Keywords: PET, Production of medical radionuclides, Cyclotrons, β+γ coincidence Highlights

This paper summarizes the properties, applications and feasible production of all known radioisotopes that can be used in the novel β+γ coincidence PET technique. These radioisotopes include: 10 C, 14 O, 22 Na, 34m Cl, 44g Sc, 48 V, 52m Mn, 55 Co, 60 Cu, 66 Ga, 69 Ge, 72 As, 76 Br, 82g Rb, 86g Y, 94m Tc, 110m In and 124 I.

Introduction

During the recent years, we have witnessed the birth and the steady development of a new approach in Positron Emission Tomography (PET) for the nuclear imaging, namely a β+γ coincidence technique [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF][START_REF] Pentlow | Quantitative imaging of yttrium-86 with PET: the occurrence and correction of anomalous apparent activity in high density regions[END_REF][START_REF] Herzog | PET quantitation and imaging of the non-pure positron-emitting iodine isotope 124 I[END_REF]Lubberink et al., 2002a;[START_REF] Beattie | Quantitative imaging of bromine-76 and yttrium-86 with PET: a method for the removal of spurious activity introduced by cascade gamma rays[END_REF][START_REF] Buchholz | PET imaging with yttrium-86: comparison of phantom measurements acquired with different PET scanners before and after applying background subtraction[END_REF][START_REF] Sandström | Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT[END_REF][START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF][START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF]. Compared to the classical PET, it offers potentially better spatial resolution [START_REF] Sandström | Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT[END_REF][START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF][START_REF] Duval | MPGDs in Compton imaging with liquidxenon[END_REF] or, alternatively, provides the same image quality with less radioactivity (hence reducing the dose to the patient). It also reduces the exposure time that may translate to the increased number of consultations in hospitals per day.

Today, the conventional PET is used worldwide and has been acknowledged as the gold standard in oncology imaging when used with FDG. Its principle and numerous applications were summarized recently by The International Atomic Energy Agency (IAEA, 2008) and The European Association of Nuclear Medicine (EANM 2010[START_REF] Eanm | Principles and Practice of PET/CT Part 2[END_REF]. In general, PET is a technique commonly used in medicine for diagnostic purposes as it allows quantitative in vivo measurements of the distribution of administered positron-emitting radioisotopes in the human body. In short, the radioactive tracer (which have been defined to accumulate in some specific cells) is injected in the patient, decays and produces the positron (β+) that travels few millimetres (depending on the energy) from the decay vertex before annihilating with an electron. Positron-electron annihilation converts them into two 511 keV energy photons (with over 99% probability), which are emitted in opposite directions (in positron-electron center of mass system) and can escape the human body. These photons are then detected in parallel rings of scintillation crystals surrounding the patient. Two detected photons of the right energy allow to assume that the positron emitter is located somewhere in between, at the Line of Response (LoR). In the first approximation, the intersection of multiple LoR provides the distribution of the tracer (although in practice many additional corrections are applied).

The β+γ coincidence is one of the possible extensions of PET modality and its key element is the use of a β+ source that emits additional γ quanta (sometimes called "third γ"). To prevent the overlap of the signals, the typical constraint in the acquisition systems is that the third γ should be emitted from the radioisotope few ps after the β+ decay allowing coincidence measurements [START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF]. Assuming that the β+ particle and the third γ are emitted at the same location, the position of the radioisotope is then obtained by the intersection of the arrival direction of the third γ with the conventional LoR (Fig. 1). This technique allows to localize the emission point on the event-by-event basis [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF][START_REF] Pentlow | Quantitative imaging of yttrium-86 with PET: the occurrence and correction of anomalous apparent activity in high density regions[END_REF][START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF][START_REF] Duval | MPGDs in Compton imaging with liquidxenon[END_REF]. The localization via direction cone implies the Compton scattering of the third γ and the detection of the scattered photon in the photoelectric interaction. This favours a third γ of high energy, around 1 MeV [START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF]. While it would give additional radiation dose to the patient, the precision of the β+γ PET is supposed to allow reducing the administered activity, significantly reducing the overall dose [START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF].

In this article, we review the medical radioisotopes suitable for β+γ coincidence PET. The most important criteria for the candidates are the β+ decay followed by a γ quanta of around 1 MeV emitted few ps later. However, there are many more requirements related to the practical aspects of medical radioisotopes. In particular, β+ branching ratio as well as the intensity of third γ should be as high as possible (preferably 100% for both) to assure the highest probability for the signal detection in the PET scanner. At the same time, radioisotope of interest should emit a limited number of additional γ lines (which would only introduce the noise to the imaging and dose to the patient). Finally, the radioisotope should have feasible production route and convenient half-life (from few hours to few days), suitable for the clinical practice. Obviously, no radioisotope fulfils all these criteria. However, some are very close and could be potentially investigated in β+γ coincidence PET, depending on the parameters of available scanner and the aim of the research or imaging. The most promising radioisotopes are presented in this work, including their applications and production routes investigated so far. The physical properties of all candidates are listed in Table 1 and the natural abundance of the targets discussed for their production is shown in Table 2 (although in certain cases the discussed production route and its yield requires the use of an enriched target with modified composition discussed in the text). Fig. 1. Principle of the β+γ coincidence PET [START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF].

Finally, it is worth mentioning that with the development of new PET scanners, further advancement in β+γ coincidence technique can be expected. Already mentioned XEMIS and XEMIS2 machines offer a sub-millimetre position resolution, a good energy resolution, and a possibility to measure third γ of up to 5 MeV [START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF][START_REF] Duval | MPGDs in Compton imaging with liquidxenon[END_REF][START_REF] Cussonneau | 3γ Medical Imaging with a Liquid Xenon Compton Camera and 44Sc Radionuclide[END_REF][START_REF] Gallego Manzano | XEMIS2: A liquid xenon detector for small animal medical imaging[END_REF]. At the same time, the first PET scanner build from plastic scintillators, J-PET, offers cost-effective whole-body scans with the feasibility of ortho-positronium imaging [START_REF] Gajos | Trilateration-based reconstruction of ortho-positronium decays into three photons with the J-PET detector[END_REF][START_REF] Kamińska | A feasibility study of ortho-positronium decays measurement with the J-PET scanner based on plastic scintillators[END_REF][START_REF] Moskal | Feasibility study of the positronium imaging with the J-PET tomograph[END_REF]. Recently constructed EXPLORER might be also of interest as it has proved its high-sensitive total-body scan [START_REF] Badawi | First Human Imaging Studies with the EXPLORER Total-Body PET Scanner[END_REF].

As a side remark, it is possible to imagine an approach in which LoR is replaced with two (or more) γ-rays emitted from the nucleus, forcing the reconstruction based on three complete Compton events. Some radioisotopes satisfy this criterion, with three high-intensity γ lines and low β+ branching ratio: 94g Tc (T1/2 = 4.9 h), 96 Tc (T1/2 = 4.3 d), 108 In (T1/2 = 58 min), 110g

In (T1/2 = 4.9 h) and 206 Bi (T1/2 = 6.2 d). However, the imaging with this method would require more activity compared to the β+γ coincidence counterpart and is not discussed further in this paper.

There is also a similar PET technique which utilizes a rare three γ quanta emission from the ortho-positronium annihilation [START_REF] Kacperski | Three-gamma annihilation imaging in positron emission tomography[END_REF][START_REF] Kacperski | Performance of three-photon PET imaging: Monte Carlo simulations[END_REF][START_REF] Abuelhia | Three-photon annihilation in PET: 2D imaging experiments[END_REF][START_REF] Gajos | Trilateration-based reconstruction of ortho-positronium decays into three photons with the J-PET detector[END_REF][START_REF] Kamińska | A feasibility study of ortho-positronium decays measurement with the J-PET scanner based on plastic scintillators[END_REF][START_REF] Moskal | Feasibility study of the positronium imaging with the J-PET tomograph[END_REF]. This method can be applied with all β+ radionuclides and is not discussed further here.

34m Cl

Compared to other radioisotopes from this overview, 34m Cl is less popular in the nuclear medicine field. However, it was recognized as potential PET radionuclide [START_REF] Qaim | Production of some medically important short-lived neutrondeficient radioisotopes of halogens[END_REF][START_REF] Helus | Cyclotron production of 34m Cl for biomedical use[END_REF] and has already been used to label dopamine D1 agonists [START_REF] Dejesus | Development of 34m Cl-labeled dopamine D1 agonists as PET imaging agents[END_REF][START_REF] Murali | Synthesis of 34m Cl labeled D1 agonists using electrophilic chlorination[END_REF]. The first factor limiting its popularity is the number of high-intensity γ lines increasing the dose without providing the relevant diagnostic data. The γ line of the highest intensity could be used in β+γ coincidence imaging although other radioisotopes discussed here offer better physical properties for this purpose.

The second limiting factor is the difficult production of 34m Cl. The practical no-carrieradded production uses nat S( ⍺ ,x) reaction. According to the cross-section data [START_REF] Hintz | Excitation Functions to 100 MeV[END_REF][START_REF] Umbarger | Excitation Functions for the Reactions 34 S(p,n) 34 Cl and 31 P(⍺,n) 34[END_REF][START_REF] Nagatsu | Measurement of thick target yields of the nat S(⍺,x) 34m Cl nuclear reaction and estimation of its excitation function up to 70 MeV[END_REF], the required beam energy is around 65 MeV. The saturation of the thick target irradiation results in radio-contaminant-free 1500 MBq/μA 34m Cl [START_REF] Zatolokin | Thick Target Yields of 34m Cl and 38 Cl Produced by Various Charged Particles On Phosphorus, Sulphur and Chlorine Targets[END_REF][START_REF] Takei | Remote control production of an aqueous solution of no-carrier-added 34m Cl-via the 32 S(⍺,pn) nuclear reaction[END_REF][START_REF] Nagatsu | Measurement of thick target yields of the nat S(⍺,x) 34m Cl nuclear reaction and estimation of its excitation function up to 70 MeV[END_REF]. A feasible production chain was also developed, consisting of the 80% effective separation using heated water and HPLC pump [START_REF] Takei | Remote control production of an aqueous solution of no-carrier-added 34m Cl-via the 32 S(⍺,pn) nuclear reaction[END_REF]. Even though this production requires high energy ⍺ beam. Alternative methods face even more difficult problems.

