Review Article the Copper Radioisotopes: a Systematic Review with Special Interest to Cu

Home , Isotopes of nickel

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 𝑇 Isotope 1/2 Decay mode Energy (keV) Incident Yield at recovery beam energy Reaction (MBq/𝜇Ah or MBq/mg) (MeV) + 𝛽 (93%) 2940 60Cu 23.7 min Cyclotron 11 60Ni(p,n)60Cu 370 𝛾 (7%) 511/467/826/1332 + 𝛽 (60%) 1159 ∗∗ 61Cu 3.32 h Cyclotron 19 61Ni(p,n)61Cu 573 𝛾 (40%) 511/283/589/656 + 𝛽 (98%) 2925 ∗∗ 62Cu 9.7 min Cyclotron 5–14 62Ni(p,n)62Cu 19800 𝛾 (2%) 511 + ∗∗∗ 𝛽 (19%) 657 12 64Ni(p,n)64Cu 243 Cyclotron 64 64 ∗∗∗ 𝛾 (43%) 511/1346 19 Ni(d,2n) Cu 388 64Cu 12.7 h ND natZn(p,xn)64Cu 67 𝛽− ∗ ∗∗∗∗ (38%) 141 Reactor 1.8 64Zn(n,p)64Cu 14.5 ND 63Cu(n,𝛾)64Cu ND − 𝛽 (100%) 390/482/575 ND 68Zn(p,2p)67Cu ND

67 70 67 Cu 61.83 h Cyclotron ND Zn(p,a) Cu ND 𝛾 (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 𝛽 emitter with decay properties making it possible candidate tracer for positron emission tomography (PET), even it has the disadvantage of 𝛾 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/𝜇A⋅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 𝛾 + 62 thermal neutron reactions, or (n, )reactions,wherethe 𝛽 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 𝑇1/2 = 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. The disadvantage is that on-demand production would be Currently the proton induced reactions on natural copper problematic, since the major radionuclide produced is long- 67 isthemethodofchoicefortheproductionofthemother lived Ga (𝑇1/2 =72h). 62 62 67 nuclide Zn. Recently, Cu production was also investigated The production of Ga, which has identical gamma ener- nat 67 via Zn + p reactions [15, 16]. gies to Cu, makes activity measurements prior to separation This isotope is currently the most intensively studied 64 difficult. In addition, isotopes of nickel, cobalt, manganese, copper radioisotope besides Cu [4]. andchromiumhavebeenobservedthatwhilebeingrelatively easy to separate add complexity to the required separation 64 64 scheme [5]. 64 2.4. Cu. Cu is a highly unusual isotope because it decays Although the proton induced reaction on enriched Ni by three processes, namely, positron, electron capture, and plays a key role for practical production, recently the beta decays. This property allows either cyclotron or reactor deuteron induced reactions are also intensively studied and production, with the latter route resulting in either low seem to be very promising [29]. specific activity (n,𝛾) or high specific activity (n,p) products 67 [5]. 2.5. Cu. This isotope of copper, owning to interesting decay At present, the most common production method for 64 64 64 properties, is potentially useful for radioimmunotherapy, but Cu utilizes the Ni(p,n) Cu reaction [17, 18]. 64 duetolimitedavailability,researchesthatactuallyusethis The production of noncarrier-added Cu via the 64 64 isotope are few, compared to other Cu isotopes [30, 31]. Ni(p,n) Cu reaction on a biomedical cyclotron was pro- Dynamic growth of radioimmunotherapy can increase posed by Szelecsenyi et al. Subsequent studies by McCarthy demand for this isotope. Medvedev et al. reported an attempt et al. were performed, and this method is now used to provide 67 64 to produce Cu in a larger scale, which gives perspectives for Cu to researchers throughout the United States [17, 19]. 64 64 wider commercial availability of the isotope in the near future The target for producing Cu is enriched Ni (99.6%). [32]. 64 67 The Ni (typically 10–50 mg) is prepared and electroplated Cu is the longest living copper radioisotope and also one onto a gold disk using a procedure modified from Piel et al. of the most difficult to produce, since it requires fast neutron 68 [20]. flux reactor or high-energy proton beams and costly Zn The target is bombarded on the cyclotron. Recently, Obata 67 64 target [33]. Therapeutic amounts of Cu can be produced et al. reported the production of Cu on a 12 MeV cyclotron, via several reactions on Zn. The production by the reaction 68 67 67 which is more representative of the modern cyclotrons Zn(p,2p) Cu is the largest contributor of Cu in North currently in operation [21]. 