Avoid common mistakes on your manuscript.
Since its first introduction some 20 years ago, [68Ga]-radiolabelled somatostatin receptor agonists (SSAs) have gained high importance in the management of neuroendocrine tumours [1], especially due to the better delineation of small structures compared with the licensed product [111In]In-pentetreotide ([111In]In-DTPA-[D-Phe1]-octreotide, OctreoScan®) [2, 3]. In clinical routine PET imaging of the somatostatin receptor (SSTR) in patients with neuroendocrine tumours (NETs) employing on [68Ga]Ga-DOTA-peptides such as [68Ga]Ga-DOTATOC or [68Ga]Ga-DOTATATE is the gold standard [4]. Current guidelines recommend a preplacement of [111In]In-DTPA-octreotide by [68Ga]-labelled SSAs [5]. The theranostic pair with [177Lu]Lu-DOTATOC or [177Lu]Lu-DOTATATE as radiotracers for peptide receptor radionuclide therapy (PRRT) has been established [6].
The big advantage of the positron-emitting radiometal [68Ga] is its availability from a [68Ge]/[68Ga] generator, providing an independence from a local cyclotron installation. This aspect and the fact that some of the available generators have received regulatory approval have spread [68Ge]/[68Ga] generators and their production facilities worldwide in recent years. Nevertheless [68Ga] has at the same time several disadvantages. With a relatively short half-life (68 min) [7], the possibilities for decentralized production are very limited and restrict its use in centres that have no adequate radiopharmacy. Another limiting point is that the low overall activity yield per synthesized batch is only sufficient for a maximum of four patients per production. In addition to logistical disadvantages, [68Ga] also has drawbacks based on its physical properties. [68Ga] is a long-range positron emitter (> 1 mm) with a relatively high positron energy (Emean = 0.83 MeV) which corresponds to a relatively long positron range (Rmean = 3.5 mm) resulting in relatively blurred images due to a suboptimal spatial resolution compared with the radiohalogen [18F] [8, 9]. For these reasons, the implementation of especially [18F] labelling of SSAs for PET imaging of NETs has been studied.
Concerning clinical PET imaging, [18F] is the most commonly used positron-emitting radiohalogen. Unlike [68Ga], it offers several logistic and physical benefits. [18F] with a half-life of 109.77 min [10] can be produced in large amounts by cyclotrons, and locally synthesized PET tracers can consecutively be easily transported over a longer distance to hospitals and departments without cyclotron (satellite concept). Another advantage is that [18F] is a short-range positron emitter (< 1 mm) with a low positron energy (Emean = 0.25 MeV) and a corresponding shorter positron range (Rmean = 0.6 mm) resulting in a higher spatial resolution [8, 9].
To meet the high radiotracer demand in PET imaging of NETs, the group of Hans-Jürgen Wester evaluated already more than 10 years ago a fluorine-18-labelled somatostatin receptor agonist, Gluc-Lys([18F]FP)-TOCA, which showed a superior diagnostic performance compared with [111In]In-DTPA-octreotide. Due to its complex multistep synthesis and the poor radiochemical yield, this tracer was not implemented in clinical practice [11,12,13]. The chemical advantages in using silicon-fluoride acceptor (SiFA) chemistry allowing a simple and mild radiolabeling procedure without generating radiochemical by-products or derivatives were demonstrated [14]. A promising fluorine-18-based SSA tracer, [18F]SiFAlin-TATE [15], was explored in a patient with metastatic NET and compared with [68Ga]Ga-DOTATOC. This case report demonstrated that the uptake of [18F]SiFAlin-TATE in healthy and tumour tissue is in the same range as [68Ga]Ga-DOTATOC [16]. A tracer synthesizing method which combines the advantages of a chelator-based radiolabelling and the properties of [18F] was developed in 2009 [17]. Laverman et al. introduced [18F]AIF-NOTA-octreotide and compared it with [111In]In-DTPA-octreotide and [68Ga]Ga-NOTA-octreotide in preclinical models. This comparison confirmed a high in vitro binding affinity of [18F]AIF-NOTA-octreotide towards SSTR2 [18, 19]. In 2019, the first clinical experience with [18F]AIF-NOTA-octreotide in 22 NET patients was reported showing that the tracer displays a favourable biodistribution and provides an excellent detection of tumoural lesions with a high tumour-to-background ratio; however, there was no comparison with a [68Ga]-labelled SSA [20]. It took almost 10 years until an automated GMP compliant production of [18F]AIF-NOTA-octreotide was published and a GMP grade precursor became commercially available [21].
