WO2021234741A1

WO2021234741A1 - Microwave device for the rapid labelling of in kit-formulated radiopharmaceuticals

Info

Publication number: WO2021234741A1
Application number: PCT/IT2020/000039
Authority: WO
Inventors: Elena COLOMIBINI; Mattia ASTI; Michele Iori; Paolo Veronesi
Original assignee: C.M.S. S.P.A.
Priority date: 2020-05-18
Filing date: 2020-05-18
Publication date: 2021-11-25
Also published as: EP4168173A1

Abstract

The invention relates to a microwave device able to trigger the labelling of gallium-68 radiopharmaceuticals in kit in order to provide the completion of the complexation reaction in a few seconds. The invention also relates, more in general, to a microwave device able to enhance the labelling conditions of gallium-68 labelled radiopharmaceuticals most commonly used in positron emission tomography (PET) application.

Description

TITLE

MICROWAVE DEVICE FOR THE RAPID LABELLING OF IN KIT-FORMULATED RADIOPHARMACEUTICALS

TECHNICAL FIELD

The present invention relates to a microwave device specifically designed for radiopharmaceutical applications and able to enhance the commonly used labelling conditions of gallium-68. In particular, it relates to a process in which, thanks to this device, the labelling of bioconjugates compounds with gallium-68, obtained from whatever the current in-use ⁶⁸Ge/⁶⁸Ga generators, is performed directly, without pre purification, in a single vessel and in a few seconds. Such ⁶⁸Ga-labelled radiopharmaceuticals can be used for diagnosis and follow up of neoplastic diseases, inflammatory pathologies and/or metabolic disorders.

BACKGROUND OF THE INVENTION

Radiopharmaceuticals or radiotracers are molecules used in the diagnostic imaging field, for example in positron emission tomography (PET) and in single photon emission computed tomography (SPECT) for diagnosing the presence of diseases, in particular tumours. Radiotracers can also be used for therapeutic purpose in procedures known as peptide receptor radionuclide therapy (PRRT) or immuno-mediated radiotherapy (IRT) depending on the radionuclide associated to the chemical structure.

A radiotracer consists in a molecule covalently bound to a chelating agent able to form stable coordination compounds with a radioactive metal isotope, for example gallium-68, lutetium-177 or technetium-99m. This molecule shows high affinity for a specific molecular receptor which, for example, is over-expressed by tumour cells.

A radiotracer consists also of a molecule following a determinate metabolic pathways, enhanced or in whatever way modified in tumours or other pathologies, covalently bond to a radioactive isotope, for example fluorine-18.

Moreover, a radiotracer also consists in a coordination compound where the complex formed by a ligand and a radioactive metal, for example technetium-99m, is a molecule whose metabolic pathway and accumulation is modified by physiological conditions like disease.

The PET technique has numerous advantages with respect to the SPECT technique in terms of spatial resolution and sensitivity. For this reason, positron- emitting radionuclides are normally preferred over g-emitting radionuclides for labelling peptides or other molecules for diagnostic purposes. Among positron emitters, gallium-68 is one of the most commonly used since it has a positron energy and a half-life suitable for applications in diagnostic nuclear medicine. Furthermore, gallium-68 can be obtained by commercially available ⁶⁸Ge /⁶⁸Ga generators in a chemical form and purity suitable for labelling small molecules and, in particular, peptides. The possibility to use pharmaceutical grade ⁶⁸Ge /⁶⁸Ga generators represents a great advantage for hospital facilities since it avoids the needing to possess a cyclotron in situ as needed, instead, for the production of other radionuclide such as, for example, fluorine-18.