44g

Sc

The 44g Sc radioisotope is one of the most promising β+γ candidate (mentioned as such by [START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF] and the perfect one to set-up the proof of concept of this new imaging modality. It has a convenient half-life (T1/2 = 3.9 h) and emits only one, high-intensity γ-line with a desirable energy (1157 keV, 99%). It has been already used in the study of β+γ coincidence PET with the use of XEMIS and XEMIS2 detectors [START_REF] Grignon | Nuclear medical imaging using β+ γ coincidence from 44 Sc radio-nuclide with liquid xenon as detection medium[END_REF][START_REF] Duval | MPGDs in Compton imaging with liquidxenon[END_REF][START_REF] Cussonneau | 3γ Medical Imaging with a Liquid Xenon Compton Camera and 44Sc Radionuclide[END_REF][START_REF] Gallego Manzano | XEMIS2: A liquid xenon detector for small animal medical imaging[END_REF]. The general interest of 44g Sc was also stressed by [START_REF] Huclier-Markai | Promising Scandium Radionuclides for Nuclear Medicine: A Review on the Production and Chemistry up to In Vivo Proofs of Concept[END_REF] It is not only related to its convenient physical properties, but also to the feasible chemistry (reported mainly for the labelling of DOTA-peptides) supported with the stability and biodistribution studies [START_REF] Koumarianou | Comparison of receptor affinity of nat Sc-DOTA-TATE versus nat Ga-DOTA-TATE[END_REF][START_REF] Cydzik | Labelling of DOTATATE with cyclotron produced 44 Sc and 43 Sc[END_REF][START_REF] Krajewski | Simple procedure of DOTATATE labelling with cyclotron produced 44 Sc and 43 Sc[END_REF][START_REF] Krajewski | Cyclotron production of 44 Sc for clinical application[END_REF][START_REF] Pruszyǹski | Radiolabeling of DOTATOC with the long-lived positron emitter 44[END_REF][START_REF] Roesch | Scandium-44: Benefits of a Long-Lived PET Radionuclide Available from the 44 Ti/ 44 Sc Generator System[END_REF][START_REF] Severin | Cyclotron produced 44g Sc from natural calcium[END_REF][START_REF] Müller | Promises of cyclotron-produced 44 Sc as a diagnostic match for trivalent β-emitters: in vitro and in vivo study of a 44 Sc-DOTA-folate conjugate[END_REF][START_REF] Huclier-Markai | Optimization of reaction conditions for the radiolabeling of DOTA and DOTApeptide with 44m/44 Sc and experimental evidence of the feasibility of an in vivo PET generator[END_REF]Alliot et al., 2015aAlliot et al., , 2015b;;[START_REF] Valdovinos | Separation of cyclotron-produced 44 Sc from a natural calcium target using a dipentyl pentylphosphonate functionalized extraction resin[END_REF][START_REF] Van Der Meulen | Cyclotron production of 44 Sc: from bench to bedside[END_REF][START_REF] Domnanich | 44 Sc for labeling of DOTA-and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations[END_REF][START_REF] Kilian | Separation of 44 Sc from Natural Calcium Carbonate Targets for Synthesis of 44 Sc-DOTATATE[END_REF]. Additionally, its metastable state, 44m Sc (T1/2 = 58.6 h), can be used as long-lived in vivo generator [START_REF] Huclier-Markai | Optimization of reaction conditions for the radiolabeling of DOTA and DOTApeptide with 44m/44 Sc and experimental evidence of the feasibility of an in vivo PET generator[END_REF]Alliot et al., 2015aAlliot et al., , 2015b;;[START_REF] Alliot | Is there an interest to use deuteron beams to produce non-conventional radionuclides?[END_REF] as it decays mainly by a low energy transition to the ground state. Finally, 44g Sc can be used as counterpart of therapeutic partners. It forms a theranostic pair with 47 Sc (T1/2 = 3.35 d), which is a low-energy β-emitter for targeted radiotherapy, allowing the application of the theranostic approach [START_REF] Müller | Promising prospects for 44 Sc-/ 47 Sc-based theragnostics: application of 47 Sc for radionuclide tumor therapy in mice[END_REF][START_REF] Müller | Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application[END_REF]. It can also be used with the therapeutic 177 Lu as they share similar chemistry [START_REF] Umbricht | 44 Sc-PSMA-617 for radiotheragnostics in tandem with 177 Lu-PSMA-617preclinical investigations in comparison with 68 Ga-PSMA-11 and 68 Ga-PSMA-617[END_REF].

The most interesting production route is via 44 Ca(p,n) reaction with the CaCO3 or CaO, [START_REF] Khandaker | Investigations of the nat Ti[END_REF][START_REF] Krajewski | Simple procedure of DOTATATE labelling with cyclotron produced 44 Sc and 43 Sc[END_REF][START_REF] Krajewski | Cyclotron production of 44 Sc for clinical application[END_REF][START_REF] Severin | Cyclotron produced 44g Sc from natural calcium[END_REF][START_REF] Müller | Promises of cyclotron-produced 44 Sc as a diagnostic match for trivalent β-emitters: in vitro and in vivo study of a 44 Sc-DOTA-folate conjugate[END_REF][START_REF] Müller | Promising prospects for 44 Sc-/ 47 Sc-based theragnostics: application of 47 Sc for radionuclide tumor therapy in mice[END_REF][START_REF] Hernandez | 44 Sc: an attractive isotope for peptide-based PET imaging[END_REF][START_REF] Hoehr | 44g Sc production using a water target on a 13 MeV cyclotron[END_REF][START_REF] Valdovinos | Separation of cyclotron-produced 44 Sc from a natural calcium target using a dipentyl pentylphosphonate functionalized extraction resin[END_REF][START_REF] Van Der Meulen | Cyclotron production of 44 Sc: from bench to bedside[END_REF][START_REF] Singh | Scandium-44 DOTATOC PET/CT: first in-human molecular imaging of neuroendocrine tumors and possible perspectives for theranostics[END_REF][START_REF] Domnanich | 44 Sc for labeling of DOTA-and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations[END_REF][START_REF] Carzaniga | Measurement of 43 Sc and 44 Sc production crosssection with an 18 MeV medical PET cyclotron[END_REF][START_REF] Sitarz | Production of Sc medical radioisotopes with proton and deuteron beams[END_REF] which can be later easily dissolved for the chemical separation (Cydzik et al., 2012;[START_REF] Krajewski | Simple procedure of DOTATATE labelling with cyclotron produced 44 Sc and 43 Sc[END_REF][START_REF] Krajewski | Cyclotron production of 44 Sc for clinical application[END_REF][START_REF] Pruszyǹski | Radiolabeling of DOTATOC with the long-lived positron emitter 44[END_REF][START_REF] Severin | Cyclotron produced 44g Sc from natural calcium[END_REF][START_REF] Müller | Promises of cyclotron-produced 44 Sc as a diagnostic match for trivalent β-emitters: in vitro and in vivo study of a 44 Sc-DOTA-folate conjugate[END_REF][START_REF] Huclier-Markai | Optimization of reaction conditions for the radiolabeling of DOTA and DOTApeptide with 44m/44 Sc and experimental evidence of the feasibility of an in vivo PET generator[END_REF]Alliot et al., 2015b;[START_REF] Valdovinos | Separation of cyclotron-produced 44 Sc from a natural calcium target using a dipentyl pentylphosphonate functionalized extraction resin[END_REF][START_REF] Van Der Meulen | Cyclotron production of 44 Sc: from bench to bedside[END_REF][START_REF] Domnanich | 44 Sc for labeling of DOTA-and NODAGA-functionalized peptides: preclinical in vitro and in vivo investigations[END_REF][START_REF] Kilian | Separation of 44 Sc from Natural Calcium Carbonate Targets for Synthesis of 44 Sc-DOTATATE[END_REF]. A standard 16 MeV proton beam of 1 μA can produce up to 20 MBq (CaCO3) or 35 MBq (CaO) after 1 h of irradiation of natural targets and 40-50 times more if the commercially available >90% enrichment is used. In case of natural target, 43 Sc (T1/2 = 3.89 h) is present at the level of 3% while the use of the enriched target eliminates the radioactive impurities almost completely [START_REF] Sitarz | Production of Sc medical radioisotopes with proton and deuteron beams[END_REF]. Alternatively, 44g Sc can be obtained from 44 Ti/ 44g Sc generator (T1/2 = 59.1 y) as pointed out by [START_REF] Filosofov | A 44 Ti/ 44 Sc radionuclide generator for potential nuclear-medical application of 44 Sc-based PET-radiopharmaceuticals[END_REF][START_REF] Pruszyǹski | Post-elution processing of Ti-44/Sc-44 generator-derived Sc-44 for clinical application[END_REF][START_REF] Pruszyǹski | Radiolabeling of DOTATOC with the long-lived positron emitter 44[END_REF][START_REF] Roesch | Scandium-44: Benefits of a Long-Lived PET Radionuclide Available from the 44 Ti/ 44 Sc Generator System[END_REF] and summarized recently by [START_REF] Hassan | Production of 44 Ti⍺ 44 Sc Generator in Comparison with Direct Routes by Cyclotrons: Cross Section Evaluation Using Nuclear Models Codes[END_REF]. Currently, such generator is available in Mainz, with 185 MBq 44 Ti and the possibility to extract 97% 44g Sc in 20 mL solution [START_REF] Filosofov | A 44 Ti/ 44 Sc radionuclide generator for potential nuclear-medical application of 44 Sc-based PET-radiopharmaceuticals[END_REF].