In this issue, a systematic biodistribution study of [18F]AIF-NOTA-octreotide as well as a first comparison to the clinical standard [68Ga]Ga-DOTATATE is presented by the group from Leuven, Belgium, using this automated GMP compliant production (Pauwels et al.: [18F]AlF-NOTA-octreotide PET imaging: biodistribution, dosimetry and first comparison with [68Ga]Ga-DOTATATE in neuroendocrine tumour patients, in print). While the acquisition of [68Ga]Ga-DOTATATE is recommended to be started about 45–60 min p.i. [22, 23], the authors showed that 120 min p.i. reveal the best target-to-background ratio for [18F]AIF-NOTA-octreotide imaging. This aspect has to be taken into account in the logistic planning of the scanning if the tracer would be introduced into routine. The very small group of patients does not allow the conclusion that [18F]AIF-NOTA-octreotide is superior to [68Ga]Ga-DOTATATE, but it can be stated that it is certainly not inferior to the gold standard. The favourable dosimetry, biodistribution, kinetics and binding affinity/tumour targeting hold promise for a competitive compound in the management of NET patients.
In conclusion we think that the easy to synthesize and GMP compliant tracer [18F]AIF-NOTA-octreotide has definitely the potential to become the rising star in SSR imaging and might prove to also have economical advantages.
References
Hofmann M, Maecke H, Börner R, Weckesser E, Schöffski P, Oei L, et al. Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001;28:1751–7. https://doi.org/10.1007/s002590100639.
Buchmann I, Henze M, Engelbrecht S, Eisenhut M, Runz A, Schäfer M, et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2007;34:1617–26. https://doi.org/10.1007/s00259-007-0450-1.
Van Binnebeek S, Vanbilloen B, Baete K, Terwinghe C, Koole M, Mottaghy FM, et al. Comparison of diagnostic accuracy of (111)In-pentetreotide SPECT and (68)Ga-DOTATOC PET/CT: A lesion-by-lesion analysis in patients with metastatic neuroendocrine tumours. Eur Radiol. 2016;26:900–9. https://doi.org/10.1007/s00330-015-3882-1.
Johnbeck CB, Knigge U, Loft A, Berthelsen AK, Mortensen J, Oturai P, et al. Head-to-Head Comparison of (64)Cu-DOTATATE and (68)Ga-DOTATOC PET/CT: A Prospective Study of 59 Patients with Neuroendocrine Tumors. J Nucl Med. 2017;58:451–7. https://doi.org/10.2967/jnumed.116.180430.
Zhou D, Xu J, Mpoy C, Chu W, Kim SH, Li H, et al. Preliminary evaluation of a novel (18)F-labeled PARP-1 ligand for PET imaging of PARP-1 expression in prostate cancer. Nucl Med Biol. 2018;66:26–31. https://doi.org/10.1016/j.nucmedbio.2018.08.003.
Thapa P, Parghane R, Basu S. (177)Lu-DOTATATE Peptide Receptor Radionuclide Therapy in Metastatic or Advanced and Inoperable Primary Neuroendocrine Tumors of Rare Sites. World J Nucl Med. 2017;16:223–8. https://doi.org/10.4103/1450-1147.207283.
Banerjee SR, Pomper MG. Clinical applications of Gallium-68. Appl Radiat Isot. 2013;76:2–13. https://doi.org/10.1016/j.apradiso.2013.01.039.
Conti M, Eriksson L. Physics of pure and non-pure positron emitters for PET: a review and a discussion. EJNMMI Phys. 2016;3:8. https://doi.org/10.1186/s40658-016-0144-5.
Kemerink GJ, Visser MG, Franssen R, Beijer E, Zamburlini M, Halders SG, et al. Effect of the positron range of 18F, 68Ga and 124I on PET/CT in lung-equivalent materials. Eur J Nucl Med Mol Imaging. 2011;38:940–8. https://doi.org/10.1007/s00259-011-1732-1.
Cole EL, Stewart MN, Littich R, Hoareau R, Scott PJ. Radiosyntheses using fluorine-18: the art and science of late stage fluorination. Curr Top Med Chem. 2014;14:875–900. https://doi.org/10.2174/1568026614666140202205035.
Meisetschläger G, Poethko T, Stahl A, Wolf I, Scheidhauer K, Schottelius M, et al. Gluc-Lys([18F]FP)-TOCA PET in patients with SSTR-positive tumors: biodistribution and diagnostic evaluation compared with [111In]DTPA-octreotide. J Nucl Med. 2006;47:566–73.