Some successful applications of gallium-68 are in the labelling of somatostatin analogues for the diagnosis of neuroendocrine tumours high expressing somatostatin receptors. The high affinity of the chemical structure for these receptors allows the radiotracer to accumulate in tumour cells. The most commonly used somatostatin derivatives for these applications are TOC, TATE and NOC peptide bound to a proper chelator able to complex metal radionuclides. Other successful ⁶⁸Ga-labelled radiopharmaceuticals are, for instance, the prostate specific membrane antigen (PSMA) inhibitors that are clinically used for the diagnosis and follow-up of prostate cancer. The most commonly used labelled molecules for this application are: [⁶⁸Ga]Ga-PSMA-11 , [⁶⁸Ga]Ga-PSMA-617 and [⁶⁸Ga]Ga-THP-PSMA. The most common chelator for gallium-68 used in clinic are 1 ,4,7,10-tetraacetic acid-1 ,4,7,10- tetraazacyclododecane (DOTA) and N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'- diacetic acid (FIBED-CC), but many other ligands have been studied and are commonly used in medical research.

Normally, the operations for the preparation of ⁶⁸Ga- labelled radiopharmaceuticals are carried out by means of automatic synthesizers, i.e. PLC- guided machines able to reproduce simple laboratory procedures such as generator elution, mixing of reagents, heating, purifications and filtrations without the manual intervention of the operators. However, these synthesizers are quite expensive and require the presence of trained personnel to supervise the process.

In the last years, one of the major goal in the field has been the possibility to prepare ⁶⁸Ga-labelled radiopharmaceuticals by using pre-form ulated kits. A kit for labelling is generally intended as a pharmaceutical formulation of one or more glass vessels that contain not-radioactive precursors and excipients. These formulations can be stored in the proper conditions and used offhand when needed. A kit is built in order to allow the preparation of a radiotracer by direct addition of a solution of gallium-68 to the vessel containing the precursor. Normally, the reactions take place after some minutes of strong heating at 95°C or simple stirring at RT, depending on the precursor. The use of kits allows an easier preparation of radiopharmaceuticals for routine-use in hospitals and normally spares synthetic steps such as processing (purification and concentration) of ⁶⁸Ge /⁶⁸Ga generator eluate as well as the purification post-labelling.

Advanced Accelerator Applications (AAA), a Novartis company, obtained the marketing authorization and launched two kits for the labelling with gallium-68 of somatostatin analogues DOTATOC and DOTATATE. The kits (namely, Somakit TOC™ and NETSPOT™) are approved for diagnosis of gastroentero-pancreatic neuroendocrine tumours (GEP-NET) expressing somatostatin receptors. Some other companies are nowadays applying to obtain the marketing authorization for an in kit- formulation of ⁶⁸Ga- labelled PSMA derivatives.

Due to the difficulty and to the cost of an authorization process, commercial kits are generally designed for a procedure starting from eluates provided by a single commercial generator (GalliaPharm ⁶⁸Ge /⁶⁸Ga generator, Ecker and Ziegler supplier, since it was the first ⁶⁸Ge /⁶⁸Ga generator to obtain the marketing authorization). Using this generator, the whole procedure for elution and subsequent labelling ranges from 15 to 20 minutes with a consequent yield around 81 - 85% and a final declared radiopharmaceutical purity > 91%. Adapting the process to other commercial generators (such as the GalliAd, IRE-Elit supplier, the second generator to obtain the marketing authorization) requires further longer and complicated manipulation due to the technical difference between the two devices. These issues thwart the advantages of using such kind of kits.

Hence, in spite of the goals achieved in the last years, there is still a large room of improvement in the field in order to develop a labelling process with gallium-68 able to provide radiotracers with high purity in a shorter time. The preparation time is particularly important since gallium-68 has a quite short half-life (ca. 68 minutes) and the radiochemical yield (i.e. the total amount of the final radiopharmaceutical available for the clinical application) is strongly influenced by the duration of the labelling process.