Still, the most accessible optimal production route is the irradiation of >90% enriched 44 CaCO3 or 44 CaO with proton beam, yielding up to 1000 MBq/μAh or 1700 MBq/μAh respectively and less than 1% of radioactive contaminants.

V

48

V radioisotope is well-known only as a monitor for the beam current measurements (IAEA, 2017). It emits two high-intensity γ lines and has a β+ branching ratio of only 50%. However, it has the longest half-life (16 d) among all discussed β+γ candidates, suitable for the studies of slow metabolic processes and for the labelling of organic compounds [START_REF] Qaim | Development of novel positron emitters for medical applications: nuclear and radiochemical aspects[END_REF]. The prospects of 48 V were recently reminded by [START_REF] Usman | Cyclotron production of 48 V via nat Ti(d,x) 48 V nuclear reaction; a promising radionuclide[END_REF] as it is already finding applications as a tracer in biological actions in plants (Xuam Tham et al., 2001), in material science [START_REF] Rorat | Thermoluminescence dosimetry of model line sources containing vanadium-48[END_REF] or in the renal artery brachytherapy [START_REF] Arbabi | Irradiation and dosimetry of Nitinol stent for renal artery brachytherapy[END_REF]. As suggested by [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF] it is also a promising candidate for the coincidence PET. However, it should be noted that the second high-intensity γ line from 48 V would introduce additional dose for the patient and noise in the imaging without providing the relevant diagnostic data.

As summarized in IAEA, 2017, the cross-sections for different production of 48 V are well measured and suggest the route via nat Ti(p,x) reaction [START_REF] Smith | Production and Selection of Metal PET Radioisotopes for Molecular Imaging[END_REF]. The major contribution comes from 48 Ti(p,n) reaction suitable for the energy of the commonly available cyclotrons and the target nuclide has high natural abundance. With 16 MeV beam and 1 μAh irradiation of 90% enriched 48 Ti target, over 20 MBq of 48 V can be produced, with less than 0.5% of radioactive impurity of 49 V (T1/2 = 330 d).

52m Mn

The recent advancements in hybrid MRI induced the interest in 52g Mn radioisotope. It was suggested as the tracer of Mn +2 ions [START_REF] Lewis | 52 Mn Production for PET/MRI Tracking Of Human Stem Cells Expressing Divalent Metal Transporter 1 (DMT1)[END_REF] that serve as the T1 MRI relaxation agent in the Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) [START_REF] Koretsky | Manganese-enhanced magnetic resonance imaging (MEMRI)[END_REF][START_REF] Silva | Manganese-enhanced magnetic resonance imaging(MEMRI): methodological and practical considerations[END_REF][START_REF] Wadghiri | Manganese-enhanced magnetic resonance imaging(MEMRI) of mouse brain development[END_REF][START_REF] Silva | Manganese-Enhanced MRI: An Exceptional Tool in Translational Neuroimaging[END_REF][START_REF] Massaad | Manganese-Enhanced Magnetic Resonance Imaging (MEMRI)[END_REF][START_REF] Cacace | Manganese enhanced magnetic resonance imaging (MEMRI): a powerful new imaging method to study tinnitus[END_REF]. However, in the light of the reported risk regarding the use of the bulk manganese [START_REF] Crossgrove | Manganese toxicity upon overexposure[END_REF], the use of 52g Mn in conventional PET/MRI was suggested [START_REF] Graves | Novel Preparation Methods of 52 Mn for ImmunoPET Imaging[END_REF] to obtain analogous data with lower biological toxicity. Meanwhile, its metastable level, 52m Mn, has very high β+ branching ratio and emits only one, high-energy and high-intensity γ line. Since the β+γ coincidence imaging requires less activity, the toxicity of magnesium in PET/MRI could be further reduced with the use of 52m Mn (already suggested for β+γ coincidence PET by [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF]. However, it should be noted that significant modifications might be in order for PET hardware to permit the acquisition in the presence of a strong magnetic field and radiofrequency pulses [START_REF] Disselhorst | Principles of PET/MR Imaging[END_REF].

The best access to 52m Mn is through a generator, 52g Fe/ 52m Mn, since 52g Fe decays in 100% to 52m Mn. The co-produced 52m Fe (T1/2 = 46 s) decays in 100% to 52g Mn though so it should be taken into account by managing the post-irradiation separation, rapidly removing early 52g Mn and later waiting for 52m Mn to be formed from 52g Fe. The possible production routes for 52g Fe/ 52m Mn generator have been summarized by [START_REF] Atcher | Production of 52 Fe for Use in a Radionuclide Generator System[END_REF]Steyn et al., 1990. According to the literature, a reasonable option is to irradiate thick nat Mn target with protons of energy from 40-50 to 60-75 MeV. This procedure is routinely used in Brookhaven Linac Isotope Producer. Up to 22 MBq/μAh of 52g Fe/ 52m Mn was reached, with no more than 1% of 55 Fe contaminant. 55 Co 55 Co has been acknowledged as "the emerging PET radionuclide" by [START_REF] Amjed | Evaluation of nuclear reaction cross sections for optimization of production of the emerging diagnostic radionuclide 55[END_REF], as it features high β+ branching ratio, half-life favouring the studies of slow biological process and feasible labelling with different complexes as well as satisfactory biodistribution [START_REF] Srivastava | Production and use of cobalt-55 as an antibody label for PET imaging[END_REF][START_REF] Thisgaard | Radiosynthesis of 55 Co-and 58m Co-labelled DOTATOC for positron emission tomography imaging and targeted radionuclide therapy[END_REF][START_REF] Mastren | Cyclotron Production of High-Specific Activity 55 Co and In Vivo Evaluation of the Stability of 55 Co Metal-Chelate-Peptide Complexes[END_REF][START_REF] Dam | Vivo Evaluation of a bombesin analogue labeled with Ga-68 and Co-55/57[END_REF][START_REF] Garousi | The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule[END_REF]. The mentioned paper summarized numerous applications of 55 Co which include: the lung cancer detection [START_REF] Nieweg | Detection of Lung Cancer with 55 Co-Bleomycin Using a Positron Camera. A Comparison with 57 Co-Bleomycin and 55 Co-Bleomycin Single Photon Scintigraphy[END_REF], the renal imaging [START_REF] Goethals | 55 Co-EDTA for renal imaging using positron emission tomography (PET): A feasibility study[END_REF] and the neuro-imaging [START_REF] Jansen | Visualization of damaged brain tissue after ischemic stroke with Cobalt-55 Positron Emission Tomography[END_REF][START_REF] Jansen | Cobalt-55 positron emission tomography in traumatic brain injury, a pilot study[END_REF][START_REF] Jansen | Cobalt-55 positron emission tomography in ischemic stroke[END_REF][START_REF] Stevens | 55 Cobalt (Co) as a PET-tracer in stroke, compared with blood flow,oxygen metabolism, blood volume and gadolinium-MRI[END_REF][START_REF] Reuck | Cobalt-55 positron emission tomography in symptomatic atherosclerotic carotid artery disease: borderzone versus territorial infarcts[END_REF]. These procedures can be also performed with β+γ coincidence PET (suggested by [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF] since 55 Co emits one high-intensity high-energy γ line. Additionally, there is a theranostic matched pair with Auger-emitting 58m Co. However, it is worth mentioning that two additional low-intensity γ lines from 55 Co would introduce additional dose to the patient and noise to the imaging.

The production routes of 55 Co have been thoroughly studied via different nuclear reactions, for which the cross-section and thick target yield data are very well reported. The most promising one is 54 Fe(d,n) reaction [START_REF] Sharma | Production of cobalt-55, a short-lived, positron emitting radiolabel for bleomycin[END_REF][START_REF] Zaman | Excitation functions of (d,n) and (d,α) reactions on highly enriched 54 Fe: Relevance to the production of high purity 55 Co at a small cyclotron[END_REF][START_REF] Hermanne | Experimental study of excitation functions for some reactions induced by deuterons (10-50 Mev) on natural Fe and Ti[END_REF][START_REF] Zaman | Production of 55 Co via the 54 Fe(d,n)process and excitation functions of 54 Fe(d,t) 53 Fe and 54 Fe(d,α) 52m Mn reactions from thresholds up to 13.8 MeV[END_REF][START_REF] Nakao | Measurements of deuteron-induced activation cross-sections for IFMIF accelerator structural materials[END_REF][START_REF] Király | Evaluated activation cross sections of longer-lived radionuclides produced by deuteron induced reactions on natural iron up to 10 MeV[END_REF][START_REF] Thisgaard | Radiosynthesis of 55 Co-and 58m Co-labelled DOTATOC for positron emission tomography imaging and targeted radionuclide therapy[END_REF][START_REF] Závorka | The activation of Fe by deuterons at energies up to 20 MeV[END_REF][START_REF] Khandaker | Activation cross-sections of deuteron-induced nuclear reactions on natural iron up to 24 MeV[END_REF][START_REF] Avrigeanu | Elastic deuteron scattering and optical model parameters at energies up to 100 MeV[END_REF][START_REF] Valdovinos | Cyclotron production and radiochemical separation of 55 Co and 58m Co from 54 Fe, 58 Ni and 57 Fe targets[END_REF] which requires enriched target to produce sufficient quantities as well as avoid the co-production of long-lived radioactive impurities of 56 Co and 57 Co as they emit high intensity γ lines which unnecessarily increase the dose. The commercially available enrichment exceeds 95% in the form of metal ( 54 Fe) or oxide ( 54 Fe2O3). For example, with the metal target and 1 μAh irradiation of 8 or 15 MeV deuteron beam, up to 20 MBq or 40 MBq of 55 Co respectively can be produced, with negligible amount of 56 Co and 57 Co [START_REF] Sharma | Production of cobalt-55, a short-lived, positron emitting radiolabel for bleomycin[END_REF]. Cu is a short-lived β+ emitter with an additional γ line making it suitable for β+γ coincidence PET [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF]. So far, it has only been used in standard PET technique along with the labelling studies of 60 Cu-ATSM for tumor hypoxia imaging [START_REF] Blower | Copper radionuclides and radiopharmaceuticals in nuclear medicine[END_REF][START_REF] Mccarthy | High Purity Production and Potential Applications of Copper-60 and Copper-61[END_REF][START_REF] Chao | A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy[END_REF][START_REF] Dehdashti | In vivo assessment of tumor hypoxia in lung cancer with 60 Cu-ATSM[END_REF][START_REF] Dietz | Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study[END_REF][START_REF] Lewis | An Imaging Comparison of 64 Cu-ATSM and 60 Cu-ATSM in Cancer of the Uterine Cervix[END_REF]. It also has a theranostic matched pair, 67 Cu, the β-emitter for targeted radionuclide therapy.