67 64 America. Providing a reliable supply of Cu by this method After bombardment, the Cu is separated from the target requires dedicated proton beam and chemistry station that nickel in a one-step procedure using an ion exchange column. 64 64 are rarely possible at one of these multipurpose facilities Typically, 18.5 GBq of Cu are produced with a 40 mg Ni [34, 35]. target and a bombardment time of 4 h. The specific activity 68 67 64 The Zn(p,2p) Cu reaction requires increasing proton of the Cu ranges from 47.4 to 474 GBq/𝜇mol (1280 to energy, from 20 to 70 MeV, according to Stoll et al. (which 64 12,800 mCi/𝜇mol). The typical yields for Cu productions includes data from two other studies) [36]. 4 BioMed Research International

Due to the nature of the spallation process, there will The well-established coordination chemistry of Cu allows always be a variety of products in the target and enriched for its reaction with a wide variety of chelator systems that can targets are seldom used except to determine the reaction cross potentially be linked to antibodies, proteins, peptides, and section. Targets are mainly zinc metal foils which allow for other biologically relevant small molecules [3]. greater heat dissipation and have a higher density than zinc Cu metabolism varies from individual to individual. oxide [34, 36]. Physiological and pathological conditions that influence Cu A small subset of the literature involves the use of a metabolism include inherited copper metabolic defects, such low energy proton beam, 20 MeV, driving a reaction on 70 67 67 as Menkes syndrome and Wilson disease, and acquired cop- Zn(p,a) Cu. The presence of Ga complicates gamma per metabolism disorder or imbalance caused by pregnancy, counting of the sample until after a radiochemical separation. inflammation, and tumor growth, metastasis, angiogenesis, 65 Large amounts of Znarealsoexpectedtoaccumulateinany anddrugresistance[46–48]. recycled target due to its 244-day half-life. A demonstration All Cu radioisotopes are currently investigated for clinical 64 with a larger target mass will determine if this method of applications but at the state-of- art Cu, and, in particular, its production is comparable to other techniques. In contrast to 64 70 67 form CuCl2 seems to be the most promising for its half-life, other production methods, the Zn(p,a) Cu reaction does radiation emissions, and stability with chelators. not coproduce large amounts of other radioisotopes due to the low energy protons used [34, 37]. 67 The production of Cu in a nuclear reactor by the 3.1. The Role of Cu in Oncology. In the last years, many 67 67 reaction Zn(n,p) Cu has been pursued in part due to its preclinical studies have demonstrated an effect of Cu on simplicity. One only needs to place a suitably contained zinc cancer development. In fact, in comparison with normal target in a commercial or research reactor to produce a usable human subjects, significantly higher copper levels have been 67 amount of Cu. However, access to reactors, waste concerns, measured in serum and tumor cells of patients with cancer including prostate, breast, and brain cancer [49]. and undesirable side reactions complicate the use of this 64 reaction for extended productions and medical applications. CuCl2 is the most widely isotope studied, for its poten- 67 In the literature the production of Cu by the reaction tial role in PET imaging and therapy; it has been bound 68 67 Zn(𝛾,p) Cu is also reported. Linear accelerators producing to several carrier that can be applied to monitor copper 30–60 MeV electrons were focused on a convertor plate, metabolism status and guide personalized copper chelator usually tungsten or tantalum, which produces photons with treatment in cancer patients [50]. a similar energy range [34]. 