Since the mid-1980s microwave applicators or cavities have been used to shorten reaction times in organic syntheses [1] The use of microwave technology, instead of thermal treatment, potentially implies a simplification of the technical apparatus used in some multi-step syntheses. Moreover, the reaction cavity does not retain heat after treatment of the load, as heat is generated preferentially in the load. The same apparatus can therefore be used for different loads, like reactions vessels or, alternatively, for the same load or vessel requiring several different temperatures for successive chemical transformations. The use of microwaves for improving the yield of radiotracers synthesis is already well known from the literature for many radionuclides. The increased rates reported using microwave technology provide a means of decreasing reaction time, and thus increasing the final radiochemical yield of radiopharmaceuticals [2,3] These results indicate that the rapid heating capability of microwave applicators is useful for decreasing reaction times with short-lived radionuclides, and that this technique can be conveniently applied in the synthesis of a wide variety of radiopharmaceuticals or other radiolabelled compounds. Thus the shorter microwave treatment compared to conventional heating not only leads to less decay of the radio-labelled product during synthetic procedures, but may also cause less degradation of reagents and lower generation of side-products which make difficult the isolation of the desired labelled compound.

Particularly speaking about gallium-68 labelled radiotracers, it has been previously reported that the use of microwaves substantially improves the efficiency and reproducibility of the ⁶⁸Ga-complexes formation. For instance, the use of a microwave heating-assisted procedure was reported in the labelling of DOTA-2- deoxy-D-glucosamine (DOTA-DG) but, therein, the reaction time was not bracingly shorter than using conventional heating since 10 minutes were required [4] However, the labelling efficiency and radiochemical purity were ~85% and greater than 98%, respectively. The resulting radiotracer, [⁶⁸Ga]Ga-DOTA-DG, could clearly delineate tumour xenografts in nude mice with high tumour-to-non tumour ratios, making it a potentially useful radiotracer in PET imaging.

In the application U.S. Pat. No. US2006/0188441 A1 the labelling of a radiotracer for EGFR expression by means of microwaves was described but the procedure requires purification of the generator eluates by anion exchange cartridge before the microwave activation thwarting the advantages of the process respect to a classic automated one. In a more recent study, the labelling time of DOTATOC with gallium-68 was shortened substantially up to 2 minutes but the described procedure was only referred to a small aliquot (20 uL, 0.75-1.5 MBq)) of the total generator elution [5] The study represents a good proof of concept that a microwaves heating can strongly speed up the preparation of [⁶⁸Ga]Ga-DOTATOC but the use of a so limited amount of activity and volume does not surely represent the routine clinical application. Hence, although a clearly improvement respect to the traditional labelling procedures has been shown, this kind of microwave device is unsuitable for clinical use where radiotracers have to be injected in patients in a proper amount (111- 185 MBq).

Actually, it is worth to underline that, in all the cited studies, no device has been developed specifically for the labelling of radiopharmaceuticals. In all the cases, the reactions were carried out using commercially available microwave reactors. These devices are designed for chemical processes not involving radioactivity and the reported research activity was only tentatively adapted for the preparation of radiopharmaceuticals.

Radiopharmaceutical synthesis is a close field with peculiar and specific features. Usually, reactions are chemically simple but performed in precise ranges of volume, media and conditions. For this reason, the real potential of the microwaves specifically for this field is not fully unleashed so far.

DETAILED DESCRIPTION OF THE INVENTION

One object of the invention is to provide a microwave device specifically designed for the labelling of radiopharmaceuticals. The microwave device has the function to activate and speed up the reaction in comparison to the commonly used way of heating or room environment stirring. In the contest of this invention, the words “microwave activation”, “microwaves promotion” and synonymous thereof are always referred to a radiolabelling reaction aimed to produce a radiopharmaceutical for clinical use. In this invention, a radiolabelling reaction is considered “activated” or “promoted” when its yield is > 99 % and the product of the reaction has a radiochemical purity > 99 %.

In a preferred embodiment, the device is built for the labelling of kits where kit is intended as vessel/s containing a not radioactive precursor and excipients (buffer, neutralizing agents, stabilizers) to which a solution containing a radioactive radionuclide in a suitable chemical form is added for obtaining a radiotracer.

