journal article·2019-06-21Open access

A Picture of Modern Tc-99m Radiopharmaceuticals: Production, Chemistry, and Applications in Molecular Imaging

Alessandra Boschi, Licia Uccelli, Petra Martini

Applied Sciences· Volume 9· Issue 12

Abstract

Even today, techentium-99m represents the radionuclide of choice for diagnostic radio-imaging applications. Its peculiar physical and chemical properties make it particularly suitable for medical imaging. By the use of molecular probes and perfusion radiotracers, it provides rapid and non-invasive evaluation of the function, physiology, and/or pathology of organs. The versatile chemistry of technetium-99m, due to its multi-oxidation states, and, consequently, the ability to produce a variety of complexes with particular desired characteristics, are the major advantages of this medical radionuclide. The advances in technetium coordination chemistry over the last 20 years, in combination with recent advances in detector technologies and reconstruction algorithms, make SPECT’s spatial resolution comparable to that of PET, allowing 99mTc radiopharmaceuticals to have an important role in nuclear medicine and to be particularly suitable for molecular imaging. In this review the most efficient chemical methods, based on the modern concept of the 99mTc-metal fragment approach, applied to the development of technetium-99m radiopharmaceuticals for molecular imaging, are described. A specific paragraph is dedicated to the development of new 99mTc-based radiopharmaceuticals for prostate cancer.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Radiopharmaceutical Chemistry and Applications · Medical Imaging Techniques and Applications · Medical Imaging and Pathology Studies

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari, 46, 44121 Ferrara, Italy

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Luigi Borsari, 46, 44121 Ferrara, Italy

Nuclear Medicine Unit, University Hospital, Via Aldo Moro, 8, 44124 Ferrara, Italy

Legnaro National Laboratories, Italian National Institute for Nuclear Physics (LNL-INFN), Viale dell’Università, 2, 35020 Legnaro (PD), Italy

References (72)