𝛾 However, the best yield for the ( ,p) reaction on an 3.1.1. Cu-Labeled Antibodies and Peptides for Tumor Targeting. enriched target only used a few milligrams of zinc; a demon- Monoclonal antibodies (mAbs) are a vast group of biotechno- stration with a larger target is required to produce a more logically produced proteins, with constantly rising number of accurate yield and validate this method [34]. applications in immunotherapy, targeted drug delivery, and 64 in vivo/in vitro diagnostics. Cu-labeled antibodies for PET 3. Clinical Application imaging are trastuzumab (breast cancers expressing human epidermal growth factor receptor 2 or HER2), cetuximab (tar- Nuclear medicine imaging provides information about func- geting EGFR-epidermal growth-factor receptor expressing tion and structure, using safe, not invasive, and cost-effective tumors), TRC105-Fab (targeting CD105), and etaracizumab techniques for diagnosis and therapy [38]. (antibody against human 𝛼V𝛽3 integrin) [4]. Thisdisciplineisofgreatimportancetomedicalspe- Radiolabeling of trastuzumab as well as related fragments cialties such as cardiology, neurology, oncology, orthopedics, andantibodieshavebeeninvestigatedforbothdiagnosticand endocrinology, hematology, nephrology, and pulmonology radiotherapeutic applications [51]. [38–43]. EGFR expression is increased in many human tumors Copper radioisotopes can have a “conventional role” as such as breast cancer, squamous-cell carcinoma of the head radioactive markers that can be added to carrier molecules, and neck, and prostate cancer. At present mAbs, which conferring all the biological targeting specificity that is block the binding of EGF to the extracellular ligand-binding needed; furthermore, they can be used as “real tracers,”when domain of the receptor, have shown promise from a thera- directedattheinvivostudyoftheCumetabolismitself. peutic standpoint. Cetuximab (C225; Erbitux, Bristol-Myers As molecular imaging continues to advance, PET and Squibb, New York, NY) was the first mAb targeted against the single photon emission computed tomography (SPECT) EGFRapprovedbytheU.S.FoodandDrugAdministration techniques are nowadays an integral part of the molecular (FDA) for the treatment of patients with EGFR-expressing, imaging toolbox; among all the available molecular imaging metastatic colorectal carcinoma [52]. strategies, PET and SPECT allow targeting of extracellular, The growth and metastasis of most solid tumors cell surface, intracellular proteins, and nucleic acids. depend on angiogenesis, without which they cannot grow Availability of Cu isotopes for preclinical and clinical beyond a few millimeters in size. The most widely studied research has greatly improved in recent years, also because angiogenesis-related targets include CD105 (i.e., endoglin), many potential chelators were developed during over past 20– integrin 𝛼V𝛽3, and vascular endothelial growth factor 30 years [4, 44, 45]. receptors (VEGFRs) [53]. BioMed Research International 5

CD105 immunohistochemistry is now the accepted stan- renal carcinoma therapy, Lym-1 for non-Hodgkin’s lym- dard approach for identifying actively proliferating tumor phoma, C595 an anti-MUC1 mucin antibody for bladder vessels; it has several advantages over the other targets, cancer treatment [4]. including high levels of expression in a wide variety of solid malignancies, independence from its expression on 3.1.3. Cu Labeled Somatostatin Analogs for Targeting Neuroen- neoplastic cells, lack of tumor histotype specificity, and docrine Tumors. Somatostatin is a 14-amino-acid peptide immediate accessibility of malignant lesions through the involved in the regulation and release of several hormones. bloodstream. With high affinity/specificity for CD105, radi- Somatostatin receptors (SSRs) are present in many differ- olabeled TRC105-Fab demonstrated its potential in several ent normal organ systems, such as the central nervous system preclinical tumor models to serve as a promising diagnostic (CNS), the gastrointestinal tract, the exocrine, and endocrine agent for PET imaging. [54]. pancreas, breast, and lung, making it a viable disease target [52]. 