The device includes a microwave source, preferably a solid state generator, operating within ISM bands, like the one centred on 2.45 GHz, that is connected through a coaxial cable to a single mode cavity. The model geometry is designed for focusing the microwaves action precisely in the housing where the vessel content is positioned in the upper side of the device. A technical sketch of the device is shown in figure 1 [Technical sketch of the single mode cavity].

The reflection coefficient value (i.e. an indication of the energy efficiency of the process of microwave heating) is adjusted by the presence of a stub inside the cavity. The lowest possible value is optimized for the geometries of the vessels normally used for radiopharmaceuticals in-kit preparation and for the solution volumes contained in the vessels.

The reflection coefficient value is optimized as well for the relative permittivity of the mixtures obtained after the addition of all the reagents necessary for the formulation of this kind of radiopharmaceuticals. The dependence of the reflection coefficient value (S11) on the frequency (GHz) applied for two shapes representing vessels used for the radiolabelling, is shown in figure 2 [dependence of the reflection coefficient value (S11) on the frequency applied (GHz) for a 10 ml vessel (A) and for a 30 ml vessel (B)].

The system is designed to accommodate, in a dedicated housing, 1 or more sealed glass vessels with different geometry which internal capacity ranges from 10 to 30 ml. In a preferred embodiment the microwave device is used with a single 10 ml or 25 ml vessel. The vessels can be inserted in the housing from above, sliding through a circular opening in the top of the shell and so as the aluminium ferrule is maintained outside the applicator, i.e. the region of space where microwave-matter interaction occurs. After the reaction, the vessels can be easily extracted using a telescopic tong through the same way.

The system is projected to promote the reactions of different kits containing different precursors and excipients. The relative permittivity of the media formed by the addition of precursor, excipient and radionuclide solutions has been computed in order to optimize the effect of the microwave promotion within the described applicator. In fact, the magnitude of microwaves converted into heat in the load can be measurably influenced by the relative permittivity of the reagent solution itself. Suitable promotion happens when the real part of the relative permittivity (s’) of the mixtures obtained after the addition of all the reagents ranges preferably from 60 to 100, most preferably from 66 to 81, and the imaginary part of the relative permittivity (s ) ranges preferably from 5 to 25, most preferably from 8 to 21 at room temperature.

Suitable microwaves promotion is activated for contents of the vessels comprised between a volume from 1 to 30 ml. Most preferably, when the volume is comprised from 1.1 to 5 ml.

In particular, suitably microwave activation is carried out at 80 to 120 W, preferably at 90 to 110 W, particularly preferably at about 100 W for such load volumes.

Suitable microwave activation times ranges from 10s to 90s, preferably from 30s to 60s, particularly preferably 30s in case the aforementioned output power is used.

In operative condition the reflected energy ranges preferably from 10 to 40 W, most preferably from 15 to 35 W, to minimize power losses.

In a preferred embodiment the radionuclide is gallium-68 and it is obtained by eluting a ⁶⁸Ge /⁶⁸Ga generator. Such generators are known in the art (see for instance references [6,7]) and are commercially available from many suppliers.

Generally, ⁶⁸Ge is loaded onto a column consisting of organic resin or an inorganic metal oxide like tin dioxide, aluminium dioxide, zirconium dioxide or titanium dioxide or organic resins comprising phenolic hydroxyl groups like as pyrogallol (U.S. Pat. No. 4.264,468) . In a preferred embodiment, the gallium-68 solution used with the microwave device described herein is obtained by a ⁶⁸Ge/⁶⁸Ga generator comprising a matrix of titanium dioxide or pyrogallol.

