Review

Authors: Søren Baarsgaard Hansen, Dirk Bender

After introduction of the first commercial combined PET and/or CT technology in 2001, this diagnostic tool quickly became a clinical success and was considered the fastest growing diagnostic imaging technology ever. However, this technique is very dependent on the availability of positron emitting isotopes and radiochemistry to incorporate the radioactive isotopes into larger molecules of physiological interest. Within this review article a historical overview starting with the first applications of positron emitting isotopes in the 1930's is presented. Afterwards a more detailed presentation summarizing the physical basis and advancements in cyclotron technology is given. Radiochemical and/or pharmaceutical advancements are presented systematically for the most significant isotopes like O, N, C, F and Ga Besides these major PET isotopes, advancements of other radio-metals and future perspectives regarding application of new radionuclides will be discussed. Finally, very interesting new and compact accelerator technology and microfluidic chemical reaction approaches will be discussed. Especially, new compact accelerator technology might be new quantum leap within this radiodiagnostic technology and might result in even further prevalence, ultimately envisioned by the dose-on-demand concept that will be briefly discussed.

Topics: Cyclotrons; Humans; Positron-Emission Tomography; Radiochemistry; Radioisotopes; Radiopharmaceuticals

PubMed: 34836618
DOI: 10.1053/j.semnuclmed.2021.10.003

Boron neutron capture therapy using cyclotron-based epithermal neutron source and borofalan (B) for recurrent or locally advanced head and neck cancer (JHN002): An open-label phase II trial.

Authors: Katsumi Hirose, Akiyoshi Konno, Junichi Hiratsuka...

BACKGROUND AND PURPOSE

Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (B) for recurrent or locally advanced head and neck cancer.

MATERIALS AND METHODS

In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS).

RESULTS

Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4-76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%).

CONCLUSION

These data suggest that BNCT using C-BENS with borofalan (B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck.

Topics: Boron Neutron Capture Therapy; Cyclotrons; Head and Neck Neoplasms; Humans; Neoplasm Recurrence, Local; Neutrons

PubMed: 33186684
DOI: 10.1016/j.radonc.2020.11.001

Authors: R O Rumyanstsev

Radiotheranostics is a radionuclide therapy based on the results of molecular imaging with various radiopharmaceuticals, allowing in vivo whole body imaging (SPECT, PET), and then systemically and at the same time selectively acting on pathological metabolic processes caused by a pathological process. In recent years, thanks to advances in the development of nuclear medicine (an increase in the number of cyclotrons, SPECT / CT and PET / CT in medical institutions) and, particularly, novel radiopharmaceuticals - in the world, radiotheranostics is developing very rapidly. The emergence of new radioligands labelled by 177Lu, 131I, 225Ac and other radioisotopes in the world have initiated a large number of clinical trials of radioligand therapy of neuroendocrine and chromaffin tumors, prostate cancer, etc. Radiotherapy as a new and very promising direction of nuclear medicine and it is perfectly integrated into modern diagnostic algorithms in the field of endocrinology and oncology. Methods of intraoperative radionavigation make it possible to increase the efficiency and safety of surgical methods, external beam radiation therapy, and brachytherapy. In my opinion, the future of personalized medicine will be predominantly determined by the integration of radiotherapy, multimodal imaging, intraoperative navigation and existing/new methods of diagnosis and treatment, in combination with applied genomic and post-genomic technologies.

Topics: Actinium; Humans; Iodine Radioisotopes; Male; Radiopharmaceuticals

PubMed: 33586387
DOI: 10.14341/probl12731

Review

Authors: Bryce J B Nelson, Jan D Andersson, Frank Wuest...

BACKGROUND

The radiometal gallium-68 (Ga) is increasingly used in diagnostic positron emission tomography (PET), with Ga-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional Tc agents. In precision medicine, PET applications of Ga are widespread, with Ga radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin.

MAIN BODY

These Ga radiopharmaceuticals include agents such as [Ga]Ga-macroaggregated albumin for myocardial perfusion evaluation, [Ga]Ga-PLED for assessing renal function, [Ga]Ga-t-butyl-HBED for assessing liver function, and [Ga]Ga-PSMA for tumor imaging. The short half-life, favourable nuclear decay properties, ease of radiolabeling, and convenient availability through germanium-68 (Ge) generators and cyclotron production routes strongly positions Ga for continued growth in clinical deployment. This progress motivates the development of a set of common guidelines and standards for the Ga radiopharmaceutical community, and recommendations for centers interested in establishing Ga radiopharmaceutical production.

CONCLUSION

This review outlines important aspects of Ga radiopharmacy, including Ga production routes using a Ge/Ga generator or medical cyclotron, standardized Ga radiolabeling methods, quality control procedures for clinical Ga radiopharmaceuticals, and suggested best practices for centers with established or upcoming Ga radiopharmaceutical production. Finally, an outlook on Ga radiopharmaceuticals is presented to highlight potential challenges and opportunities facing the community.

PubMed: 36271969
DOI: 10.1186/s41181-022-00180-1

Review

Authors: Kellen DeLaney, Ashley Phetsanthad, Lingjun Li...

