An overview on Ga-68 radiopharmaceuticals for positron emission tomography applications

Document Type : Review Article


Radiation Application Research School, Nuclear Science and Technology Research Institute (NSTRI), Tehran, Iran


Gallium-68 a positron emitter radionuclide, with great impact on the nuclear medicine, has been widely used in positron emission tomography (PET) diagnosis of various malignancies in humans during more recent years especially in neuroendocrine tumors (NETs). The vast number of 68Ge/68Ga related generator productions, targeting molecule design (proteins, antibody fragments, affibodies, peptides and small molecules), as well as existing numerous human clinical trials at the registration, continuation and completion levels, are indicative of great importance and future impact of gallium-68 radiopharmaceuticals in human health. A concise review on the recent production and application of 68Ga-tracers with the emphasis on the peptides, biomolecules and also small molecules available for clinical applications, clinical trials or preclinical studies are presented. The importance of Ga-68 radionuclide as a theranostic radionuclide with potential coupling application with therapeutic radioisotopes (such as 90Y and 177Lu) is increasing appreciated. This review describes the present status of availability, application and future horizons on the development of 68Ga-radiopharmaceuticals worldwide.


Main Subjects

Wu X, Wang TW, Lessmann GM, Saleh J, Liu X, Chitambar CR, Hwang ST. Chitambar C.R., Hwang S.T., Gallium maltolate inhibits human cutaneous T-cell lymphoma tumor development in mice. J Invest Dermatol. 2015 Mar;135(3):877-84.
Chitambar CR, Antholine WE. Iron-targeting antitumor activity of gallium compounds and novel insights into triapine(®)-metal complexes. Antioxid Redox Signal. 2013 Mar 10;18(8):956-72.
Holden NE. Table of the Isotopes. In: Lide DR. CRC Handbook of Chemistry and Physics. 85th ed. CRC Press; 2004.
DDEP, Decay Data Evaluation Project. Available from: http://www. (2008).
Sudbrock F, Fischer T, Zimmermanns B, Guliyev M, Dietlein M, Drzezga A, Schomäcker K. Characterization of SnO2-based (68)Ge/ (68)Ga generators and (68)Ga-DOTATATE preparations: radionuclide purity, radiochemical yield and long-term constancy. EJNMMI Res. 2014 Dec;4(1):36.
Fazaeli Y, Jalilian AR, Amini MM, Ardaneh K, Rahiminejad A, Bolourinovin F, Moradkhani S, Majdabadi A. Development of a (68)Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging Agent. Nucl Med Mol Imaging. 2012 Mar;46(1):20-6.
Velikyan I. Prospective of ⁶⁸Ga-radiopharmaceutical development. Theranostics. 2013 Dec 10;4(1):47-80.
Bandoli G, Dolmella A, Tisato F, Porchia M, Refosco F. Mononuclear six-coordinated Ga(III) complexes: A comprehensive survey. Coord Chem Rev. 2009;253(1-2):56-77.
Harris WR, Pecoraro VL. Thermodynamic binding constants for gallium transferrin. Biochemistry. 1983;22(2):292–299.
Wadas TJ1, Wong EH, Weisman GR, Anderson CJ. Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease. Chem Rev. 2010 May 12;110(5):2858-902.
Li Y, Martell AE, Hancock RD, Reibenspies JH, Anderson CJ, Welch MJ. N,N'-Ethylenedi-L-cysteine (EC) and its metal complexes: Synthesis, characterization, crystal structures, and equilibrium constants. Inorg Chem. 1996;35(2):404-414.
Jung WS, Chung YK, Shin DM, Kim SD. Crystal- and Solution-Structure characteristics of Ethylenediaminetetraacetatoaluminate(III) and Gallate(III). Bull Chem Soc Jpn. 2002;75(6):1263-1267.