Gallium-68 is obtained by eluting a ⁶⁸Ge/⁶⁸Ga generator with a solution of hydrochloric acid. The concentration and the amount of the aqueous HCI used to elute the whole amount of gallium-68 depends on the column material and it follows the indication of the company supplying the device. Suitably, 0.05 to 5 M HCI is used for the elution of gallium-68. In a preferred embodiment, gallium-68 is eluted using 0.05 to 0.1 M HCI, preferably about 0.1 M HCI. The volume of the HCI used for the elution ranges from 1 ml to 10 ml, preferably from 1.1 ml to 5 ml of HCI. In another embodiment, gallium-68 is eluted with 2.2 ml to 10 ml of HCI 0.05 M. In all cases, gallium-68 is eluted in the [⁶⁸Ga]Ga³⁺ cationic form.

In all the embodiments, the device is assumed to label in one step the whole ⁶⁸Ge/⁶⁸Ga generator eluate without none pre- or post-purification. Labelling of fractions of the eluate is also possible between the indicated ranges of volume.

Preferably, the whole volume of the generator eluate containing gallium-68 is added directly, without purification, to a mixture comprising a precursor tethered to a chelator and a neutralising agent. Most preferably the mixture is a lyophilized powder. pH of the reaction ranges from 3 to 5. Preferably from 3.2 to 4.8. Most preferably from 3.4 to 4.4.

The neutralizing agent is salt of a weak organic acid and the precursor is a molecule with a biological affinity for particular receptors or for a particular metabolism. Said molecule is bound to a proper bifunctional chelator.

Preferably neutralising agent is selected from an alkaline or alkaline-earth salt of formic acid, preferably a sodium or potassium salt of formic acid, or an alkaline or alkaline-earth salt of ascorbic acid, preferably a sodium or potassium salt of ascorbic acid, or an alkaline or alkaline-earth salt of acetic acid, preferably a sodium or potassium salt of acetic acid, or a mono-substituted alkaline or alkaline-earth salt of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) preferably a sodium or potassium salt thereof.

Precursor is preferably selected from the group consisting of: prostate-specific membrane antigen (PSMA) inhibitors, somatostatin analogues, preferably Tyr3- octreotide (TOC), -octreotate (TATE) and -1-Nal3-octreotide NOC, molecules having affinity for the VEGF receptors, bombesin analogues, molecules having affinity for the GRP receptors, molecules having affinity for the estrogen receptors, molecules having affinity for the integrin receptors (peptides RDG a(\/)b(3) and a(\/)b(3)), molecules involved in bone metabolism (diphosphonates), molecules having affinity for the chemokine receptors (CXCR4), molecules having affinity for the cholecystokinin receptor (CCK) and fibroblast activated protein inhibitors (FAPI).

Bifunctional chelator is preferably selected from the group consisting of: 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), 1,4,7- triazacyclononane-1,4,7- triacetic acid (NOTA), 3,6,9,15- tetraazabicyclo[9.3.1]pentadeca-1(15),11 ,13-triene-3,6,9-triacetic acid (PCTA), N,N'- Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBEDD), 6- [Bis(carboxymethyl)amino]-1 ,4-bis(carboxyrnethyl)-6-methyl-1 ,4-diazepane (AAZTA), tris-hydroxypyridinone (THP), 1 ,2-[[6-carboxypyridin-2-yl]methylamino]ethane) (DEDPA), 1 ,4,7-triazacyclononane phosphinic acid (TRAP), 2-[Bis[2- [bis(carboxymethyl)amino]ethyl]amino]acetic acid (DTPA), and derivates thereof.

Most preferably said precursor and chelator is selected from: DOTA-TOC, DOTA-TATE, DOTA-NOC, DOTA-peptide, DOTA-PSMA, HBEDD-PSMA, DOTA- FAPI.

In a preferred embodiment the vessel containing the precursor/neutralizing agent is already inside the resonant cavity of the device and the eluate is added directly from the generator through the elution procedure indicated by the generator supplier.

In other embodiment, the generator is eluted inside an empty vessel inserted in the resonant cavity and the mixture containing the precursor/neutralizing agent, dissolved elsewhere, is added afterwards.