Show source-provided references
1. A definition of molecular imaging
2. Molecular Imaging: Current Status and Emerging Strategies10.1016/j.crad.2010.03.011 ↗
3. Development of novel radionuclides for medical applications10.1002/jlcr.3578 ↗
4. Boschi, A., Martini, P., and Uccelli, L. (2017). 188Re(V) Nitrido Radiopharmaceuticals for Radionuclide Therapy. Pharmaceuticals, 10.10.3390/ph10010012 ↗
5. Current and future aspects of molecular imaging10.1016/j.ymeth.2009.05.012 ↗
6. Uccelli, L., Martini, M., Cittanti, C., Carnevale, A., Missiroli, L., Giganti, M., Bartolomei, M., and Boschi, A. (2019). Therapeutic Radiometals: Worldwide Scientific Literature Trend Analysis (2008–2018). Molecules, 24.10.3390/molecules24030640 ↗
7. Nuclear data for medical applications: An overview10.1524/ract.2001.89.4-5.189 ↗
8. The emerging role of copper-64 radiopharmaceuticals as cancer theranostics10.1016/j.drudis.2018.04.002 ↗
9. Technetium and Gallium Derived Radiopharmaceuticals: Comparing and Contrasting the Chemistry of Two Important Radiometals for the Molecular Imaging Era10.1021/cr1000755 ↗
10. Uccelli, L., Martini, P., Pasquali, M., and Boschi, A. (2017). Monoclonal Antibodies Radiolabeling with Rhenium-188 for Radioimmunotherapy. BioMed Res. Int., 2017.10.1155/2017/5923609 ↗
11. Lewis, J.S., Windhorst, A.D., and Zeglis, B.M. (2019). The Radiopharmaceutical Chemistry of Technetium-99m. Radiopharmaceutical Chemistry, Springer Nature Switzerland AG.10.1007/978-3-319-98947-1 ↗
12. Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides10.1016/j.addr.2008.04.006 ↗
13. Potential Technetium Small Molecule Radiopharmaceuticals10.1021/cr980435t ↗
14. Molecular imaging: Looking at problems, seeing solutions10.1126/science.1090585 ↗
15. Advances in nuclear cardiology instrumentation: Clinical potential of SPECT and PET10.1007/s12410-009-0028-3 ↗
16. IAEA (2009). Technetium-99m Radiopharmaceuticals: Status and Trends, International Atomic Energy Agency. No. 1.
17. New solid state cadmium-zinc-telluride technology for cardiac single photon emission computed tomographic myocardial perfusion imaging10.1080/17434440.2017.1296763 ↗
18. A review of 99mTc generator technology10.1016/0020-708X(82)90122-3 ↗
19. Radiochemical purity and stability of 99mTc-HMPAO in routine preparations10.1007/s10967-017-5437-1 ↗
20. Predictions regarding the supply of 99Mo and 99mTc when NRU ceases production in 2018
21. (2019, May 15). Opportunities and Approaches for Supplying Molybdenum-99 and Associated Medical Isotopes to Global Markets Proceedings of a Symposium 2018. Available online: http://www.nap.edu/24909.
22. Recent achievements in Tc-99m radiopharmaceutical direct production by medical cyclotrons10.1080/03639045.2017.1323911 ↗
23. Radioisotopic purity and imaging properties of cyclotron-produced. 99mTc using direct 100Mo(p,2n) reaction10.1088/1361-6560/aadc88 ↗
24. Capogni, M., Pietropaolo, A., Quintieri, L., Angelone, M., Boschi, A., Capone, M., Cherubini, N., De Felice, P., Dodaro, A., and Duatti, A. (2018). 14 MeV Neutrons for 99Mo/99mTc Production: Experiments, Simulations and Perspectives. Molecules, 23.10.3390/molecules23081872 ↗
25. Esposito, J., Bettoni, D., Boschi, A., Calderolla, M., Cisternino, S., Fiorentini, G., Keppel, G., Martini, P., Maggiore, M., and Mou, L. (2019). LARAMED: A Laboratory for Radioisotopes of Medical Interest. Molecules, 24.10.3390/molecules24010020 ↗
26. Design of an X-band electron linear accelerator dedicated to decentralized 99Mo/99mTc supply: From beam energy selection to yield estimation10.1103/PhysRevAccelBeams.20.104701 ↗
27. In-House Cyclotron Production of High-Purity Tc-99m and Tc-99m Radiopharmaceuticals10.1016/j.apradiso.2018.05.033 ↗
28. Assessment of the direct cyclotron production of 99mTc: An approach to crisis management of 99mTc shortage10.1016/j.apradiso.2016.03.017 ↗
29. Technetium-99m antibodies labeled with MAG3 and SHNH: An In Vitro and animal In Vivo comparison10.1016/S0969-8051(96)00131-X ↗
30. Goodbody, A., and Pollak, A. (1996). Peptide-Chelator Conjugates for Diagnostic Imaging. (W09603427), PCT International Application.
31. Synthesis and 99mTc-labelling of bz-MAG3-triprolinyl-peptides, their radiochemical evaluation and in vitro receptor-binding10.1002/1099-1344(20001030)43:12<1193::AID-JLCR406>3.0.CO;2-H ↗
32. A novel and simplified route to the synthesis of N3S chelators for 99mTc labeling10.1016/S0969-8051(01)00237-2 ↗
33. Technetium and rhenium-coordination chemistry and nuclear medical applications10.1590/S0103-50532006000800004 ↗
34. Radiochemical synthesis and tissue distribution of Tc-99m-labeled 7alpha-substituted estradiol complexes10.1016/S0969-8051(00)00083-4 ↗
35. Small and Neutral TcvO BAT, Bisaminoethanethiol (N2S2) Complexes for Developing New Brain Imaging Agents10.1016/S0969-8051(97)00153-4 ↗
36. Labeling peptides with technetium-99m using a bifunctional chelator of a N-hydroxysuccinimide ester of mercaptoacetyltriglycine
37. Heterodimeric Bis (Amino Thiol) Complexes of Oxorhenium (V) That Mimic the Structure of Steroid Hormones. Synthesis and Stereochemical Issues10.1021/jo951995k ↗
38. Binding of [99mTc]TRODAT-1 to dopamine transporters in patients with Parkinson’s disease and in healthy volunteers