The most commonly used production route of 60 Cu is via 60 Ni(p,n) or nat Ni(p,x) reactions (used in above-mentioned papers). The corresponding cross-sections have been already well reported [START_REF] Blosser | Survey of (p, n) Reactions at 12 MeV[END_REF][START_REF] Tanaka | Nuclear reactions of nickel with protons up to 56 MeV[END_REF][START_REF] Barrandon | Étude du dosage de Ti, V, Cr, Fe, Ni, Cu et Zn par activation avec des protons d'énergie limitée a 20 MeV[END_REF][START_REF] Levkovskij | Cross-section of medium mass nuclide activation (A=40-100) by medium energy protons and alpha-particles (E=10-50 MeV)[END_REF][START_REF] Singh | A study of pre-equilibrium emission in some proton-and alpha-induced reactions[END_REF][START_REF] Saleh | Excitation functions of (p,x) reactions on natural nickel between proton energies of 2.7 and 27.5[END_REF][START_REF] Amjed | Activation cross-sections of proton induced reactions on natural Ni up to 65 MeV[END_REF]. Irradiations of thick 60 Ni targets (with commercially available 99% enrichment) with proton beam of 16 MeV and 1 μA for 20 minutes, followed by 1 h post-irradiation processing time, are sufficient to achieve up to 400 MBq of 60 Cu.

66

Ga

The radioisotope of 66 Ga already has multiple applications and it has been widely used as PET radioisotope. Labelled with albumin colloids from commercially available kits designed for 99m Tc, 66 Ga was successfully used in the imaging of the lymphatic transport [START_REF] Goethals | Cyclotron production of carrier-free 66 Ga as a positron emitting label of albumin colloids for clinical use[END_REF]. The feasible 66 Ga labelling and purification was also reported for DOTA-peptides 66 Ga-DOTA-Tyr3-octreotide and 66 Ga-DOTA-biotin [START_REF] Lewis | Production and purification of gallium-66 for preparation of tumor-targeting radiopharmaceuticals[END_REF], the blood cells [START_REF] Ellis | Co, Fe and Ga chelates for cell labelling: a potential use in PET imaging[END_REF]Jalilian et al. 2003) and 66 Ga-deferoxamine-folate for in vivo and in vitro imaging [START_REF] Ke | The folate receptor as a molecular target for tumor-selective radionuclide delivery[END_REF][START_REF] Ke | Folate-receptor-targeted radionuclide imaging agents[END_REF][START_REF] Mathias | Preparation of 66 Ga-and 68 Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals[END_REF]. Additionally, the most abundant β+ emitted by 66 Ga has a uniquely high energy, which allowed the use of 66 Ga-DOTATOC for both PET imaging and radiotherapy [START_REF] Ugur | Ga-66 labeled somatostatin analogue DOTA-DPhe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors[END_REF]. Finally, 66 Ga emits high-energy γ line making it appropriate for β+γ coincidence PET. However, it also emits many less intense but high-energy γ lines that will introduce noise in the imaging and dose to the patient.

The method of choice to produce 66 Ga is via 66 Zn(p,n) reaction. In this case, several cross-section data [START_REF] Hille | Excitation functions of (p,n) and (⍺,n) reactions on Ni, Cu and Zn[END_REF][START_REF] Little | Cyclotron production of 67 Ga. Cross section and thick-target yields for the 67 Zn(p,n) and 68 Zn(p,2n) reactions[END_REF][START_REF] Kopeckỳ | Cross sections and production yields of 66 Ga and 67 Ga for proton reactions in natural zinc[END_REF][START_REF] Tárkányi | Excitation Functions of Proton Induced Nuclear Reactions on Enriched 66 Zn, 67 Zn and 68 Zn. Production of 67 Ga and 66 Ga[END_REF]Levkovskijj, 1991;[START_REF] Hermanne | Optimization of isotope production by cross-section determination[END_REF][START_REF] Nortier | Excitation function and yield of relevance to the production of 67 Ga by proton bombardment of nat Zn and nat Ga up to 100 MeV[END_REF][START_REF] Szelecsényi | Evaluated cross section and thick target yield data bases of Zn + p processes for practical applications[END_REF][START_REF] Szelecsényi | New cross-section data for the 66 Zn(p,n) 66 Ga, 68 Zn(p,3n) 66 Ga, nat Zn(p,x) 66 Ga, 68 Zn(p,2n) 67 Ga and nat Zn(p,x) 67 Ga nuclear reactions up to 100 MeV[END_REF] and thick target yield data [START_REF] Barrandon | Étude du dosage de Ti, V, Cr, Fe, Ni, Cu et Zn par activation avec des protons d'énergie limitée a 20 MeV[END_REF][START_REF] Intrator | Determination of proton spectra by thick target radioactive yields[END_REF][START_REF] Dmitriev | Radionuclide yield in reaction with protons, deuterons, alpha particles and helium-3 (hand book)[END_REF][START_REF] Kopeckỳ | Cross sections and production yields of 66 Ga and 67 Ga for proton reactions in natural zinc[END_REF][START_REF] Tárkányi | Excitation Functions of Proton Induced Nuclear Reactions on Enriched 66 Zn, 67 Zn and 68 Zn. Production of 67 Ga and 66 Ga[END_REF][START_REF] Nortier | Excitation function and yield of relevance to the production of 67 Ga by proton bombardment of nat Zn and nat Ga up to 100 MeV[END_REF][START_REF] Lewis | Production and purification of gallium-66 for preparation of tumor-targeting radiopharmaceuticals[END_REF][START_REF] Rowshanfarzad | Production and quality control of 66 Ga as a PET radioisotope[END_REF] were investigated. This reaction was also summarized and re-evaluated with ALICE/ASH 0.1 and TALYS-1.2 by [START_REF] Sadeghi | Nuclear data for the cyclotron production of 66 Ga, 86 Y, 76 Br, 64 Cu and 43 Sc in PET imaging[END_REF] The natural abundance of 66 Zn is quite low but a feasible method was reported for the preparation and recovery of the enriched target [START_REF] Rowshanfarzad | Production and quality control of 66 Ga as a PET radioisotope[END_REF]. Around 200 mg/cm 2 of 66 Zn material is enough for the optimal production of 66 Ga with the 15 MeV proton beam. The reported yield for 99% enriched target was around 500 MBq/μAh of radionuclidically pure 66 Ga. The optimal post-irradiation processing of Zn targets and 66 Ga separation was found to be a cation-exchange chromatography and/or liquid-liquid extraction method [START_REF] Lewis | Production and purification of gallium-66 for preparation of tumor-targeting radiopharmaceuticals[END_REF][START_REF] Rowshanfarzad | Production and quality control of 66 Ga as a PET radioisotope[END_REF].

69

Ge

The unravelled potential of 69 Ge [START_REF] Mirzadeh | Radiochemistry of germanium[END_REF] is mainly related to the common interest shifted on a different germanium isotope (namely, the 68 Ge/ 68 Ga generator, summarized by [START_REF] Rösch | Past, present and future of 68 Ge/ 68 Ga generators[END_REF]Velikyan, 2015). However, its physical properties make it a possible β+γ coincidence PET agent, yet with an inconveniently low β+ branching ratio, similarly low intensity of 1 MeV γ line, and the presence of additional γ lines. On the other hand, its chemistry is already well developed for the purpose of the mentioned generator. So far, it was only used to label nanoparticles for successful in vivo PET/MRI imaging [START_REF] Hernandez | 44 Sc: an attractive isotope for peptide-based PET imaging[END_REF]. Due to its long half-life, it can be also considered for immunoPET studies and antibody labelling.

The production of the applicable amounts of 69 Ge was not yet investigated but the cross-section for 69,nat Ga(p,n) reaction [START_REF] Levkovskij | Cross-section of medium mass nuclide activation (A=40-100) by medium energy protons and alpha-particles (E=10-50 MeV)[END_REF][START_REF] Porile | Nuclear reactions of Ga 69 and Ga 71 with 13-56 MeV protons[END_REF][START_REF] Johnson | Thresholds for (p,n) reactions on 26 intermediate-weight nuclei[END_REF][START_REF] Adam-Rebeles | 68 Ge/ 68 Ga production revisited: excitation curves, target preparation and chemical separation -purification[END_REF][START_REF] Hermanne | Proton and deuteron induced reactions on nat Ga: Experimental and calculated excitation functions[END_REF] seems the most cost-efficient and available for small cyclotrons. The 16 MeV beam interacting on a thick nat Ga target would produce around 110 MBq/μAh. However, no cross-section data is available to estimate the co-production of radioactive impurity of 71 Ge. The measurement is challenging due to no γ emission but important as 71 Ge is the long-lived Auger-emitter which would contribute to the dose.