In a third embodiment the mixture of eluate, precursor and neutralizing agent solutions (in any order of addition) is obtained in a vessel elsewhere and then this vessel is put in the resonant cavity.

If the precursor / neutralizing agent are dissolved before the addition of the eluate, the total volume of the reaction (eluate + precursor /neutralizing agent solution) ranges preferably from 1 to 30 ml.

In all the cases the device is then switched on for promoting the reaction of labelling. The power on consist just in an electrical activation. The irradiation parameters are already optimized depending on the precursor and on the vessel geometry. No further intervention is required from the operator.

EXAMPLES:

1- Labelling of PSMA-11 with ⁶⁸Ge/⁶⁸GaGalliAd generator (IRE-Elit)

A commercial 1850 MBq ⁶⁸Ge/⁶⁸Ga Galli-Ad generator (IRE-Elit) is eluted with 1.1 ml of HCI 0.1 M directly in a commercial vessel containing 107 mg of neutralizing agent (sodium ascorbate) and 25 ug of precursor (PSMA-11). The vessel is inserted in the microwave reactor object of this invention and it is activated for 60 second at 100 W power level, resulting in a reflected power of 30-40 W. The vessel is extracted, diluted with 9 ml of saline solution and stored in a shielding. An aliquot is withdrawn for the quality control performed by UHPLC by following the method prescribed in the draft of the European Pharmacopeia for [⁶⁸Ga]Ga-PSMA-11 preparations for injection. Results: Radiochemical yield 99%. Radiochemical Purity 99% (figure 3 - paradigmatic UHPLC chromatogram (radiochemical detector) of a [⁶⁸Ga]Ga-PSMA- 11 preparation using the microwave reactor object of this invention.)

2- Labelling of DOTATOC with ⁶⁸Ge/⁶⁸GaGalliaPharm generator (EZAG)

A commercial 1850 MBq ⁶⁸Ge/⁶⁸Ga GalliaPharm generator (EZAG) is eluted with 5 ml of HCI 0.1 M directly in a commercial vessel containing 42 mg of neutralizing agent (sodium formate) and 50 ug of precursor (DOTATOC). The vessel is inserted in the microwave reactor object of this invention and activated for 90s at 100 W power level, resulting in a reflected power of 15-20 W. The vessel is extracted, diluted with 9 ml of saline solution and stored in a shielding. An aliquot is withdraw for the quality control performed by UHPLC by following the method prescribed in the European Pharmacopeia for [⁶⁸Ga]Ga-DOTATOC preparations for injection.. Results: Radiochemical yield 99%. Radiochemical Purity 99% (figure 4 - paradigmatic UHPLC chromatogram (radiochemical detector) of a [⁶⁸Ga]Ga-DOTATOC preparation using the microwave reactor object of this invention).

3- Labelling of PSMA with ⁶⁸Ge/⁶⁸Ga GalliaPharm generator (EZAG).

A commercial 1850 MBq ⁶⁸Ge/⁶⁸Ga GalliaPharm generator (EZAG) is eluted with 5 ml of HCI 0.1 M directly in a commercial vessel. Then a 300 uL solution containing 42 mg of neutralizing agent (sodium formate) and 25 ug of precursor (PSMA-11) is added. The vessel is inserted in the microwave reactor object of this invention and activated for 30s at 100 W power level, resulting in a reflected power of 15-20 W. The vessel is extracted, diluted with 9 ml of saline solution and stored in a shielding. An aliquot is withdraw for the quality control performed by UHPLC by following the method prescribed in the draft of the European Pharmacopeia for [⁶⁸Ga]Ga-PSMA-11 preparations for injection.. Results: Radiochemical yield 99%. Radiochemical Purity 99%. REFERENCES:

1. Rudolph A. Abramovitch (1991) APPLICATIONS OF MICROWAVE ENERGY IN ORGANIC CHEMISTRY. A REVIEW, Organic Preparations and Procedures International, 23:6, 683-711, DOI: 10.1080/00304949109458244