Broan CJ, Cox JPL, Craig AS, Kataky R, Parker D, Harrison A, Randall AM, Ferguson G. Structure and solution stability of indium and gallium complexes of 1,4,7-triazacyclononanetriacetate and of yttrium complexes of 1,4,7,10-tetraazacyclododecanetetraacetate and related ligands: kinetically stable complexes for use in imaging and radioimmunotherapy. X-Ray molecular structure of the indium and gallium complexes of 1,4,7-triazacyclononane-1,4,7-triacetic acid. J Chem Soc Perkin Trans 2. 1991;1:87-99.
Viola NA, Rarig RS, Ouellette W, Doyle RP. Synthesis, structure and thermal analysis of the gallium complex of 1,4,7,10-tetraazacyclo-dodecane-N,N′,N″,N‴-tetraacetic acid (DOTA). Polyhedron. 2006;25(18):3457-3462.
Burleson RL, Johnson MC, Head H. Scintigraphic demonstration of experimental abscesses with intravenous 67Ga citrate and 67Ga labeled blood leukocytes. Ann Surg. 1973 Oct;178(4):446-52.
Jalilian AR, Novinrooz A, Motamedi-Sedeh F, Moradkhani S, Rajamand AA, Solati J. Evaluation of [67Ga] citrate in the detection of various microorganism infections in animal models. Iran J Nucl Med 2009;17(2):34-41.
Nanni C, Errani C, Boriani L, Fantini L, Ambrosini V, Boschi S, Rubello D, Pettinato C, Mercuri M, Gasbarrini A, Fanti S. 68Ga-citrate PET/CT for evaluating patients with infections of the bone: preliminary results. J Nucl Med. 2010 Dec;51(12):1932-6.
Kumar V, Boddeti DK, Evans SG, Angelides S. (68)Ga-Citrate-PET for diagnostic imaging of infection in rats and for intra-abdominal infection in a patient. Curr Radiopharm. 2012 Jan;5(1):71-5.
Rizzello A, Di Pierro D, Lodi F, Trespidi S, Cicoria G, Pancaldi D, Nanni C, Marengo M, Marzola MC, Al-Nahhas A, Rubello D, Boschi S. Synthesis and quality control of 68Ga citrate for routine clinical PET. Nucl Med Commun. 2009 Jul;30(7):542-5.
Vorster M, Mokaleng B, Sathekge MM, Ebenhan T. A modified technique for efficient radiolabeling of 68Ga-citrate from a SnO2-based 68Ge/68Ga generator for better infection imaging. Hell J Nucl Med. 2013 Sep-Dec;16(3):193-8.
Silvola JM, Laitinen I, Sipilä HJ, Laine VJ, Leppänen P, Ylä-Herttuala S, Knuuti J, Roivainen A. Uptake of 68gallium in atherosclerotic plaques in LDLR-/-ApoB100/100 mice. EJNMMI Res. 2011 Aug 17;1(1):14.
Mirzaei A, Jalilian AR, Akhlaghi M, Beiki D. Production of 68Ga-citrate based on a SnO2 generator for short-term turpentine oil-induced inflammation imaging in rats. Curr Radiopharm. 2015; [In process].
Hamazawa Y, Koyama K, Okamura T, Wada Y, Wakasa T, Okuma T, Watanabe Y, Inoue Y. Comparison of dynamic FDG-microPET study in a rabbit turpentine-induced inflammatory model and in a rabbit VX2 tumor model. Ann Nucl Med. 2007 Jan;21(1):47-55.
Rizzello A, Di Pierro D, Lodi F, Trespidi S, Cicoria G, Pancaldi D, Nanni C, Marengo M, Marzola MC, Al-Nahhas A, Rubello D, Boschi S. Synthesis and quality control of 68Ga citrate for routine clinical PET. Nucl Med Commun. 2009 Jul;30(7):542-5.
 Aghanejad A, Jalilian AR, Ardaneh K, Bolourinovin F, Yousefnia H, Bahrami Samani A. Preparation and Quality Control of 68Ga-Citrate for PET Applications. Asia Oceania J Nucl Med Biol. 2015;3(2):99-106.
de Herder WW, Hofland LJ, van der Lely AJ, Lamberts SW. Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. Endocr Relat Cancer. 2003 Dec;10(4):451-8.
