{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T16:04:41Z","timestamp":1762272281563,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2018,6,3]],"date-time":"2018-06-03T00:00:00Z","timestamp":1527984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Instruments"],"abstract":"<jats:p>Positron emitting radionuclides are used to label different compounds, allowing the study of the major biological systems using PET (positron emission tomography) imaging. Although there are several radionuclides suited for PET imaging, routine clinical applications are still based on a restrict group constituted by 18F, 11C, and, more recently, 68Ga. However, with the enlarged availability of low-energy cyclotrons and technical improvements in radionuclide production, the use of unconventional radionuclides is progressively more common. Several examples of unconventional radionuclides for PET imaging are being suggested, and 45Ti could be suggested as a model, due to its interesting properties such as its abundant positron emission (85%), reduced positron energy (\u03b2+ endpoint energy = 1040 keV), physical half-life of 3.09 h, and interesting chemical properties. This review aims to introduce the role of cyclotrons in the production of unconventional radionuclides for PET imaging while using 45Ti as an example to explore the potential biomedical applications of those radionuclides in PET imaging.<\/jats:p>","DOI":"10.3390\/instruments2020008","type":"journal-article","created":{"date-parts":[[2018,6,4]],"date-time":"2018-06-04T08:52:03Z","timestamp":1528102323000},"page":"8","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Cyclotron Production of Unconventional Radionuclides for PET Imaging: the Example of Titanium-45 and Its Applications"],"prefix":"10.3390","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9280-2750","authenticated-orcid":false,"given":"Pedro","family":"Costa","sequence":"first","affiliation":[{"name":"Nuclear Medicine Department, School of Health, Polytechnic Institute of Porto, 4200-072 Porto, Portugal"},{"name":"Health and Environment Research Center (CISA), Polytechnic Institute of Porto, 4200-072 Porto, Portugal"}]},{"given":"Lu\u00eds F.","family":"Metello","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Department, School of Health, Polytechnic Institute of Porto, 4200-072 Porto, Portugal"},{"name":"Is\u00f3topos para Diagn\u00f3stico e Terap\u00eautica (IsoPor), S.A., 4445-526 Ermesinde, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8054-4267","authenticated-orcid":false,"given":"Francisco","family":"Alves","sequence":"additional","affiliation":[{"name":"Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Coimbra Health School, Polytechnic Institute of Coimbra , 3046-854 Coimbra, Portugal"}]},{"given":"M.","family":"Duarte Naia","sequence":"additional","affiliation":[{"name":"Physics Department, University of Tr\u00e1s-os-Montes e Alto Douro, 5000-801 Vila Real, Portugal"},{"name":"Centre for Mechanical Engineering, Materials and Processes (CEMMPRE), University of Coimbra, 3030-788 Coimbra, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/0895-6111(94)00043-3","article-title":"Biomedical imaging modalities: A tutorial","volume":"19","author":"Acharya","year":"1995","journal-title":"Comput. Med. Imaging Graph."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev.bioeng.8.061505.095728","article-title":"Multimodality in vivo imaging systems: Twice the power or double the trouble?","volume":"8","author":"Cherry","year":"2006","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_3","unstructured":"World Health Organization (1972). Technical Report Series No 492, World Health Organization."},{"key":"ref_4","unstructured":"(2018, April 20). Nuclear Medicine and Radiopharmaceuticals Market 2012\u20132017. Available online: https:\/\/healthmanagement.org\/c\/imaging\/news\/nuclear-medicine-and-radiopharmaceuticals-market-2012-2017."},{"key":"ref_5","unstructured":"Saha, G.B. (2005). Diagnostic Uses of Radiopharmaceuticals in Nuclear Medicine. Fundamentals of Nuclear Pharmacy, Springer."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Saha, G.B. (2010). Cyclotron and Production of PET Radionuclides. Basics of PET Imaging: Physics, Chemistry and Regulations, Springer.","DOI":"10.1007\/978-1-4419-0805-6"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40658-016-0144-5","article-title":"Physics of pure and non-pure positron emitters for PET: A review and a discussion","volume":"3","author":"Conti","year":"2016","journal-title":"EJNMMI Phys."},{"key":"ref_8","first-page":"1","article-title":"The Application of Unconventional PET Tracers in Nuclear Medicine","volume":"17","author":"Jalilian","year":"2009","journal-title":"Iran. J. Nucl. Med."},{"key":"ref_9","unstructured":"Schubiger, P.A., Lehmann, L., and Friebe, M. (2007). Production of Non-Standard PET Radionuclides and Application of Radiopharmaceuticals Labeled with these Nuclides. PET Chemistry: The Driving Force in Molecular Imaging Series, Springer."