As

In the nuclear medicine, another popular PET radioisotope, 72 As, can be considered in the β+ɣ coincidence PET thanks to its additional γ line. It has proven its favourable physical and chemical properties in labelling and preclinical studies [START_REF] Hosain | Synthesis of radioarsenic labeled dimethylchloroarsine for derivation of a new group of radiopharmaceuticals[END_REF][START_REF] Emran | Synthesis and biodistribution of radioarsenic labeled dimethylarsinothiols: Derivatives of penicillamine and mercaptoethanol[END_REF][START_REF] Ballard | Radioarsenic from a portable 72 Se/ 72 As generator: a current perspective[END_REF][START_REF] Ellison | High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals[END_REF]. Furthermore, it has a therapeutic matched pair in the form of the β-emitting 77 As. Both radioisotopes have been studied in preclinical and clinical research [START_REF] Nayak | Radioimmunoimaging with Longer-Lived Positron-Emitting Radionuclides: Potentials and Challenges[END_REF][START_REF] Ellison | High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals[END_REF]. Arsenic itself, in the form of the arsenic trioxide, is a popular anticancer drug [START_REF] Ravandi | Arsenic trioxide: expanding roles for an ancient drug[END_REF], successfully used recently in the clinical treatment of the acute promyelocytic leukemia [START_REF] Miller | Mechanisms of action of arsenic trioxide[END_REF][START_REF] Lu | Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide[END_REF].

There are many methods for the direct production of 72 As, however much more attention is paid to the generator 72 Se/ 72 As due to its convenient half-life of 8.4 d. Many practical extraction methods for this generator have already been reported (Al-Kouraishi and Boswell, 1978;[START_REF] Phillips | Chemistry and Concept for an Automated 72 Se/ 72 As Generator[END_REF][START_REF] Jennewein | A no-carrieradded 72 Se/ 72 As radionuclide generator based on distillation[END_REF][START_REF] Jennewein | A no-carrier-added 72 Se/ 72 As radionuclide generator based on solid phase extraction[END_REF][START_REF] Ballard | Radioarsenic from a portable 72 Se/ 72 As generator: a current perspective[END_REF]Ballard et al., , 2012b;;[START_REF] Chajduk | Novel radiochemical separation of arsenic from selenium for 72 Se/ 72 As generator[END_REF][START_REF] Wycoff | Chromatographic separation of selenium and arsenic: a potential 72 Se/ 72 As generator[END_REF][START_REF] Feng | Evaluation of 72 Se/ 72 As generator and production of 72 Se for supplying 72 As as a potential PET imaging radionuclide[END_REF]. According to the literature, the best method for the production of 72 Se/ 72 As leads via 70 Ge( ⍺ ,2n) reaction [START_REF] Amiel | Reactions of Alpha Particles with Germanium-70 and Zinc-70[END_REF]Al-Kouraishi and Boswell, 1978;[START_REF] Calboreanu | Formation and Decay of the Compound Nucleus in Alpha Induced Reaction on 70 Ge[END_REF][START_REF] Mushtaq | Excitation Function of ⍺-and 3 He-Particle Induced Nuclear Reactions on Natural Germanium: Evaluation of production routes for 73 Se[END_REF][START_REF] Levkovskij | Cross-section of medium mass nuclide activation (A=40-100) by medium energy protons and alpha-particles (E=10-50 MeV)[END_REF][START_REF] Jennewein | A no-carrier-added 72 Se/ 72 As radionuclide generator based on solid phase extraction[END_REF][START_REF] Szkliniarz | Medical radioisotopes produced using the alpha particle beam from the warsaw heavy ion cyclotron[END_REF][START_REF] Takács | Activation cross sections of longer-lived radionuclides produced in germanium by alpha particle irradiation[END_REF][START_REF] Feng | Evaluation of 72 Se/ 72 As generator and production of 72 Se for supplying 72 As as a potential PET imaging radionuclide[END_REF]. To reduce the formation of radioactive impurity 75 Se that decays to stable 75 As, the enriched 70 Ge target is recommended (commercially available enrichment is about 96%). The 6 h irradiation with 20 μ A and the energy range of 47→0 MeV produces around 250 MBq 72 Se [START_REF] Feng | Evaluation of 72 Se/ 72 As generator and production of 72 Se for supplying 72 As as a potential PET imaging radionuclide[END_REF] from which around 70 MBq 72 As can be extracted each day during the following week. The reported radioactive impurities of arsenic can be removed during the preparation of the generator.

Br

The radioisotope of 76 Br has a large number of accompanying γ rays, from which the most intensive makes 76 Br a possible β+γ candidate (as suggested by Lubberink et al., 2002a;[START_REF] Sandström | Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT[END_REF][START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF] whose coincidence PET imaging and γ cascade correction have already been investigated (Lubberink et al., 2002a). There are two factors limiting the possible interest in 76 Br: the γ line used for the coincidence has quite low energy and other γ lines contribute to the dose. However, the labelling chemistry of bromine is similar to that of iodine, which is relatively well investigated [START_REF] Maziere | Radiopharmaceuticals labelled with bromine isotopes[END_REF] and might render 76 Br worth considering. So far, it has been successfully used to study the dopamine receptors associated with the diagnosis of schizophrenia [START_REF] Martinot | The estimated density of D2 striatal receptors in schizophrenia. A study with positron emission tomography and 76 Brbromolisuride[END_REF]1994), as the amino acid tracer [START_REF] Hanaoka | Development of a Widely Usable Amino Acid Tracer: 76Br-⍺-Methyl-Phenylalanine for Tumor PET Imaging[END_REF], as the monitor for corticotropin-releasing hormone (Jagoda et al., 2011), as the bromo analogue marker to diagnose heart disease [START_REF] Loc'h | Preparation and pharmacological characterization of [ 76 Br]-meta-brombenzylguanidine[END_REF], for the labelling of mouse epidermal growth factor [START_REF] Scott-Robson | Distribution and stability in the rat of a 76 Br/ 125 I-labelled polypeptide, epidermal growth factor[END_REF] and to study the tumor angiogenesis by labelling a human antibody [START_REF] Rossin | Small-Animal PET of Tumor Angiogenesis Using a 76Br-Labeled Human Recombinant Antibody Fragment to the ED-B Domain of Fibronectin[END_REF]. Additionally, 76 Br was used to verify the thymidine analogue, BUdR, as the tumor cell proliferation imaging agent (Gardelle et al., 2001).

As summarized by [START_REF] Hassan | Experimental studies and nuclear model calculations on proton-induced reactions on nat Se, 76 Se and 77 Se with particular reference to the production of the medically interesting radionuclides 76 Br and 77[END_REF][START_REF] Sadeghi | Nuclear data for the cyclotron production of 66 Ga, 86 Y, 76 Br, 64 Cu and 43 Sc in PET imaging[END_REF], the most feasible method for production of 76 Br is the direct route via 76 Se(p,n) reaction for which the crosssection data [START_REF] Kovàcs | Production of 75 Br via 76 Se(p,2n) 75 Br reaction at a compact cyclotron[END_REF][START_REF] Levkovskij | Cross-section of medium mass nuclide activation (A=40-100) by medium energy protons and alpha-particles (E=10-50 MeV)[END_REF][START_REF] Hassan | Experimental studies and nuclear model calculations on proton-induced reactions on nat Se, 76 Se and 77 Se with particular reference to the production of the medically interesting radionuclides 76 Br and 77[END_REF][START_REF] El-Azony | Excitation functions of proton induced reactions on natural selenium up to 62 MeV[END_REF] and experimental yields [START_REF] Janssen | The reactions 77 Se(p,n) and 78 Se(p,2n) as production routes for 77[END_REF][START_REF] Tolmachev | Production of 76 Br by a low-energy cyclotron[END_REF] are well measured. However, the favourable cross-section requires an enriched target due to the low abundance of 76 Se. The literature indicates that around 360 MBq/μA of 76 Br can be produced by the irradiation of the commercially available 97% enriched metal target with 15→8 MeV proton beam. The radioactive impurity of 77 Br was observed at the level below 2% and originated from 77 Se impurity in the target.

82g Rb An interesting case, 82g Rb (T1/2 = 1.3 min), emits β+ radiation followed by only one low-intensity γ line. Still, it was introduced as the β+γ PET candidate [START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF].