Hofmann M, Maecke H, Börner R, Weckesser E, Schöffski P, Oei L, Schumacher J, Henze M, Heppeler A, Meyer J, Knapp H. Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001 Dec;28(12):1751-7.
Gabriel M, Decristoforo C, Kendler D, Dobrozemsky G, Heute D, Uprimny C, Kovacs P, Von Guggenberg E, Bale R, Virgolini IJ. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007 Apr;48(4):508-18.
Jindal T, Kumar A, Venkitaraman B, Dutta R, Kumar R. Role of (68)Ga-DOTATOC PET/CT in the evaluation of primary pulmonary carcinoids. Korean J Intern Med. 2010 Dec;25(4):386-91. 
Zolghadri S, Yousefnia H, Ramazani A, Jalilian AR. Preclinical studies of 68Ga-DOTATOC: biodistribution assessment in syrian rats and absorbed dose evaluation in human organs. Asia Oceania J Nucl Med Biol. 2015; [In press].
Velikyan I, Sundin A, Sörensen J, Lubberink M, Sandström M, Garske-Román U, Lundqvist H, Granberg D, Eriksson B. Quantitative and qualitative intrapatient comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: net uptake rate for accurate quantification. J Nucl Med. 2014 Feb;55(2):204-10.
Aghanejad A, Jalilian AR, Maus S, Geramifar P, Beiki D. Optimized production and quality control of 68Ga-DOTATATE. Iran J Nucl Med. 2016:24(1):29-36.
Sudbrock F, Fischer T, Zimmermanns B, Guliyev M, Dietlein M, Drzezga A, Schomäcker K. Characterization of SnO2-based (68)Ge/ (68)Ga generators and (68)Ga-DOTATATE preparations: radionuclide purity, radiochemical yield and long-term constancy. EJNMMI Res. 2014 Dec;4(1):36.
Yang J, Kan Y, Ge BH, Yuan L, Li C, Zhao W. Diagnostic role of Gallium-68 DOTATOC and Gallium-68 DOTATATE PET in patients with neuroendocrine tumors: a meta-analysis. Acta Radiol. 2014 May;55(4):389-98.
Ocak M, Demirci E, Kabasakal L, Aygun A, Tutar RO, Araman A, Kanmaz B. Evaluation and comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET/CT imaging in well-differentiated thyroid cancer. Nucl Med Commun. 2013 Nov;34(11):1084-9.
68Ga DOTATATE PET/CT in neuroendocrine tumors (expanded access). Available from:
Investigation of 68Ga-DOTATATE, as a PET imaging agent in neuroendocrine tumor patients. Available from:
Wild D, Bomanji JB, Benkert P, Maecke H, Ell PJ, Reubi JC, Caplin ME. Comparison of 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT within patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2013 Mar;54(3):364-72.
68Ga-DOTA-NOC PET/CT in patients with idiopathic pulmonary fibrosis. Available from:
Herrmann K, Czernin J, Wolin EM, Gupta P, Barrio M, Gutierrez A, Schiepers C, Mosessian S, Phelps ME, Allen-Auerbach MS. Impact of 68Ga-DOTATATE PET/CT on the management of neuroendocrine tumors: the referring physician's perspective. J Nucl Med. 2015 Jan;56(1):70-5.
Clinical translation of a novel albumin-binding PET radiotracer 68Ga-NEB. Available from:
68Ga-BNOTA-PRGD2 PET/CT in evaluation of stroke (GRGDS). Available from:
PET/CT imaging study of the safety and diagnostic performance of [68Ga]RM2 in patients with primary prostate cancer. Available from:
PET study of breast cancer patients using [68Ga]ABY-025. Available from:
68Ga-DOTA-Bombesin PET/MRI in imaging patients with prostate cancer. Available from:
Evaluation of a new radiotracer (68Ga-NOTA-AE105) for diagnosing aggressive cancer with positron emission tomography (uPAR-PET). Available from:
68Ga-AlfatideII for the Differential Diagnosis of of Lung Cancer and Lung Tuberculosis by PET/CT. Available from:
Wang Z, Zhang M, Wang L, Wang S, Kang F, Li G, Jacobson O, Niu G, Yang W, Wang J, Chen X.  Prospective Study of (68)Ga-NOTA-NFB: Radiation dosimetry in healthy volunteers and first application in glioma patients. Theranostics. 2015 Apr 28;5(8):882-9.