39. Clinical acceptance of a molecular imaging agent: A long march with [99mTc]TRODAT10.1016/j.nucmedbio.2007.03.010 ↗
40. Imaging of dopamine transporters in humans with technetium-99m TRODAT-110.1007/BF01254479 ↗
41. Somatostatin receptor imaging of non-small cell lung cancer with 99mTc depreotide10.1053/snuc.2002.31564 ↗
42. Somatostatin receptor scintigraphy with 99mTc-Depreotide (NeoSpect) in discriminating between malignant and benign lesions in the diagnosis of lung cancer: A pilot study10.1080/02841850410001394 ↗
43. Preparation of hydrazino-modified proteins and their use for the synthesis of technetium-99m-protein conjugates10.1021/bc00011a007 ↗
44. Synthesis and Characterization of Organohydrazino Complexes of Technetium, Rhenium, and Molybdenum with the {M(η1-HxNNR)(η2-HyNNR)} Core and Their Relationship to Radiolabeled Organohydrazine-Derivatized Chemotactic Peptides with Diagnostic Applications10.1021/ic970352f ↗
45. 6-Hydrazinonicotinamide Derivatives as Bifunctional Coupling Agents for 99mTc-Labeling of Small Biomolecules10.1007/b101226 ↗
46. 99mTc-Hynic-TOC imaging in the diagnostic of neuroendocrine tumors10.4103/wjnm.WJNM_41_17 ↗
47. Incremental value of 99mTc-HYNIC-TOC SPECT/CT over whole-body planar scintigraphy and SPECT in patients with neuroendocrine tumours10.3413/Nukmed-0851-16-10 ↗
48. 99mTc-EDDA/HYNIC-TOC in the diagnosis of differentiated thyroid carcinoma refractory to radioiodine treatment10.5603/NMR.2016.0015 ↗
49. Detection of somatostatin receptor-positive tumours using the new 99mTc-tricine-HYNIC-D-Phe1-Tyr3-octreotide: First results in patients and comparison with 111In-DTPA-D-Phe1-octreotide10.1007/s002590050556 ↗
50. Development of Technetium-99m and Rhenium-188 Radiopharmaceuticals Containing a Terminal Metal–Nitrido Multiple Bond for Diagnosis and Therapy10.1007/b101225 ↗
51. Labeling of fatty acid ligands with the strong electrophilic metal fragment [99mTc(N)(PNP)]2+ (PNP = diphosphane ligand)10.1021/bc7002378 ↗
52. Evaluation of (99)(m)TcN-MPO as a new myocardial perfusion imaging agent in normal dogs and in an acute myocardial infarction canine model: Comparison with (99)(m)Tc-sestamibi10.1007/s11307-010-0304-2 ↗
53. Development of kit formulations for (99m)TcN-MPO: A cationic radiotracer for myocardial perfusion imaging10.1002/jlcr.3221 ↗
54. Asymmetrical Nitrido Tc-99m Heterocomplexes as Potential Imaging Agents for Benzodiazepine Receptors10.1021/bc034124n ↗
55. The [99mTc(N)(PNP)]2+ Metal Fragment: A Technetium-Nitrido Synthon for Use with Biologically Active Molecules. The N-(2-Methoxyphenyl)piperazyl-cysteine Analogues as Examples10.1021/bc034100g ↗
56. First application of fac-[99mTc(OH2)3(CO)3]+ in bioorganometallic chemistry: Design, structure, and In Vitro affinity of a 5-HT1A receptor ligand labeled with 99mTc10.1021/ja990765a ↗
57. Preparation and evaluation of 99mTc-labeled tridentate chelates for pre-targeting using bioorthogonal chemistry
58. Phase 2 study of 99mTc-trofolastat SPECT/CT to identify and localize prostate cancer in intermediate- and high-risk patients undergoing radical prostatectomy and extended pelvic LN dissection10.2967/jnumed.116.187807 ↗
59. A Novel organometallic aqua complex of technetium for the labeling of biomolecules: Synthesis of [99mTc(OH2)3(CO)3]+ from [99mTcO4]− in aqueous solution and its reaction with a bifunctional ligand10.1021/ja980745t ↗
60. fac-99mTc/Re-tricarbonyl complexes with tridentate aminocarboxyphosphonate ligands: Suitability of the phosphonate group in chelate ligand design of new imaging agents10.1016/j.ica.2018.11.012 ↗
61. “Click to chelate”: Synthesis and installation of metal chelates into biomolecules in a single step10.1021/ja066779f ↗
62. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer10.2967/jnumed.114.147413 ↗
63. Dosimetry of 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: Correlations between Pretherapeutic Imaging and Whole-Body Tumor Dosimetry with Treatment Outcomes10.2967/jnumed.118.219352 ↗
64. Lutetium-177 PSMA radioligand therapy of metastatic castration-resistant prostate cancer: Safety and efficacy10.2967/jnumed.115.168443 ↗
65. Response and tolerability of a single dose of 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: A multicenter retrospective analysis10.2967/jnumed.116.173757 ↗
66. PSMA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with Lu-177 labeled PSMA-61710.2967/jnumed.115.171397 ↗
67. Novel preclinical and radiopharmaceutical aspects of [68Ga] Ga-PSMA-HBED-CC: A new PET tracer for imaging of prostate cancer10.3390/ph7070779 ↗
68. Comparison of PET/CT and PET/MRI hybrid systems using a 68Ga-labelled PSMA ligand for the diagnosis of recurrent prostate cancer: Initial experience10.1007/s00259-013-2660-z ↗
69. 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer10.2967/jnumed.112.116624 ↗
70. Clinical translation of a PSMA inhibitor for 99mTc-based SPECT10.1016/j.nucmedbio.2017.01.012 ↗
71. Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer10.2967/jnumed.116.178939 ↗
72. 99mTechnetium-Based Prostate-Specific Membrane Antigen-Radioguided Surgery in Recurrent Prostate Cancer10.1016/j.eururo.2018.03.013 ↗