Schottelius M, Poethko T, Herz M, Reubi JC, Kessler H, Schwaiger M, et al. First (18)F-labeled tracer suitable for routine clinical imaging of sst receptor-expressing tumors using positron emission tomography. Clin Cancer Res. 2004;10:3593–606. https://doi.org/10.1158/1078-0432.Ccr-03-0359.
Wester HJ, Schottelius M, Scheidhauer K, Meisetschläger G, Herz M, Rau FC, et al. PET imaging of somatostatin receptors: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide. Eur J Nucl Med Mol Imaging. 2003;30:117–22. https://doi.org/10.1007/s00259-002-1012-1.
Wängler C, Waser B, Alke A, Iovkova L, Buchholz HG, Niedermoser S, et al. One-step 18F-labeling of carbohydrate-conjugated octreotate-derivatives containing a silicon-fluoride-acceptor (SiFA): in vitro and in vivo evaluation as tumor imaging agents for positron emission tomography (PET). Bioconjug Chem. 2010;21:2289–96. https://doi.org/10.1021/bc100316c.
Niedermoser S, Chin J, Wängler C, Kostikov A, Bernard-Gauthier V, Vogler N, et al. In Vivo Evaluation of 18F-SiFAlin-Modified TATE: A Potential Challenge for 68Ga-DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with PET. J Nucl Med. 2015;56:1100–5. https://doi.org/10.2967/jnumed.114.149583.
Ilhan H, Todica A, Lindner S, Boening G, Gosewisch A, Wängler C, et al. First-in-human (18)F-SiFAlin-TATE PET/CT for NET imaging and theranostics. Eur J Nucl Med Mol Imaging. 2019;46:2400–1. https://doi.org/10.1007/s00259-019-04448-8.
McBride WJ, Sharkey RM, Karacay H, D'Souza CA, Rossi EA, Laverman P, et al. A novel method of 18F radiolabeling for PET. J Nucl Med. 2009;50:991–8. https://doi.org/10.2967/jnumed.108.060418.
Laverman P, D'Souza CA, Eek A, McBride WJ, Sharkey RM, Oyen WJ, et al. Optimized labeling of NOTA-conjugated octreotide with F-18. Tumour Biol. 2012;33:427–34. https://doi.org/10.1007/s13277-011-0250-x.
Laverman P, McBride WJ, Sharkey RM, Eek A, Joosten L, Oyen WJ, et al. A novel facile method of labeling octreotide with (18)F-fluorine. J Nucl Med. 2010;51:454–61. https://doi.org/10.2967/jnumed.109.066902.
Long T, Yang N, Zhou M, Chen D, Li Y, Li J, et al. Clinical Application of 18F-AlF-NOTA-Octreotide PET/CT in Combination With 18F-FDG PET/CT for Imaging Neuroendocrine Neoplasms. Clin Nucl Med. 2019;44:452–8. https://doi.org/10.1097/rlu.0000000000002578.
Tshibangu T, Cawthorne C, Serdons K, Pauwels E, Gsell W, Bormans G, et al. Automated GMP compliant production of [(18)F]AlF-NOTA-octreotide. EJNMMI Radiopharm Chem. 2020;5:4. https://doi.org/10.1186/s41181-019-0084-1.
Boy C, Poeppel T, Kotzerke J, Krause BJ, Amthauer H, Baum RP, et al. Somatostatin receptor PET/CT (SSTR-PET/CT). Nuklearmedizin. 2018;57:4–17. https://doi.org/10.1055/s-0038-1636560.
Bozkurt MF, Virgolini I, Balogova S, Beheshti M, Rubello D, Decristoforo C, et al. Guideline for PET/CT imaging of neuroendocrine neoplasms with (68)Ga-DOTA-conjugated somatostatin receptor targeting peptides and (18)F-DOPA. Eur J Nucl Med Mol Imaging. 2017;44:1588–601. https://doi.org/10.1007/s00259-017-3728-y.
Funding
Open Access funding provided by Projekt DEAL. FMM is supported by the Deutsche Forschungsgemeinschaft (DFG) in the framework of the Research Training Group “Tumor-targeted Drug Delivery” grant 331065168. FMM receives research funding from the ITN INTRICARE of European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska Curie (grant 722609).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors declare that they have no conflict of interest.
Studies with human participants or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Oncology - gastrointestinal tract
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Sahnoun, S., Conen, P. & Mottaghy, F.M. The battle on time, money and precision: Da[18F] id vs. [68Ga]liath. Eur J Nucl Med Mol Imaging 47, 2944–2946 (2020). https://doi.org/10.1007/s00259-020-04961-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00259-020-04961-1