64 Targeting of SSRs in tumors has been a goal in cancer 3.1.2. Cu Labeled Peptides for Tumor Angiogenesis. Cu treatment and diagnosis since the 1980s, labeling octreotide labeled peptides for targeted cancer therapy/imaging are one 67 (OC) with 123I, 111In, and Ga [52]. of the largest groups of copper radiopharmaceuticals cur- 64 In the first-in-humans study, Pfeifer et al. found Cu- rently researched. They are built of a targeting peptide such as DOTATATE PET useful for clinical somatostatin receptor bombesin or octreotide analogue, a linker, and a bifunctional 111 imaging. Compared with In-DTPA-octreotride SPECT, chelator (BFC), commonly tetraazamacrocycle derivate, like 64 Cu-DOTATATE PET provided superior image quality, TETA or DOTA. The peptide binds to a specific receptor detected more true-positive lesions, and was associated with expressed by cancer cells, while copper isotope-BFC moiety a lower radiation burden [56]. allows localization of the tumor by positron emission detection. Attractiveness of peptides for targeted radiotherapy, in comparison to monoclonal antibodies, comes from their 3.1.4. Imaging Tumor Hypoxia. It is well established that good tissue distribution, fast clearance, low immunogenicity, hypoxia is an important determinant of the overall tumor and inexpensive, automated production [4]. response to conventional therapy. Hypoxia can result in an It was also observed that copper salts were the simplest increase in tumor aggressiveness, failure of local control, and angiogenic component of the tumor extract, acting through activation of transcription factors that support cell survival a stimulation of the migration of the endothelial cells [49]. and migration [57]. The ability to locate and quantify the extent of hypoxia Alpha V beta 3 (𝛼V𝛽3)isoneofthemostwidelystudied integrins, since it is upregulated in endothelial cells involved within solid tumors by using noninvasive nuclear imaging in active angiogenesis but not in quiescent endothelial cells, would facilitate early diagnosis and help clinicians select the most appropriate treatment for each individual patient [52]. making it an ideal biomarker for angiogenesis and tumor 4 imaging. Tumors where 𝛼V𝛽3 isfoundtobehighlyexpressed Diacetyl-2,3-bis(N -methyl-3-thiosemicarbazone) include glioblastomas, breast and prostate tumors, malignant (ATSM) seems to be an innovative compound for hypoxia 𝛼V𝛽3 imaging which could be labeled with copper positron emitter melanomas, and ovarian carcinomas. The integrin binds 60/61/62/64 to extracellular proteins through a specific binding pocket radioactive isotopes like Cu. The metabolism and that recognizes the three-amimo-acid sequence, arginine- pharmacological pathway of Cu-ATSM complex is the same glycine-aspartic acid (Arg-Gly-Asp or RGD). for all the copper isotopes, and the choice for clinical use Sprague et al. conjugated c (RGDyK) to a different between these isotopes is based on physical properties. 64 60 chelator, CB-TE2A, and found that the corresponding Cu Cu-ATSM was clinically studied for monitoring tumor complex was taken up specifically by osteoclasts, which are hypoxia in lung and cervical cancer and found to be feasible upregulatedinosteolyticlesionsandbonemetastases.These for prediction of tumor response to therapy [57, 58]. Chao 60 investigations open the possibility of other applications for et al. suggested that PET images obtained with Cu-ATSM imaging 𝛼V𝛽3 in diseases, such as osteoarthritis or osteoporo- can be used for intensity-modulated radiation therapy of sis, as well as imaging osteolytic bone metastases [52, 54]. head and neck cancer [59]. 