68Ga-NOTA-NFB: radiation dosimetry in healthy volunteers and applications in glioma patients or breast cancer patients (GNNGB). Available from:
Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, Graner FP, Kübler H, Haberhorn U, Eisenhut M, Wester HJ, Gschwend JE, Schwaiger M. Evaluation of Hybrid ⁶⁸Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. 2015 May;56(5):668-74.
68Ga-PSMA PET/CT or PET/MRI in evaluating patients with recurrent prostate cancer. Available from:
ImmunoTEP au 68-Ga- IMP-288 for patients with a recurrence of HER2 negative breast carcinoma expressing CEA (iTEPsein). Available from:
Schoffelen R, Sharkey RM, Goldenberg DM, Franssen G, McBride WJ, Rossi EA, Chang CH, Laverman P, Disselhorst JA, Eek A, van der Graaf WT, Oyen WJ, Boerman OC. Pretargeted immuno-positron emission tomography imaging of carcinoembryonic antigen-expressing tumors with a bispecific antibody and a 68Ga- and 18F-labeled hapten peptide in mice with human tumor xenografts. Mol Cancer Ther. 2010 Apr;9(4):1019-27. 
Biodistribution and dosimetry of serial PET imaging with Ga-68 labeled F(ab') 2- Trastuzumab. Available from:
Imaging of atherosclerosis with 68Ga-MSA. Available from:
Pandit-Taskar N, Larson SM, Carrasquillo JA. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: α therapy with 223Ra-dichloride. J Nucl Med. 2014 Feb;55(2):268-74.
Ayati N, Aryana K, Jalilian AR, Hoseinnejad T, Samani AB, Ayati Z, Treatment efficacy of 153Sm-EDTMP for painful bone metastasis. Asia Oceania J Nucl Med Biol. 2013;1:27–31.
Alavi M, Omidvari S, Mehdizadeh A, Jalilian AR, Bahrami-Samani A. Metastatic bone pain palliation using 177Lu‑Ethylenediaminetetramethylene phosphonic acid. World J Nucl Med. 2015;14:109-115.
Bahrami-Samani A, Anvari A, Jalilian AR, Shirvani-Arani S, Yousefnia H, Aghamiri MR, Ghannadi-Maragheh M. Production, quality control and pharmacokinetic studies of (177)Lu-EDTMP for human bone pain palliation therapy trials. Iran J Pharm Res. 2012;11(1):137-44.
Mitterhauser M, Toegel S, Wadsak W, Lanzenberger RR, Mien LK, Kuntner C, Wanek T, Eidherr H, Ettlinger DE, Viernstein H, Kluger R, Dudczak R, Kletter K. Pre vivo, ex vivo and in vivo evaluations of [68Ga]-EDTMP. Nucl Med Biol. 2007 May;34(4):391-7.
Mirzaei A, Jalilian AR, Badbarin A, Mazidi M, Mirshojaei F, Geramifar P, Beiki D. Optimized production and quality control of (68)Ga-EDTMP for small clinical trials. Ann Nucl Med. 2015 Jul;29(6):506-11.
Ogawa K, Ishizaki A, Takai K, Kitamura Y, Kiwada T, Shiba K, Odani A. Development of novel radiogallium-labeled bone imaging agents using oligo-aspartic acid peptides as carriers. PLoS One. 2013 Dec 31;8(12):e84335.
Meckel M, Nauth A, Timpe J, Zhernosekov K, Puranik AD, Baum RP, Rösch F. Development of a [177Lu]BPAMD labeling kit and an automated synthesis module for routine bone targeted endoradiotherapy. Cancer Biother Radiopharm. 2015 Mar;30(2):94-9. 
Yousefnia H, Zolghadri S, Jalilian AR. Preparation and biodistribution assessment of 111In-BPAMD as a novel agent for bone SPECT Imaging. Radiochim Acta. 2015; [In press].