The radioisotope of 82 Sr (T1/2 = 25.4 d) that decays to 82g Rb is the only reasonable method to acquire 82g Rb. The generator 82 Sr/ 82g Rb has already gained incredible popularity and is widely used to diagnose the cardiovascular disease (a leading cause of death in modern industrialized countries) in myocardial perfusion imaging [START_REF] Yano | Rubidium-82 Generators for Imaging Studies[END_REF][START_REF] Kensett | Experience with a 82 Sr/ 82 Rb generator for clinical use[END_REF][START_REF] Go | A Prospective Comparison of Rubidium-82 PET and Thallium-201 SPECT Myocardial Perfusion Imaging Utilizing a Single Dipyridamole Stress in the Diagnosis of Coronary Artery Disease[END_REF][START_REF] Saha | Use of the 82 Sr/ 82 Rb Generator in Clinical PET Studies[END_REF][START_REF] Carli | Clinical Myocardial Perfusion PET/CT[END_REF][START_REF] Klein | Precision-controlled elution of a 27/38 82 Sr/ 82 Rb generator for cardiac perfusion imaging with positron emission tomography[END_REF][START_REF] Merhige | Impact of myocardial perfusion imaging with PET and 82 Rb on downstream invasive procedure utilization, costs, and outcomes in coronary disease management[END_REF][START_REF] Yoshinaga | Generator-produced rubidium-82 positron emission tomography myocardial perfusion imaging -From basic aspects to clinical applications[END_REF][START_REF] Dhar | Rubidium-82 Cardiac Positron Emission Tomography Imaging: An Overview for the General Cardiologist[END_REF][START_REF] Scholtens | Rubidium-82 myocardial perfusion PET/CT[END_REF]. It provides significantly better precision compared to 201 Tl [START_REF] Go | A Prospective Comparison of Rubidium-82 PET and Thallium-201 SPECT Myocardial Perfusion Imaging Utilizing a Single Dipyridamole Stress in the Diagnosis of Coronary Artery Disease[END_REF] and presents less radiation exposure for patients compared to 99m Tc scan [START_REF] Yoshinaga | Generator-produced rubidium-82 positron emission tomography myocardial perfusion imaging -From basic aspects to clinical applications[END_REF]. Many studies have also been performed on the elution system and the optimized chemical separation [START_REF] Grant | A 82 Sr-82 Rb isotope generator for use in nuclear medicine[END_REF][START_REF] Yano | Rubidium-82 Generators for Imaging Studies[END_REF][START_REF] Kensett | Experience with a 82 Sr/ 82 Rb generator for clinical use[END_REF][START_REF] Mausner | Production of 82 Sr by proton irradiation of RbCl[END_REF][START_REF] Saha | Use of the 82 Sr/ 82 Rb Generator in Clinical PET Studies[END_REF][START_REF] Cackette | 82 Sr Production from Metallic Rb Targets and Development of an 82 Rb Generator System[END_REF][START_REF] Bilewicz | Separation of 82 Sr from rubidium target for preparation of 82 Sr/ 82 Rb generator[END_REF][START_REF] Klein | Precision-controlled elution of a 27/38 82 Sr/ 82 Rb generator for cardiac perfusion imaging with positron emission tomography[END_REF][START_REF] Yoshinaga | Generator-produced rubidium-82 positron emission tomography myocardial perfusion imaging -From basic aspects to clinical applications[END_REF].

The method of choice for 82 Sr/ 82g Rb generator production is the (p,4n) reaction on 85Rb which benefits from high natural abundance. This method was studied multiple times and is most often employed for the large-scale production [START_REF] Mausner | Production of 82 Sr by proton irradiation of RbCl[END_REF][START_REF] Huszár | Development of a production process for 82 Sr[END_REF][START_REF] Deptula | Excitation functions and yields for medically generator Sr 82 -Rb 82[END_REF][START_REF] Lagunas-Solar | Radionuclide production with > 70-MeV proton accelerators : current and future prospects[END_REF][START_REF] Cackette | 82 Sr Production from Metallic Rb Targets and Development of an 82 Rb Generator System[END_REF][START_REF] Gilabert | Cross sections for the proton-induced production of krypton isotopes from Rb, Sr, Y, and Zr for energies up to 1600 MeV[END_REF][START_REF] Ido | Excitation functions of proton induced nuclear reactions on nat Rb from 30 to 70 MeV. Implication for the production of 82 Sr and other medically important Rb and Sr radioisotopes[END_REF][START_REF] Buthelezi | Excitation functions for the production of 82 Sr by proton bombardment of nat Rb at energies up to 100 MeV[END_REF], although, as summarized by [START_REF] Takács | Validation and upgrading of the recommended cross section data of charged particle reactions used for production of PET radioisotopes[END_REF], significant discrepancies still exist. For the proton energy of 70-60 MeV (with 40 MeV exiting from the thick Rb or RbCl target), the 82 Sr/ 82g Rb production yields of 8-13 MBq/μAh were reported. The observed long-lived radioactive impurity of 85 Sr was below 1%. As the typical generator activity used for clinical studies reaches 4 GBq [START_REF] Saha | Use of the 82 Sr/ 82 Rb Generator in Clinical PET Studies[END_REF], the typical irradiation lasts for few days and requires high beam current.

86g Y

The potential of 86g Y lies within its theranostic matched pair [START_REF] Lopci | Matched pairs dosimetry: 124 I/ 131 I metaiodobenzylguanidine and 124 I/ 131 I and 86 Y/ 90 Y antibodies[END_REF][START_REF] Rösch | The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair 86 Y and 90[END_REF][START_REF] Bandara | Matched-pair, 86 Y/ 90 Y-labeled, bivalent RGD/bombesin antagonist, [RGD-Glu-[DO3A]-6-Ahx-RM2], as a potential theranostic agent for prostate cancer[END_REF], the β-emitter 90 Y available from the long-lived 90 Sr/ 90 Y generator system, which is a versatile therapy agent (as reviewed by [START_REF] Goffredo | Yttrium-90 ( 90 Y) in the principal radionuclide therapies: An efficacy correlation between peptide receptor radionuclide therapy, radioimmunotherapy and transarterial radioembolization therapy. Ten years of experience[END_REF]. However, the emission of multiple intensive, dose-contributing γ rays from 86g Y and the recent development of the 90 Y imaging with the bremsstrahlung photons (summarized by [START_REF] Wright | Theranostic Imaging of Yttrium-90[END_REF] might render the matched pair obsolete. Still, many radiochemicals and in vivo PET imaging studies were performed with 86g Y (summarized by [START_REF] Nayak | 86 Y based PET radiopharmaceuticals: radiochemistry and biological applications[END_REF] and its dominating γ line was recognized for the β+ɣ coincidence PET [START_REF] Pentlow | Quantitative imaging of yttrium-86 with PET: the occurrence and correction of anomalous apparent activity in high density regions[END_REF][START_REF] Beattie | Quantitative imaging of bromine-76 and yttrium-86 with PET: a method for the removal of spurious activity introduced by cascade gamma rays[END_REF][START_REF] Buchholz | PET imaging with yttrium-86: comparison of phantom measurements acquired with different PET scanners before and after applying background subtraction[END_REF][START_REF] Sandström | Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT[END_REF][START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF]. In fact, the quantitative coincidence imaging for this radioisotope have been already investigated [START_REF] Pentlow | Quantitative imaging of yttrium-86 with PET: the occurrence and correction of anomalous apparent activity in high density regions[END_REF][START_REF] Beattie | Quantitative imaging of bromine-76 and yttrium-86 with PET: a method for the removal of spurious activity introduced by cascade gamma rays[END_REF][START_REF] Buchholz | PET imaging with yttrium-86: comparison of phantom measurements acquired with different PET scanners before and after applying background subtraction[END_REF].

Several methods of 86g Y production were investigated (in each, the co-produced 86m Y decays with T1/2 = 47.4 min to 86g Y). As reviewed by Schmitz, 2011, the most commonly used is the direct production via 86 Sr(p,n) reaction, for which the excitation function has been also re-evaluated with nuclear codes by [START_REF] Sadeghi | Nuclear data for the cyclotron production of 66 Ga, 86 Y, 76 Br, 64 Cu and 43 Sc in PET imaging[END_REF]. It requires about 14 MeV as higher energies increase the percentage of the contaminants. The reported irradiation of around 200 mg/cm 2 of the commercially available 95% enriched 86 SrCO3 target yields about 150 MBq/μAh with less than 3% of radioactive impurities (Rösch et al., 1993a(Rösch et al., ,1993b;;[START_REF] Kettern | Radiochemical studies relevant to the production of 86 Y and 88 Y at a small-sized cyclotron[END_REF][START_REF] Yoo | Preparation of high specific activity 86 Y using a small biomedical cyclotron[END_REF], Avila-Rodriguez et al., 2008[START_REF] Lukić | High efficiency production and purification of 86 Y based on electrochemical separation[END_REF][START_REF] Elbinawi | Excitation function of proton induced nuclear reaction on strontium: Special relevance to the production of 88[END_REF]. For comparison, around 10 MBq of 86g Y is enough for in vivo mice studies [START_REF] Lövqvist | PET Imaging of 86 Y-Labeled Anti-Lewis Y Monoclonal Antibodies in a Nude Mouse Model: Comparison Between 86 Y and 111 In Radiolabels[END_REF][START_REF] Mcquade | Imaging of Melanoma Using 64 Cu-and 86 Y-DOTA-ReCCMSH(Arg 11 ), a Cyclized Peptide Analogue of ⍺-MSH[END_REF].

94m Tc Despite the clear dominance of 99m Tc in nuclear medicine, other technetium radioisotope, 94m Tc, is of a potential interest as a PET quantification of 99m Tcradiopharmaceuticals [START_REF] Bigott | Production, processing and uses of 94m Tc[END_REF][START_REF] Qaim | The present and future of medical radionuclide production[END_REF] due to the same chemistry of both isotopes. It decays completely to 94 Mo and emits one high-intensity high-energy ɣ line making it suitable for β+γ coincidence imaging [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF][START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF]. The feasibility of standard in vivo PET studies has been already reported [START_REF] Nickles | Technetium-94m-Teboroxime: Synthesis, Dosimetry and Initial PET Imaging Studies[END_REF][START_REF] Stone | Technetium 94m-labeled methoxyisobutyl isonitrile: Dosimetry and resting cardiac imaging with positron emission tomography[END_REF][START_REF] Luyt | 7⍺-and 17⍺-Substituted Estrogens Containing Tridentate Tricarbonyl Rhenium/Technetium Complexes: Synthesis of Estrogen Receptor Imaging Agents and Evaluation Using MicroPET with Technetium-94m[END_REF].

The method of choice for the 94m Tc production is the bombardment of 94 Mo with medium energy proton beam (Rösch and Qaim, 1993c;[START_REF] Rösch | Thermochromatographic Separation of 94m Tc from Enriched Molybdenum Targets and its Large Scale Production for Nuclear Medical Application[END_REF][START_REF] Bigott | Production, processing and uses of 94m Tc[END_REF][START_REF] Bigott | Advances in the production, processing and microPET image quality of technetium-94m[END_REF][START_REF] Uddin | Experimental studies on the proton-induced activation reactions of molybdenum in the energy range 22-67 MeV[END_REF][START_REF] Kakavand | Cyclotron production of 94m Tc via 94 Mo(p,n) 94m Tc reaction[END_REF]. The commercially available enrichment of about 95% is available in MoO3 powder form. The irradiation with the optimal energy range of 13→8 MeV produces about 2 GBq/μ Ah 94m Tc with about 8% of 94g Tc impurity. A 1 h irradiation with 4 μA beam followed by 0.5 h thermochromatographic separation with 90% efficiency results in 1300 MBq 94m TcO4 -, ready for medical application [START_REF] Rösch | Thermochromatographic Separation of 94m Tc from Enriched Molybdenum Targets and its Large Scale Production for Nuclear Medical Application[END_REF]. Other purification and target recovery methods were also investigated (summarized in [START_REF] Bigott | Advances in the production, processing and microPET image quality of technetium-94m[END_REF].

