Hindawi Publishing Corporation BioMed Research International Volume 2014, Article ID 786463, 9 pages http://dx.doi.org/10.1155/2014/786463 Review Article The Copper Radioisotopes: A Systematic Review with Special Interest to 64Cu Artor Niccoli Asabella,1 Giuseppe Lucio Cascini,2 Corinna Altini,1 Domenico Paparella,1 Antonio Notaristefano,1 and Giuseppe Rubini1 1 NuclearMedicine,UniversityofBariAldoMoro,PiazzaG.Cesare11,70124Bari,Italy 2 Nuclear Medicine, University of Catanzaro Magna Graecia, Viale Europa, Localita´ Germaneto, 88100 Catanzaro, Italy Correspondence should be addressed to Artor Niccoli Asabella; [email protected] Received 23 December 2013; Accepted 18 April 2014; Published 7 May 2014 Academic Editor: Gianluca Valentini Copyright © 2014 Artor Niccoli Asabella et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Copper (Cu) is an important trace element in humans; it plays a role as a cofactor for numerous enzymes and other proteins crucial 63 for respiration, iron transport, metabolism, cell growth, and hemostasis. Natural copper comprises two stable isotopes, Cu and 65 60 61 62 64 Cu, and 5 principal radioisotopes for molecular imaging applications ( Cu, Cu, Cu, and Cu) and in vivo targeted radiation 64 67 therapy ( Cu and Cu). The two potential ways to produce Cu radioisotopes concern the use of the cyclotron or the reactor. A noncopper target is used to produce noncarrier-added Cu thanks to a chemical separation from the target material using ion exchange chromatography achieving a high amount of radioactivity with the lowest possible amount of nonradioactive isotopes. In recent years, Cu isotopes have been linked to antibodies, proteins, peptides, and nanoparticles for preclinical and clinical research; pathological conditions that influence Cu metabolism such as Menkes syndrome, Wilson disease, inflammation, tumor growth, metastasis, angiogenesis, and drug resistance have been studied. We aim to discuss all Cu radioisotopes application focusing on 64 64 Cu and in particular its form CuCl2 that seems to be the most promising for its half-life, radiation emissions, and stability with chelators, allowing several applications in oncological and nononcological fields. 1. Introduction images of the human body noninvasively, diagnose illness, andchoosetreatmentregimensbaseduponthem[3]. Copper (Cu) is a transition metal with atomic number 29, New radioisotopes in Nuclear Medicine can be used known since ancient times. It is an important trace element in their simple form or bound with carrier molecules for for most organisms in all kingdoms. In humans, copper plays the production of complex radiopharmaceutical, creating a role as a cofactor for numerous enzymes, such as Cu/Zn- new opportunities for different metabolic imaging of several superoxide dismutase, cytochrome c oxidase, tyrosinase, organs and systems. ceruloplasmin, and other proteins, crucial for respiration, For widespread use in medicine of any radioisotope, two iron transport and metabolism, cell growth, and hemostasis factors are essential: availability of the isotope and a stable [1, 2]. and effective mode of binding with an appropriate chemical In the last decades, the scientific knowledge and the carrier [4]. technological development permitted to overcome the limit Selection of the proper radionuclide in radiopharmaceu- of the morphological imaging and to move in the way of tical design is critical and depends upon several factors. The biometabolic imaging. This new approach creates further half-lifeoftheradionuclideshouldallowsufficientuptake opportunities for clinical research, diseases diagnosis, and and distribution to yield considerable contrast and quality treatment. It allows physicians to generate high-resolution images. The energies of the radionuclide emission should be 2 BioMed Research International Table 1: Main characteristic of the medically relevant Cu radioisotopes. Production Isotope 1/2 Decay mode Energy (keV) Incident Yield at recovery beam energy Reaction (MBq/Ah or MBq/mg) (MeV) + (93%) 2940 60Cu 23.7 min Cyclotron 11 60Ni(p,n)60Cu 370 (7%) 511/467/826/1332 + (60%) 1159 ∗∗ 61Cu 3.32 h Cyclotron 19 61Ni(p,n)61Cu 573 (40%) 511/283/589/656 + (98%) 2925 ∗∗ 62Cu 9.7 min Cyclotron 5–14 62Ni(p,n)62Cu 19800 (2%) 511 + ∗∗∗ (19%) 657 12 64Ni(p,n)64Cu 243 Cyclotron 64 64 ∗∗∗ (43%) 511/1346 19 Ni(d,2n) Cu 388 64Cu 12.7 h ND natZn(p,xn)64Cu 67 − ∗ ∗∗∗∗ (38%) 141 Reactor 1.8 64Zn(n,p)64Cu 14.5 ND 63Cu(n,)64Cu ND − (100%) 390/482/575 ND 68Zn(p,2p)67Cu ND 67 70 67 Cu 61.83 h Cyclotron ND Zn(p,a) Cu ND (52%) 91/93/185 ND 67Zn(n,p)67Cu ND ND 68Zn(g,p)67Cu ND ND: data not available. ∗ Approximate minimum neutron energy. ∗∗ Predicted yield. ∗∗∗ Maximum of results. ∗∗∗∗ Mean of results. appropriate for proper detection by the equipment, while cost The following fundamental step is the extraction of and availability