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1007\/s00259-017-3878-y","article-title":"Prognostic value of vasodilator response using rubidium-82 positron emission tomography myocardial perfusion imaging in patients with coronary artery disease","volume":"45","author":"Arasaratnam","year":"2018","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1007\/s00259-017-3802-5","article-title":"Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors","volume":"44","author":"Rossi","year":"2017","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s00259-017-3803-4","article-title":"89Zr-labeled nivolumab for imaging of T-cell infiltration in a humanized murine model of lung cancer","volume":"45","author":"England","year":"2018","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_13","unstructured":"Chu, S.Y.F., Ekstr\u00f6m, L.P., and Firestone, R.B. (2018, April 23). WWW Table of Radioactive Isotopes, database version 1999-02-28. Available online: http:\/\/nucleardata.nuclear.lu.se\/nucleardata\/toi\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1524\/ract.2012.1964","article-title":"Inorganic chemistry in nuclear imaging and radiotherapy: Current and future directions","volume":"100","author":"Carrol","year":"2012","journal-title":"Radiochim. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Saha, G.B. (2010). Production of Radionuclides, Springer. [6th ed.].","DOI":"10.1007\/978-1-4419-5860-0_4"},{"key":"ref_16","unstructured":"International Atomic Energy Agency (IAEA) (2006). Directory of Cyclotrons used for Radionuclide Production in Member States\u20142006 Update, IAEA."},{"key":"ref_17","unstructured":"International Atomic Energy Agency (IAEA) (2008). Technical Report Series No465\u2014Cyclotron Produced Radionuclides: Principles and Practice, IAEA."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1134\/S1063779608040060","article-title":"Commercial Cyclotrons. Part I: Commercial Cyclotrons in the Energy Range 10\u201330 MeV for Isotope Production","volume":"39","author":"Papash","year":"2008","journal-title":"Phys. Part. Nucl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1524\/ract.2001.89.4-5.223","article-title":"Nuclear data relevant to the production and application of diagnostic radionuclides","volume":"89","author":"Qaim","year":"2001","journal-title":"Radiochim. Acta"},{"key":"ref_20","first-page":"C9","article-title":"Particle accelerators for PET radionuclides","volume":"15","author":"Jensen","year":"2012","journal-title":"Nucl. Med. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2310\/7290.2010.00008","article-title":"Unconventional Nuclides for Radiopharmaceuticals","volume":"9","author":"Holland","year":"2010","journal-title":"Mol. Imaging"},{"key":"ref_22","first-page":"293","article-title":"Nuclear data for the cyclotron production of 66Ga, 86Y, 76Br, 64Cu and 43Sc","volume":"55","author":"Sadeghi","year":"2010","journal-title":"Nucleonika"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.apradiso.2017.01.037","article-title":"A simple thick target for production of 89Zr in an 11 MeV cyclotron","volume":"122","author":"Link","year":"2017","journal-title":"Appl. Radiat. Isot."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/S0969-8051(00)00104-9","article-title":"Production of High Purity 94mTc for Positron Emission Tomographic Studies","volume":"27","author":"Qaim","year":"2000","journal-title":"Nucl. Med. Biol."},{"key":"ref_25","first-page":"786463","article-title":"The Copper Radioisotopes: A systematic review with special interest to 64Cu","volume":"2014","author":"Asabella","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1007\/s00259-011-1782-4","article-title":"The production of [124I]iodine and [86Y]yttrium","volume":"38","author":"Schmitz","year":"2011","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_27","unstructured":"Costa, P., Metello, L.F., do Carmo, S.J.C., Alves, F., and Duarte Naia, M. (2016, January 15\u201319). Titanium-45 as an innovative radionuclide for PET imaging: From cyclotron production to potential biomedical applications. Proceedings of the 29th Annual Congress of the European Association of Nuclear Medicine 2016, Barcelona, Spain. Oral Presentation 447."},{"key":"ref_28","unstructured":"Ishiwata, K., Ido, T., Monma, M., Murakami, M., Fukuda, H., Yamada, K., Endo, S., Yoshioka, H., Sato, T., and Matsuzawa, T. (1981). Preparation and Medical Application of 45Ti, CYRIC. CYRIC Annual Report."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/0883-2889(91)90173-X","article-title":"Potential radiopharmaceuticals labeled with titanium-45","volume":"42","author":"Ishiwata","year":"1991","journal-title":"Int. J. Radiat. Appl. Instrum. Part A Appl. Radiat. Isot."},{"key":"ref_30","unstructured":"Waterhouse, R.N., Mattner, F., Najdovski, L., Collier, T.L., and Fallon, J. (1995, January 13\u201317). Synthesis and Characterisation of [111In]-Liposome Encapsulated [45Ti]-Budotitane. Proceedings of the Eleventh International Symposium on Radiopharmaceutical Chemistry, Vancouver, BC, Canada."