Fellner M, Riss P, Loktionova N, Zhernosekov K, Thews O, Geraldes CFGC, Kovacs Z, Lukes I, Rosch F. Comparison of different phosphorus-containing ligands complexing 68Ga for PET-imaging of bone metabolism. Radiochem Acta. 2011;99:43–51.
Fellner M, Biesalski B, Bausbacher N, Kubícek V, Hermann P, Rösch F, Thews O. (68)Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter. Nucl Med Biol. 2012 Oct;39(7):993-9.
Fellner M, Baum RP, Kubícek V, Hermann P, Lukes I, Prasad V, Rösch F. PET/CT imaging of osteoblastic bone metastases with (68)Ga-bisphosphonates: first human study. Eur J Nucl Med Mol Imaging. 2010 Apr;37(4):834.
Mirzaei A, Jalilian AR, Aghanejad A, Mazidi M, Yousefnia H, Shabani G, Ardaneh K, Geramifar P, Beiki D. Preparation and evaluation of (68)Ga-ECC as a PET renal imaging agent. Nucl Med Mol Imaging. 2015 Sep;49(3):208-16.
MirzaeiA, Jalilian AR, Shabani G, Fakhari A, Akhlaghi M, Beiki D. Development of 68Ga ethyl cysteinate dimer for PET studies. J Radioanal Nucl Chem. 2015; DOI 10.1007/s10967-015-4185-3
Shanehsazzadeh S, Lahooti A, Yousefnia H, Geramifar P, Jalilian AR. Comparison of estimated human dose of (68)Ga-MAA with (99m)Tc-MAA based on rat data. Ann Nucl Med. 2015 Oct;29(8):745-53.
Hofman M, Binns D, Johnston V, Siva S, Thompson M, Eu P, Collins M, Hicks RJ. 68Ga-EDTA PET/CT imaging and plasma clearance for glomerular filtration rate quantification: comparison to conventional 51Cr-EDTA. J Nucl Med. 2015 Mar;56(3):405-9.
Ahtinen H, Kulkova J, Lindholm L, Eerola E, Hakanen AJ, Moritz N, Söderström M, Saanijoki T, Jalkanen S, Roivainen A, Aro HT. (68)Ga-DOTA-Siglec-9 PET/CT imaging of peri-implant tissue responses and staphylococcal infections. EJNMMI Res. 2014 Aug 8;4:45.
Sharma V, Sivapackiam J, Harpstrite SE, Prior JL, Gu H, Rath NP, Piwnica-Worms D. A generator-produced gallium-68 radiopharmaceutical for PET imaging of myocardial perfusion. PLoS One. 2014 Oct 29;9(10):e109361.
Aljammaz I, Al-Otaibi B, Al-Hokbany N, Amer S, Okarvi S. Development and pre-clinical evaluation of new 68Ga-NOTA-folate conjugates for PET imaging of folate receptor-positive tumors. Anticancer Res. 2014 Nov;34(11):6547-56.
Eichendorff S, Svendsen P, Bender D, Keiding S, Christensen EI, Deleuran B, Moestrup SK. Biodistribution and PET imaging of a novel [68Ga]-anti-CD163-antibody conjugate in rats with collagen-induced arthritis and in controls. Mol Imaging Biol. 2015 Feb;17(1):87-93.
Jindal A, Mathur A, Pandey U, Sarma HD, Chaudhari P, Dash A. Development of 68Ga-labeled fatty acids for their potential use in cardiac metabolic imaging. J Labelled Comp Radiopharm. 2014 Jun 15;57(7):463-9.
Holub J1, Meckel M, Kubíček V, Rösch F, Hermann P. Gallium(III) complexes of NOTA-bis (phosphonate) conjugates as PET radiotracers for bone imaging. Contrast Media Mol Imaging. 2015 Mar-Apr;10(2):122-34.
Zoghi M, Niazi A, Jalilian AR, Johari-daha F, Alireapour B, Ramezanpour S. Development of a Ga-68 labeled triptorelin analog for GnRH receptor imaging. Radiochimica Acta. 2015; [In press].