110m In So far, the radioisotope of 110m In has not drawn a lot of attention in the nuclear medicine field. However, as confirmed by in vivo clinical studies, it provides 3 times better resolution than the typical 111 In SPECT (Lubberink et al., 2002b) which opens the possibilities for the detection of small tumors with indium-labelled radiopharmaceuticals. This might be important in the light of an emerging radioisotope 114m In (IAEA, 2007), an Auger emitter with almost instant β-emissions (from its short-lived daughter), whose therapeutic properties are expected [START_REF] Tolmachev | 114m In, a candidate for radionuclide therapy: low-energy cyclotron production and labeling of DTPA-ᴅ-Pheoctreotide[END_REF]. Additionally, 110m In emits medium-energy but high-intensity γ line which could be potentially interesting for β+γ coincidence PET.

Several cross-sections measurements are available, suggesting the potential 110m In direct and indirect production options (summarized by [START_REF] Tárkányi | New cross section data and review of production routes of medically used 110m In[END_REF]. The direct production of 110m In (J π = 2 + ) always leads to the co-formation of the radioactive impurity 110g In (J π = 7 + ) but the higher isomeric ratio can be achieved with lower projectile energies. The recommended reaction, 110 Cd(p,n) [START_REF] Otozai | Excitation functions for the reactions induced by protons on Cd up to 37 MeV[END_REF][START_REF] Abramovich | Isobaric Analog Resonances Appearing during Elastic Scattering of Protons and in the (p[END_REF][START_REF] Skakun | Excitation Functions of (p,n)-and (p,2n)-Reactions on Cadmium Isotopes[END_REF][START_REF] Kormali | Charged particle activation of medium Z elements II. Proton excitation functions[END_REF][START_REF] Marten | Preequilibrium Neutron Emission in 109 Ag( 3 He,xn) and 111 Cd(p,xn) Reactions[END_REF][START_REF] Nortier | Excitation functions and production rates of relevance to the production of 111 In by proton bombardment of nat Cd and nat In up to 100 MeV[END_REF][START_REF] Tárkányi | Activation crosssections on cadmium: proton induced nuclear reactions up to 80 MeV[END_REF][START_REF] Tárkányi | New cross section data and review of production routes of medically used 110m In[END_REF][START_REF] Al-Saleh | Cross sections of proton induced nuclear reactions on natural cadmium leading to the formation of radionuclides of indium[END_REF][START_REF] Khandaker | Production cross-sections for the residual radionuclides from the nat Cd(p,x) nuclear processes[END_REF][START_REF] Büyükuslu | Production cross sections of medical 110,111 In radionuclides[END_REF], at 15 MeV energy (available in the commonly used machines) and with electroplated nat Cd target (Kakavand et al., 2015b) yields 160 MBq/uAh of 110m In with reported 3% of 110g In and 6% of 111g In radioactive impurities [START_REF] Mukhammedov | Application of proton and neutron activation method of analysis for the determination of elements with Z greater than 42[END_REF]Kakavand et al., 2015b).

I

A textbook medical radionuclide 124 I has relatively low β+ branching ratio and the medium-intensive medium-energy γ line but was still suggested as β+γ PET candidate [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF][START_REF] Herzog | PET quantitation and imaging of the non-pure positron-emitting iodine isotope 124 I[END_REF][START_REF] Sandström | Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT[END_REF][START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF] and the quantitative coincidence imaging have also been investigated [START_REF] Herzog | PET quantitation and imaging of the non-pure positron-emitting iodine isotope 124 I[END_REF]. This is mainly because it is the only isotope of iodine suitable for PET that can be paired with the strategic therapeutical 131 I [START_REF] Lopci | Matched pairs dosimetry: 124 I/ 131 I metaiodobenzylguanidine and 124 I/ 131 I and 86 Y/ 90 Y antibodies[END_REF] commonly used for the treatment of hyperthyroidism and thyroid cancer (overviewed by [START_REF] De Klerk | 131 I Therapy: Inpatient or Outpatient?[END_REF][START_REF] Higashi | Radioactive iodine ( 131 I) therapy for differentiated thyroid cancer in Japan: current issues with historical review and future perspective[END_REF]. Furthermore, 124 I itself has already been used for the imaging of tissue proliferation [START_REF] Blasberg | 124 I]-iododeoxyuridine imaging tumor proliferation[END_REF][START_REF] De Klerk | 131 I Therapy: Inpatient or Outpatient?[END_REF][START_REF] Roelcke | PET Imaging Drug Distribution After Intratumoral Injection: The Case for 124 I-Iododeoxyuridine in Malignant Gliomas[END_REF] and for multiple in vivo cancer imaging studies [START_REF] Langen | SPECT studies of brain tumors with L-3-[ 123 I] iodoalpha-methyl tyrosine: comparison with PET, 124 IMT and first clinical results[END_REF][START_REF] Snook | Preparation and in vivo study of 124 I-labelled monoclonal antibody H17E2 in a human tumour xenograft model. A prelude to positron emission tomography (PET)[END_REF][START_REF] Wilson | Quantitative measurement of monoclonal antibody distribution and blood flow using positron emission tomography and 124 iodine in patients with breast cancer[END_REF], including thyroid [START_REF] Frey | Tomographic imaging of the human thyroid using 124 I[END_REF][START_REF] Phan | The diagnostic value of 124 I-PET in patients with differentiated thyroid cancer[END_REF][START_REF] Capoccetti | The effectiveness of 124I PET/CT in patients with differentiated thyroid cancer[END_REF][START_REF] Kharazi | 124 I in differentiated thyroid cancer: An educational exhibit[END_REF][START_REF] Plyku | Recombinant Human Thyroid-Stimulating Hormone Versus Thyroid Hormone Withdrawal in 124 I PET/CT-Based Dosimetry for 131 I Therapy of Metastatic Differentiated Thyroid Cancer[END_REF]. It is also considered as a potential Auger-emitter for the radiotherapy [START_REF] Stepanek | Auger-electron spectra of radionuclides for therapy and diagnostics[END_REF].

The methods for production of 124 I were thoroughly studied by many groups with the use of protons, deuterons and ⍺ -particles (summarized by [START_REF] Schmitz | The production of [ 124 I]iodine and[END_REF][START_REF] Azizakram | An overview of 124 I production at a medical cyclotron by ALICE/ASH, EMPIRE-3.2.2 and TALYS-1.6 codes[END_REF]. As one of the "emerging isotopes", its production cross-sections are also collected in IAEA database (IAEA, 2007). The most typical 124 I production method is the 124 Te(p,n) reaction [START_REF] Kondo | Cyclotron Isotopes and Radiopharmaceuticals-XXII, Improved Targetry and Radiochemistry for Production of 123 I and 124 I[END_REF][START_REF] Scholten | Excitation Functions of 124 Te(p,xn) 124,123 I Reactions from 6 to 31 MeV with Special Reference to the Production of 124 I at a Small Cyclotron[END_REF][START_REF] Qaim | Some optimisation studies relevant to the production of high-purity 124 I and 120g I at a small-sized cyclotron[END_REF][START_REF] Sajjad | Optimization of 124 I production via 124 Te(p,n) 124 I reaction[END_REF][START_REF] Nye | A new binary compound for the production of 124 I via the 124 Te(p,n) 124 I reaction[END_REF][START_REF] Aslam | Evaluation of excitation functions of proton and deuteron induced reactions on enriched tellurium isotopes with special relevance to the production of iodine-124[END_REF] suitable for popular small cyclotrons but requiring the enriched target material (which is crucial to increase the yield and to reduce the radioactive impurities). Recent thick target yield measurements [START_REF] Sajjad | Optimization of 124 I production via 124 Te(p,n) 124 I reaction[END_REF] indicate that the irradiation of the commercially available 124 TeO2 targets (99.9% 124 Te) with the energy range of 14→7 MeV produces around 21 MBq/μAh of 124 I with around 0.03% of radioactive impurities of 125 I and 126 I, followed by the dry distillation. Basically, a few hours run with around 20 μA is enough to produce several 50 MBq batches used for the imaging [START_REF] Plyku | Recombinant Human Thyroid-Stimulating Hormone Versus Thyroid Hormone Withdrawal in 124 I PET/CT-Based Dosimetry for 131 I Therapy of Metastatic Differentiated Thyroid Cancer[END_REF].

Online monitors ( 10 C, 14 O)

There are two very short-lived β+γ PET radionuclide candidates mentioned in the literature [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF][START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF], namely: 10 C (T1/2 = 19.3 s) and 14 O (T1/2 = 70.6 s). They are formed via the fragmentation of the high energy heavy ions or different nuclear reactions induced by the high-energy projectiles on 12 C, 14 N, 16 O nuclides which are immensely abundant in the organic compounds. The beams used in the ion therapy, apart from the delivery of the radiation dose, produce 10 C and 14 O allowing the visualization of the treatment with the online acquisition system.