are also important considerations [3]. each Cu radioisotope from the target, performed using ion With the progress in medical sciences, copper has gained exchange chromatography [5]. alotofattention. The two potential ways to produce Cu radioisotopes 63 Natural copper comprises two stable isotopes, Cu concern the use of the cyclotron or the reactor. At the state 65 (69.17%) and Cu (30.83%), and 27 known radioisotopes, five oftheart,thecyclotronproductionisthemoststudied. of them are particularly interesting for molecular imaging The main characteristics of the Cu radioisotopes of 60 61 62 64 applications ( Cu, Cu, Cu, and Cu),andinvivo medical interest and their most common ways of production 64 67 targeted radiation therapy ( Cu and Cu) [4]. arereportedonTable 1. Copper radionuclides offer a varying range of half-lives 60 60 + and decay modes [3]. 2.1. Cu. Cu is a emitter with decay properties making it possible candidate tracer for positron emission tomog- raphy (PET), even it has the disadvantage of emissions 60 2. Production of Cu Radioisotopes [4]. Cu is a proton-rich nuclide that decays to its stable Ni isotopes through a combination of positron decay and One of the major challenges is the production of radionu- electron capture processes. It can be produced on a medical clides with high specific activity, that is, a high amount of cyclotron at relatively low costs using proton or deuteron 60 radioactivity with the lowest possible amount of nonradioac- induced reactions on enriched Ni targets [5, 6]. Other ways 3 tive isotopes. of production have been recently developed (e.g. natCo + He, Preparing high specific activity Cu radionuclides is an natCo + a) [7, 8]. even bigger challenge, since Cu is ubiquitous in the environ- ment. For all of the Cu isotopes, a noncopper target is used 61 61 to produce noncarrier-added Cu. In using a target, having a 2.2. Cu. Cu isotope can be produced from zinc, nickel, different atomic number, a chemical separation of the copper or cobalt targets on a medical cyclotron using proton or radionuclide from the target material is possible. In addition, deuteron or alpha particles induced reactions. Necessity of the experimental conditions for preparing the target and highly enriched Ni and Zn targets or high-energy particle 61 separating the copper radionuclides from it must be as metal- beams limited accessibility of Cu for biomedical use, until free as possible [3]. more economic production methods from natural Zn or Co BioMed Research International 3 60 64 64 will be developed [9, 10]. Half-life longer than that of Cu are 0.2 mCi/A⋅hpermg Ni.Theenriched Ni can be 85– 62 61 and Cu makes Cu better choice for prolonged imaging of 95% recovered as previously described and reused for future processes with slower kinetics. This isotope, however, is much bombardments, which contributes to the cost-efficiency of 64 less popular in today’s biomedical studies than other copper this method of Cu production [3]. 64 radioisotopes [4, 8, 11–14]. Another method of Cu production is the 64 64 Zn(n,p) Cu reaction in a nuclear reactor [22, 23]. 62 62 Most reactor-produced radionuclides are produced using 2.3. Cu. Cu has unique properties being almost pure + 62 thermal neutron reactions, or (n, )reactions,wherethe emitter (98%) with short half-life of 9.7 min. Cu is thermal neutron is of relatively low energy, and the target a proton-rich nuclide that decays to its stable Ni isotope materialisofthesameelementastheproductradionuclide. 64 through a combination of positron decay and electron cap- For producing high specific activity Cu, fast neutrons ture processes. It can be produced on a medical cyclotron areusedtobombardthetargetina(n,p)reaction[22–26]. 62 64 using proton or deuteron induced reactions on enriched Ni Unfortunately, one of the byproducts of producing Cu 62 targets. Cucanalsobeproducedindirectlythroughits 65 1/2 = 245 62 62 62 with a natural Zn target was Zn ( d), which limits parent Zn in a Zn/ Cu generator system. This is the the practicality of production by this method [27]. 64 preferred option, reducing the levels of radioactivity that need Smith et al. separated large amounts of Cu by product 62 67 68 67 to be manipulated and allowing Cu to be eluted as required from cyclotron production of Ga via the Zn(p,2n) Ga [5]. 62 62 62 reaction at the National Medical Cyclotron, Sydney, Aus- Current Zn/ Cu generators can start with Zn activ- 62 tralia [28]. This method of production has the advantage ities of 5-6 GBq, 93% of this activity being released as Cu of being very economical and allows for the production of in the first 3.2 mL of eluate; however relatively short half-life very large amounts (>111 GBq (>3 Ci)) of reasonably high 62 of parent Zn makes these generators operable for not more specific activity material (∼31.8 TBq/mmol (∼860 Ci/mmol)). than three days.