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.nucmedbio.2004.10.003","article-title":"Production, processing and small animal PET imaging of titanium-45","volume":"32","author":"Vavere","year":"2005","journal-title":"Nucl. Med. Biol."},{"key":"ref_32","first-page":"683","article-title":"Preparation, biodistribution, and small animal PET of 45Ti-transferrin","volume":"46","author":"Vavere","year":"2005","journal-title":"J. Nucl. Med."},{"key":"ref_33","unstructured":"Price, R.I., Sheil, R.W., Scharli, R.K., Chan, S., Gibbons, P., Jeffery, C., and Morandeau, L. (2015, January 18\u201321). Titanium-45 as a Candidate for PET Imaging: Production, Processing & Applications. Proceedings of the 15th International Workshop on Targetry and Target Chemistry, Prague, Czech Republic."},{"key":"ref_34","unstructured":"Siikanen, J., Hong, H., Valdovinos, H., Hernandez, R., Zhang, Y., Barnhart, T., Cai, W., and Nickles, R. (2013, January 8\u201312). Production, separation and labeling of 45Ti. Proceedings of the SNMMI Annual Meeting, Vancouver, BC, Canada."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1002\/ejic.200900198","article-title":"Cytotoxic Titanium(IV) Complexes: Renaissance","volume":"2009","author":"Tshuva","year":"2009","journal-title":"Eur. J. Inorg. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2775","DOI":"10.1002\/chem.200902312","article-title":"Cytotoxic Titanium Salan Complexes: Surprising Interaction of Salan and Alkoxy Ligands","volume":"16","author":"Immel","year":"2010","journal-title":"Chem. Eur. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.drudis.2014.01.003","article-title":"The role of molecular imaging in modern drug development","volume":"19","author":"Cunha","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7591","DOI":"10.1021\/acs.jmedchem.5b01167","article-title":"Bringing Radiotracing to Titanium-Based Antineoplastics: Solid Phase Radiosynthesis, PET and ex Vivo Evaluation of Antitumor Agent [45Ti](salan)Ti(dipic)","volume":"58","author":"Severin","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_39","first-page":"149","article-title":"Nanotechnology and nuclear medicine; research and preclinical applications","volume":"14","author":"Assadi","year":"2011","journal-title":"Hell. J. Nucl. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1134\/S1995078009090158","article-title":"An Examination of the Ability of Titanium Dioxide Nanoparticles and Its Conjugates with Oligonucleotides to Penetrate into Eucariotis Cells","volume":"4","author":"Zarytova","year":"2009","journal-title":"Nanotechnol. Russia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.cattod.2010.02.016","article-title":"Effects of UV-irradiated titania nanoparticles on cell proliferation, cancer metastasis and promotion","volume":"151","author":"Stefanou","year":"2010","journal-title":"Catal. Today"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12951-014-0048-2","article-title":"Molecular mechanism of DNA damage induced by titanium dioxide nanoparticles in toll-like receptor 3 or 4 expressing human hepatocarcinoma cell lines","volume":"12","author":"Ali","year":"2014","journal-title":"J. Nanobiotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1007\/s11051-014-2739-x","article-title":"Novel titanium oxide nanoparticles for effective delivery of paclitaxel to human breast cancer cells","volume":"16","author":"Mund","year":"2014","journal-title":"J. Nanopart. Res."},{"key":"ref_44","first-page":"2321","article-title":"Anticancer efficacy enhancement and attenuation of side effects of doxorubicin with titanium dioxide nanoparticles","volume":"6","author":"Chen","year":"2011","journal-title":"Int. J. Nanomed."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1007\/s00204-011-0701-6","article-title":"Radiolabelling of engineered nanoparticles for in vitro and in vivo tracing applications using cyclotron accelerators","volume":"85","author":"Gibson","year":"2011","journal-title":"Arch. Toxicol."},{"key":"ref_46","unstructured":"Salber, D., Manuvelpillai, J., Spahn, I., Klein, S., Uhlenbruck, F., Palm, C., Matusch, A., Becker, S., Langen, K.J., and Coenen, H.H. (2010, January 8\u201311). 45Ti-cations as potential PET-tracers for cerebral neurodegeneration. Proceedings of the International Symposium on Technetium and Other Radiometals in Chemistry and Medicine, Bressanone, Italy."}],"container-title":["Instruments"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2410-390X\/2\/2\/8\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:07:03Z","timestamp":1760195223000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2410-390X\/2\/2\/8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,3]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["instruments2020008"],"URL":"https:\/\/doi.org\/10.3390\/instruments2020008","relation":{},"ISSN":["2410-390X"],"issn-type":[{"type":"electronic","value":"2410-390X"}],"subject":[],"published":{"date-parts":[[2018,6,3]]}}}