2. Thorell, J.-O., Stone-Elander, S., & Elander, N. (1992). Use of a microwave cavity to reduce reaction times in radiolabelling with [¹¹C]cyanide. J Labelled Comp Rad 31(3), 207-217. doi:10.1002/jlcr.2580310306

3. Hwang, D.-R., Moerlein, S. M., Lang, L, & Welch, M. J. (1987). Application of microwave technology to the synthesis of short-lived radiopharmaceuticals. J Chem Soc, Chem Comm. (23), 1799. doi:10.1039/c39870001799 4. Yang Z, Xiong C, Zhang R, Zhu H, Li C. Synthesis and evaluation of ⁶⁸Ga- labeled DOTA-2-deoxy-D-glucosamine as a potential radiotracer in mRET imaging. Am J Nucl Med Mol Imaging. 2012; 2(4): 499-507.

5. Yagi Y, Shimizu Y, Arimitsu K, Higuchi T, Togashi K, Kimura H. Efficient gallium-68 radiolabeling reaction of DOTA derivatives using a resonant-type microwave reactor. 2019;62(3): 132-138

6. Loch C, Maziere B, Comar D. A new generator for ionic Gallium-68. J Nucl Med 1980; 21:171-173

7. Schuhmacher J, Maier-Borst W. A new ⁶⁸Ge/⁶⁸Ga radioisotope generator system for production of ⁶⁸Ga in dilute HCI. Int J Appl Radiat Isotopes 1981; 32:31-36

Claims

1. A microwave device specifically designed for the labelling of radiopharmaceuticals The microwave source being preferably a solid state generator operating within ISM bands from 0.3 to 30 GHz.

2. A device of the claim 1, wherein radiopharmaceuticals are gallium-68 labelled molecules.

3. A device of claims 1, 2, wherein radiopharmaceutical are obtained by means of a pre-form ulated kit.

4. A system of claim 1, wherein, in a dedicated housing, the system can irradiate vessels with different geometry which internal capacity ranges from 10 to 40 ml. Preferably, with a single 10 ml or 25 ml vessel.

5. A device of claims 1 ,4, wherein the vessels can be inserted in the housing from above and so as the aluminium ferrule is maintained outside the resonance chamber.

6. A device of claim 1, wherein promotion happens when the real part of the relative permittivity (s’) of the mixtures obtained after the addition of all the reagents ranges preferably from 60 to 100, most preferably from 66 to 81, and the imaginary part of the relative permittivity (s ) ranges preferably from 5 to 25, most preferably from 8 to 21 at RT.

7. A device of claims 1 ,4, wherein microwaves promotion is activated for contents of the vessels comprised between a volume from 1 to 30 ml. Most preferably, when the volume is comprised from 1.1 to 5 ml.

8. A device of claim 1 , wherein microwave activation is carried out at 80 to 120 W, preferably at 90 to 110 W, particularly preferably at about 100 W.

9. A device of claims 1-7 wherein microwave activation times ranges from 20s to 90s, preferably from 30s to 60s, particularly preferably 30s.

10. A device of claims 1-7, wherein, in operative condition, the reflected energy ranges preferably from 10 to 40 W, most preferably from 15 to 35 W.

11. A device of claims 1,2, wherein gallium-68 is obtained by eluting a commercial 6⁸Ge /⁶⁸Ga generator.

12. A method of claim 11, wherein the gallium-68 solution is obtained by a 6⁸Ge/⁶⁸Ga generator comprising a matrix of titanium dioxide or pyrogallol.

13. A method of claims 11,12, wherein gallium-68 is obtained by eluting a 6⁸Ge/⁶⁸Ga generator with a solution of hydrochloric acid.

14. A method of claims 11-13, wherein hydrochloric acid used for the elution of gallium-68 is from 0.05 to 0.1 M.

15. A method of claims 11-14, wherein hydrochloric acid used for the elution is 0.1 M and the elution volumes range from 1 ml to 10 ml. Preferably, from 1.1 ml to 5 ml.

