup>+</sup> ] concentration to facilitate further processing of the final product [21]:


*Medical Isotopes*

**Figure 3.**

For the 68Ge/68Ga system, equilibrium is reached after 14.1 h, representing maximum obtainable activity. Even if idle times of 12.5 half-lives are necessary to obtain maximum activities, the generators can be used more frequently. Within two halflives of gallium-68 already 75% of the maximum value is build-up and could be used. The 68Ge/68Ga-generator system introduced in the 1960s by Gleason [10] underwent a lot of changes until today. From the first gallium cow providing gallium-68 after liquid–liquid extraction [10], nowadays the generators, based on a solid matrix (inorganic or organic) providing "ionic" 68Ga3+ eluates. The first commercially available generator of this type was developed by Cyclotron Ltd., Obninsk, Russian Federation [25] eluting gallium-68 with 0.1 M HCl with initial elution yields of ~80% and 68Ge breakthrough of 0.001% [26]. Since the introduction of this generator in 1996 [26], a lot has happened on the market. Today several manufacturers produce 68Ge/68Ga-generators, including ones with GMP grade (e.g. Isotopen Technologien Garching (ITG)) or with approval (e.g. GalliPharm® Eckert & Ziegler in the EU with marketing authorization, in the USA with type II drug

Even though these generators represent considerable improvements in 68Ga-production, there are still some obstacles to direct radiolabeling with

breakthrough, especially the presence of other trivalent metal ions is an inconvenience. As 1 GBq gallium-68 is equal to 9.73 pmol (9.73×10<sup>−</sup>12 mol), these metallic impurities, even present at low levels (<ppm), can be a serious problem as they can compete with gallium-68 for the chelating function of the precursor. In addition to the IAEA recommendations on externally introduced metallic contaminations [21], several procedures are available to reduce those metallic impurities, either intrinsic or externally introduced. These post-elution purification methods, so called

radionuclidic as well as chemical purity of the 68Ga-eluate. Beside fractionation of the eluate [11], anion-exchange (AEX) [13], cation-exchange (CEX) [27–29] and a combination thereof [30, 31] found to be suitable but only for fractionation but also

Although 68Ge/68Ga-generators represent a convenient possibility for persistent

patient care with 68Ga-radiopharmaceuticals, their 68Ga-activity available for

] concentration and 68Ge

] concentration and the

**28**

master file (DMF) on file with FDA).

gallium-68. Beside the low radioactive and high [H+

*Build-up kinetics of gallium-68 on the generator column after initial elution.*

post-processing's, aim to improve the radioactive and [H+

are commercially used for cation-exchange.

**6.2 Work in progress: cyclotron**