61 61 61 Haoetal.found Cu-1,4,7,10-tetraazacyclododecane- Cu-2-acetylpyridine thiosemicarbazone ( Cu-APTS) 1,4,7,10-tetraacetic acid (DOTA)-human serum albumin to be complex, for PET imaging of cancer, was proposed by good blood pool imaging agent and suggested its application Belicchi-Ferrari et al. Using APTS as a ligand can give in antiangiogenic therapy monitoring [55]. additional antiproliferative activity to the compound, which 67 was previously observed by other authors [60]. Cu is one of the best-suited isotopes for radioim- 62 4 munotherapy, because its half-life is long enough to allow Cu-pyruvaldehyde-bis(N -methylthiosemicarbazone) 62 62 good biodistribution within tumor (similar to biological ( Cu-PTSM)canbeusedtogetherwith Cu-ATSM to half-life of many mAbs), relatively low gamma radiation obtaincomplementarydataontumorhypoxiaandblood abundance (lower whole body dose for patient and safer circulation in a single PET session [4, 61]. 64 for medical personnel), higher tumor uptake (compared to Cu presents the best compromise between adapted iodine-131), and simple radiolabeling procedure. Examples physical properties (sufficiently long half-life, better intrinsic 67 + of Cu labelled mAbs are chCE7, an anti-L1-cell adhesion image resolution with low 𝛽 maximal energy) and good molecule antibody for neuroblastoma, ovarian, and some production yield (reasonable production costs) [57]. 6 BioMed Research International

60/61/62 64 Similar to Cu isotopes, Cu-ATSMissubject gene makes it difficult to screen and diagnose WD by genetic 64 of many ongoing researches as selective tumor hypoxia testing. CuCl2 PET may change the management of WD 64 imaging agent. Phase II clinical trials of Cu-ATSM patients because it could reflect the symptoms variation PET/CT are monitoring therapeutic progress in patients of WD and thus affect the treatment strategy. With more 64 with cervical cancer. Similar compound, Cu-diacetyl- detailed information and a SUV cut-off value obtained from 4 64 64 bis(N ethylthiosemicarbazone) ( Cu-ATSE), has wider further validation of the methodology, CuCl2 PET could 64 tissue-oxygenation level specificity than Cu-ATSM. In serve as a simple, straightforward, and noninvasive method 64 various clinical trials, Cu-ATSMprovidedimagesoftumor for WD diagnosis [63]. Diagnosis of Alzheimer’s disease has been investigated hypoxia that improved the clinical outcome of patients 𝛽 submitted to external beam radiotherapy [57]. using imaging agent that targets amyloid plaque burden, 64 but new approach highlights altered copper homeostasis. A In conclusion, Cu-ATSMhasseveraladvantagesover 64 other radiopharmaceuticals used for PET of hypoxia, includ- bis-(thiosemicarbazonato) complex radiolabeled with Cu ing a simple and rapid method for radiolabeling, faster clear- can be used for a new and alternative method for the ance from normoxic tissues (allowing a short time between noninvasive diagnosis of Alzheimer’s disease using PET. injection and imaging), a simple method for quantification, This approach has the potential to offer complementary andverygoodimagequality[57]. information to other diagnostic procedures that elucidate plaque burden [64]. Furthermore, studies in Parkinson’s patients and cerebral 3.1.5. Chemotherapy Resistance. The chemotherapeutic agent perfusion preclinical studies have been performed in freely 60/61/62/64 62 Cisplatin (DDP) is a highly polar molecule not readily moving subjects using Cu-PTSM and later Cu- diffusible across lipid membranes. In many cell types, DDP 62 ethylglyoaxal bis(thiosemicarbazone) ( Cu-ETS), suggest- triggers, as the Cu, a rapid degradation of human cop- ing their potential application to clinical neurology or neu- per transporter 1 (hCtr1). This DDP action is obtained at ropsychiatry [65–68]. much lower concentrations and more rapidly respect to copper. hCtr1 expression decreases with the acquisition of a DDP resistance, so, in accordance with this phenomenon, a reduced Cu intracellular uptake should be observed in 3.3. Other Potential Roles. Studies over the last 20 years presence