Online PET scans with 10 C and 14 O have already been reported [START_REF] Litzenberg | On-line monitoring of radiotherapy beams: Experimental results with proton beams[END_REF][START_REF] Enghardt | Charged hadron tumour therapy monitoring by means of PET[END_REF][START_REF] Lopes | First in situ TOF-PET study using digital photon counters for proton range verification[END_REF][START_REF] D'ascenzo | New Digital Plug and Imaging Sensor for a Proton Therapy Monitoring System Based on Positron Emission Tomography[END_REF]. Still, this technique poses a challenge from the point of the time resolution [START_REF] Oelfke | Proton dose monitoring with PET: quantitative studies in Lucite[END_REF][START_REF] Beebe-Wang | Simulation of Proton Therapy Treatment Verification via PET Imaging of Induced Positron-Emitters[END_REF][START_REF] Lopes | First in situ TOF-PET study using digital photon counters for proton range verification[END_REF]. The method with β+ɣ coincidence PET can be potentially considered in cases where the lower statistic is expected.

Calibration source ( 22 Na)

12/38 22 Na is a common calibration source, used even in the recent PET research [START_REF] D'ascenzo | New Digital Plug and Imaging Sensor for a Proton Therapy Monitoring System Based on Positron Emission Tomography[END_REF]. It has a very long half-life of 2.6 years and high β+ branching ratio, making it a convenient β+ emitter for the repetitive calibrations. 22 Na also emits 1274.5 keV gamma-line that was used as a trigger during the calibration of liquid argon detector [START_REF] Amaudruz | Measurement of the scintillation time spectra and pulse-shape discrimination of low-energy β and nuclear recoils in liquid argon with DEAP-1[END_REF]. Being already recognized as the β+γ PET candidate [START_REF] Martin | Quantitative PET with Positron Emitters that Emit Prompt Gamma Rays[END_REF][START_REF] Lang | Sub-millimeter nuclear medical imaging with reduced dose application in positron emission tomography using β+ γ coincidences[END_REF][START_REF] Thirolf | Perspectives for highly-sensitive PET-based medical imaging using β+γ coincidences[END_REF], 22 Na can be therefore considered as a calibration source for β+γ coincidence PET.

22 Na sources can be bought from the different suppliers or produced on-site with the proton beam of low and medium energy (as summarized by [START_REF] Takács | Excitation function of 22 Ne(p,n) 22 Na reaction: Possibility of production of 22 Na at a small cyclotron[END_REF]. Today, the only large-scale production is performed with the use of 70 MeV proton cyclotron by iThemba LABS in South Africa.

Summary

In this paper, we summarized the properties and availability of radioisotopes suitable for the β+γ coincidence PET imaging. The 44g Sc radioisotope is undoubtedly most useful for the proof of concept. However, there are many other attractive candidates, in particular those already popular in nuclear medicine: 66 Ga, 72 As, 82 Sr/ 82g Rb and 124 I. The coincidence imaging can also be employed in PET/MRI technique with the use of 52m Mn and 69 Ge or with many 99m Tc-radiopharmaceuticals with the use of 94m Tc. The summary of β+γ PET radioisotopes is shown in Table 3. Despite discussed drawbacks, the presented radioisotopes can be useful in the β+γ coincidence PET depending on the available scanner and the nature of the study.

  89%,76 Se = 9.37%, 77 Se = 7.63%, 78 Se = 28.77%, 80 Se = 49..17%, 63 Zn = 27.73%, 67 Zn = 4.04%, 68 Zn = 18.45%, 70 Zn = 0.61%

Table 1 .

 1 Physical properties of the possible β+γ PET radioisotopes(IAEA, 2019)

	Isotope	T1/2	Decay (%)	Main gamma lines [keV] (intensity; delay)
	10 C	19.3 s	EC (0.1), β+ (99.9)	718.4 (100%; 0.71 ns)
	14 O	70.6 s	EC (0.1), β+ (99.9)	2312.6 (99.4%; 68 fs)
	22 Na	2.6 y	EC (10), β+ (90)	1274.5 (99.9%; 3.6 ps)
	34m Cl	32 min	EC (1.1), β+ (54.3), IT (44.6)	146.4 (40.5%; instant), 1176.6 (14.1%; 136 fs), 2127.5 (42.8%; 318 fs), 3304.0 (12.3%; 136 fs)
	44g Sc	3.9 h	EC (5.7), β+ (94.3)	1157.0 (99.9%; 2.61 ps)
	48 V	16.0 d	EC (50.1), β+ (49.9)	983.5 (100%; 4.04 ps), 1312.1 (97.5%; 0.76 ps)
	52m Mn	21 min	EC (1), β+ (97), IT (2) 1434.1 (98.3%; 0.783 ps)
	55 Co	17.5 h	EC (24), β+ (76)	477.2 (20.2%; 37.9 ps), 931.1 (75%; 8 ps), 1408.4 (16.9%; 37.9 ps)
	60 Cu	24 min	EC (7), β+ (93)	826.1 (22%; 0.59 ps), 1332.5 (88%; 0.735 ps)
	66 Ga	9.49 h	EC (44), β+ (56)	1039.2 (37%; 1.68 ps), 2752 (23%; not found)
	69 Ge	39 h	EC (76), β+ (24)	574.2 (13.3%; 1.7 ps), 872.1 (11.9%; 0.25 ps), 1107 (36%; 0.222 ps)
	72 As	26 h	EC (14), β+ (86)	834.0 (80%; 3.35 ps)
	76 Br	16.2 h	EC (44.4), β+ (55.6)	559.1 (74.0%; 12.3 ps), 657.0 (15.9%; 11 ps), 1853.7 (14.7%; not found)
	82g Rb	1.3 m	EC (5), β+ (95)	776.5 (13%; 4.45 ps)
				443.1 (16.9%; 5 ns), 627.7 (32.6%; 0.9 ps),
	86g Y	14.7 h	EC (68.1), β+ (31.9)	703.3 (15.4%; 5 ns), 777.4 (22.4%; 0.386 ps), 1076.6 (82.5%; 1.46 ps), 1153.1 (30.5%; 1.73
				ps), 1920.7 (20.8%; not found)
	94m Tc	52 min	EC (28), β+ (72)	871.1 (94%; 2.77 ps)
	110m In	69.1 min EC (38.8), β+ (61.2)	657.8 (97.7%; 5.42 ps)
	124 I	4.2 d	EC (77.3), β+ (22.7)	602.7 (62.9%, 6.2 ps), 722.7 (10.4%; 1.04 ps), 1691.0 (11.2%; 0.17 ps)

Table 2 .

 2 Natural abundance of the targets discussed in the text (IAEA, 2019). 25%, 108 Cd = 0.89%, 110 Cd = 12.49%, 111 Cd = 12.80%, 112 Cd = 24.13%, 113 Cd = 12.22%, 114 Cd = 28.73%, 116 Cd = 7.49% Cr Cr = 4.35%, 52 Cr = 83.79%, 53 Cr = 9.5%, 54 Cr = 2.37% Fe Fe = 5.85%, 56 Fe = 91.754%, 57 Fe = 2.12%, 58 Fe = 0.28% Ga Ga = 60.11%, 71 Ga = 39.89% Ge Ge = 20.57%, 72 Ge = 27.45%, 73 Ge = 7.75%, 74 Ge = 36.5%, 76 Ge = 7.73% Mo Mo = 14.53%, 94 Mo = 9.15%, 95 Mo = 15.84%, 96 Mo = 16.67%, 97 Mo = 9.6%, Mo = 24.39%, 100 Mo = 9.82%

	Element	Natural isotopic composition
	Al	Al = 100%
	C	C = 98.93%, 13 C = 1.07%
	Ca	Ca = 96.94%, 42 Ca = 0.647%, 43 Ca = 0.135%, 44 Ca = 2.09%, 46 Ca = 0.04%,
		Ca = 0.19%
	Cd	Cd = 1.

Table 3 .

 3 The arbitrary summary of β+γ PET radioisotopes discussed in the text. "Plus" sign indicates favourable characteristic, "minus" stands for unfavourable, and "plus/minus" marks moderate. The order of the radioisotopes in the table corresponds to their overall score.

	radio-isotope	T1/2	high β+ branching ratio	intensive third γ (~1 MeV)	no additional γ lines	feasible production	already used in practice	theranostic pair
	44g Sc	3.9 h	+	+	+	+	+/-	+
	72 As	26 h	+	+	+	+/-	+	+
	55 Co	17.5 h	+	+	+/-	+/-	+	+
	60 Cu	24 min	+	+	+/-	+	-	+
	52m Mn	21 min	+	+	+	+/-	+/-	-
	66 Ga	9.49 h	+/-	+/-	+/-	+	+	+/-
	110m In	69.1 min	+/-	+/-	+	+	-	+
	82g Rb	1.3 m	+	-	+	+/-	+	-
	94m Tc	52 min	+/-	+	+	+	-	-
	124 I	4.2 d	-	+/-	+/-	+/-	+	+
	48 V	16.0 d	+/-	+	-	+	+/-	-
	86g Y	14.7 h	-	+	-	+	-	+
	76 Br	16.2 h	+/-	+/-	+/-	+	+/-	-
	69 Ge	39 h	-	+/-	+/-	+/-	-	-
	34m Cl	32 min	+/-	+/-	-	-	-	-

Acknowledgements

The cyclotron Arronax is supported by CNRS, Inserm, INCa, the Nantes University, the Regional Council of Pays de la Loire, local authorities, the French government and the European Union. This work has been, in part, supported by a grant from the French National Agency for Research called "Investissements d'Avenir", Equipex ArronaxPlus no. ANR-11-EQPX-0004, Labex IRON no. ANR-11-LABX-18-01 and ISITE NEXT no. ANR-16-IDEX-0007. Part of this work was performed within the framework of EU Horizon 2020 project RIA-ENSAR2 (654 002). The PhD cotutelle scholarship from French Government for Mateusz Sitarz is also acknowledged.

Radionuclide candidates for β+γ coincidence PET: An overview

Mateusz Sitarz 1,2,3, *, Jean-Pierre Cussonneau 4 , Tomasz Matulewicz 2 , Férid Haddad 1,4