16. A method of claims 11-14, wherein hydrochloric acid used for the elution is 0.05 M and the elution volumes range from 2.2 ml to 10 ml.

17. A device of claims 1-16, wherein the labelling is carried out in one step without neither pre- or post-purification and using the whole ⁶⁸Ge/⁶⁸Ga generator eluate.

18. A method of claim 11-17, wherein the ⁶⁸Ge/⁶⁸Ga generator eluate, a molecular precursor tethered to a chelator and a neutralising agent are mixed and the reaction among them is promoted by a device of claims 1-10.

19. A method of claim 11-18, wherein, the precursor is a biological molecule bound to a proper bifunctional chelator. Precursor is preferably selected from the group consisting of: prostate-specific membrane antigen (PSMA) inhibitors, somatostatin analogues, preferably Tyr3-octreotide (TOC), -octreotate (TATE) and -1-Nal3-octreotide NOC, molecules having affinity for the VEGF receptors, bombesin analogues, molecules having affinity for the GRP receptors, molecules having affinity for the estrogen receptors, molecules having affinity for the integrin receptors (peptides RDG a(\/)b(3) and a(\/)b(3)), molecules involved in bone metabolism (diphosphonates), molecules having affinity for the chemokine receptors (CXCR4), molecules having affinity for the cholecystokinin receptor (CCK) and fibroblast activated protein inhibitors (FAPI). Bifunctional chelator is preferably selected from the group consisting of: 1,4,7,10- tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA), 1,4,7- triazacyclononane-1 ,4,7- triacetic acid (NOTA), 3,6,9,15- tetraazabicyclo[9.3.1 ]pentadeca-1 (15), 11 , 13-triene-3,6,9-triacetic acid (PCTA), N,N'-Di(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBEDD), 6- [Bis(carboxymethyl)amino]-1 ,4-bis(carboxymethyl)-6-methyl-1 ,4-diazepane (AAZTA), tris-hydroxypyridinone (THP), 1 ,2-[[6-carboxypyridin-2- yl]methylamino]ethane) (DEDPA), 1 ,4,7-triazacyclononane phosphinic acid (TRAP), 2-[Bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetic acid (DTPA), and derivates thereof. Most preferably said precursor and chelator bound together is selected from: DOTA-TOC, DOTA-TATE, DOTA-NOC, DOTA-peptide, DOTA- PSMA, HBEDD-PSMA, DOTA-FAPI.

20. A method of claims 11-18, wherein the neutralizing agent is salt of a weak organic acid. Preferably, the organic acid is selected among formic acid, acetic acid, ascorbic acid or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES). Most preferably formic and ascorbic acid. Preferably, the salt is selected among an alkaline or alkaline-earth salt thereof. Most preferably a sodium or potassium salt.

21. A method of claims 11-20 wherein, the mixture chelator-precursor/neutralizing agent is a lyophilized powder contained in a vessel.

22. A method of claims 11-21 wherein, and the reaction occurs when pH ranges from 3 to 5. Preferably from 3.2 to 4.8. Most preferably from 3.4 to 4.4.

23. A method of claims 11-22, wherein: i. the vessel containing the precursor/neutralizing agent is already inside the resonant cavity of the device and the eluate is added directly from the generator ii. the generator is eluted inside an empty vessel inserted in the resonant cavity and the mixture containing the precursor/neutralizing agent, dissolved elsewhere, is added afterwards iii. the mixture of eluate/precursor and neutralizing agent solutions (in any order of addition) is obtained in a vessel elsewhere and then this vessel is put in the resonant cavity.

24. A method of claims 11-17, wherein If the precursor / neutralizing agent are dissolved before the addition of the eluate, the total volume of the reaction (eluate + precursor /neutralizing agent solution) ranges preferably from 1 to 10 ml.