of a DDP resistance [49]. investigated the usefulness of Cu radioisotopes complexed 64 62 In particular, CuCl2 canbeusedtotestthedrugresis- with ATSM for the detection of myocardial perfusion. Cu- ATSM complex is widely researched for PET imaging of tance to therapeutic schemes based on DDP, as in patients 64 affected by breast, ovarian, or colon cancer [49]. myocardial ischaemia; Cu-ATSM seems to be useful to study myocardial hypoxia [69–72]. Furthermore, 5,13-dioximino-6,9,9,12-tetramethyl-7,11- 3.1.6. Prostate Cancer. In view of the fact that human tumor 64 diazaheptadeca-6,11-diene complex of Cu synthesized by tissues contain high concentrations of copper, Peng et al. Packardetal.canbepotentiallyusedasmyocardialperfusion hypothesized that human prostate cancers express high levels 64 imaging agent and PECAM-1 antibody conjugated with ofhCtr1andcanbedetectedby Cu PET. hCtr1 is a high- 64 DOTA and labeled with Cu was successfully performed affinity copper transporter that mediates cellular uptake of to evaluate induced myocardial infarction in mouse model copper in humans and is highly expressed in the liver [62]. [70]. ThehCtr1expressionlevelmayberelatedtothe Novel approach for therapy of multinodular goitre, using aggressiveness or prognosis of the prostate cancer and to human chorionic gonadotropin (hCG) directly labeled with theresponseofprostatecancertocisplatinchemotherapy + ionic Cu 𝛽 emitters was proposed by Maiti et al. [73]. because hCtr1 was recently reported to be able to mediate Initial studies indicate that copper-hCG complex half-life cellular uptake of cisplatin [62]. 64 is shorter than that of a hCG-TSH (thyroid stimulating On the Cu PET images, there was less background 64 hormone) receptor complex, thus hyperactive thyroid cells activity in the urinary bladder region because CuCl2 was can be destroyed before internalization of the receptor occurs. cleared mainly by the hepatobiliary pathway, instead of 18 More in vitro and in vivo studies are required to assess renally as F-FDG [62]. usefulness of this purpose [4]. Interesting perspectives for copper imaging with PET 3.2. The Role of Cu in Neurology. It was assumed that Wilson could be related to the analysis of inflammatory conditions [49]. Disease (WD) patient will have increased uptake of copper in 64 brain tissue and pathologic analysis of the brain may show Nanoparticles labeled with Cu were used to detect gliosis and neuronal loss in association with increased Cu macrophages in atherosclerotic plaques showing high sensi- deposition. Some WD patients have copper accumulation in tivity and direct correlation with CD68 expression [74]. 64 the brain and show neurological disorder, while others do not Locke et al. showed in mouse model that Cu labeled [63]. peptides targeting the formil peptide receptor on neutrophil Diagnosis of WD can be challenging as symptoms mimic in vitro accumulate at sites of inflammation in vivo, suggest- other diseases and may gradually appear over time. In ing that new radiolabeled peptides may prove to be a useful addition, the presence of many different mutations in Atp7b tool to probe inflammation [75]. BioMed Research International 7

61 4. Conclusions of Cu by proton irradiation of natZn at a medical cyclotron,” Applied Radiation and Isotopes,vol.64,no.12,pp.1563–1573, Copper isotopes are gaining a worthy role in the PET 2006. radionuclide scenario. Versatility of copper isotopes gives [10] S. S. Das, S. Chattopadhyay, L. Barua, and M. K. Das, “Pro- 61 them a strong position in development of new pharmaceu- duction of Cu using natural cobalt target and its separation ticals. Currently, there are few applications in medicine but using ascorbic acid and common anion exchange resin,” Applied numerous ongoing studies will most likely result in novel use Radiation and Isotopes,vol.70,no.2,pp.365–368,2012. in the future. [11] T. Fukumura, K. Okada, F. Szelecsenyi,´ Z. 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