Research in the field of neurobiology and neurochemistry has seen a rapid expansion in the last several years due to advances in technologies and instrumentation, facilitating the detection of biomolecules critical to the complex signaling of neurons. Part of this growth has been due to the development and implementation of high-resolution Fourier transform (FT) mass spectrometry (MS), as is offered by FT ion cyclotron resonance (FTICR) and Orbitrap mass analyzers, which improves the accuracy of measurements and helps resolve the complex biological mixtures often analyzed in the nervous system. The coupling of matrix-assisted laser desorption/ionization (MALDI) with high-resolution MS has drastically expanded the information that can be obtained with these complex samples. This review discusses notable technical developments in MALDI-FTICR and MALDI-Orbitrap platforms and their applications toward molecules in the nervous system, including sequence elucidation and profiling with de novo sequencing, analysis of post-translational modifications, in situ analysis, key advances in sample preparation and handling, quantitation, and imaging. Notable novel applications are also discussed to highlight key developments critical to advancing our understanding of neurobiology and providing insight into the exciting future of this field. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.

Topics: Cyclotrons; Fourier Analysis; Neurobiology; Specimen Handling; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

PubMed: 33165982
DOI: 10.1002/mas.21661

Review

Authors: Jason P Holland, Matthew J Williamson, Jason S Lewis...

Rapid and widespread growth in the use of nuclear medicine for both diagnosis and therapy of disease has been the driving force behind burgeoning research interests in the design of novel radiopharmaceuticals. Until recently, the majority of clinical and basic science research has focused on the development of 11C-, 13N-, 15O-, and 18F-radiopharmaceuticals for use with positron emission tomography (PET) and 99mTc-labeled agents for use with single-photon emission computed tomography (SPECT). With the increased availability of small, low-energy cyclotrons and improvements in both cyclotron targetry and purification chemistries, the use of "nonstandard" radionuclides is becoming more prevalent. This brief review describes the physical characteristics of 60 radionuclides, including beta+, beta-, gamma-ray, and alpha-particle emitters, which have the potential for use in the design and synthesis of the next generation of diagnostic and/or radiotherapeutic drugs. As the decay processes of many of the radionuclides described herein involve emission of high-energy gamma-rays, relevant shielding and radiation safety issues are also considered. In particular, the properties and safety considerations associated with the increasingly prevalent PET nuclides 64Cu, 68Ga, 86Y, 89Zr, and 124I are discussed.

Topics: Humans; Nuclear Medicine; Positron-Emission Tomography; Radiation, Ionizing; Radioisotopes; Radiopharmaceuticals; Radiotherapy; Tomography, Emission-Computed, Single-Photon

PubMed: 20128994
DOI: No ID Found

Review

Authors: Trisha Tucholski, Ying Ge

Proteoforms contribute functional diversity to the proteome and aberrant proteoforms levels have been implicated in biological dysfunction and disease. Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS), with its ultrahigh mass-resolving power, mass accuracy, and versatile tandem MS capabilities, has empowered top-down, middle-down, and native MS-based approaches for characterizing proteoforms and their complexes in biological systems. Herein, we review the features which make FT-ICR MS uniquely suited for measuring proteoform mass with ultrahigh resolution and mass accuracy; obtaining in-depth proteoform sequence coverage with expansive tandem MS capabilities; and unambiguously identifying and localizing post-translational and noncovalent modifications. We highlight examples from our body of work in which we have quantified and comprehensively characterized proteoforms from cardiac and skeletal muscle to better understand conditions such as chronic heart failure, acute myocardial infarction, and sarcopenia. Structural characterization of monoclonal antibodies and their proteoforms by FT-ICR MS and emerging applications, such as native top-down FT-ICR MS and high-throughput top-down FT-ICR MS-based proteomics at 21 T, are also covered. Historically, the information gleaned from FT-ICR MS analyses have helped provide biological insights. We predict FT-ICR MS will continue to enable the study of proteoforms of increasing size from increasingly complex endogenous mixtures and facilitate the benchmarking of sensitive and specific assays for clinical diagnostics. © 2020 John Wiley & Sons Ltd. Mass Spec Rev.

Topics: Cyclotrons; Fourier Analysis; Mass Spectrometry; Protein Processing, Post-Translational; Proteome; Proteomics

PubMed: 32894796
DOI: 10.1002/mas.21653

Review

Authors: Sergio J C do Carmo, Peter J H Scott, Francisco Alves...

Over the last several years, the use of radiometals has gained increasing relevance in supporting the continuous development of new, complementary and more specific biological targeting agents. Radiopharmaceuticals labelled with radiometals from elements such as Tc, Zr, Y, Ga and Cu received increasing attention as they find application in both diagnostic SPECT and PET imaging techniques and radiotherapeutic purposes. Such interest stems from the wide variety of radionuclides available with distinct and complementary nuclear decay characteristics to choose from with unequalled specificity, but can also be explained by growing demand in targeted radionuclide therapy. As a result, as routine supply of these radiometals becomes mandatory, studies describing their production processes have expanded rapidly. Although most radiometals are traditionally provided by the irradiation of solid targets in specialized cyclotrons, recently developed techniques for producing radiometals through the irradiation of liquid targets have received growing attention due to compatibility with commonly available small medical cyclotrons, promising characteristics and encouraging results. Irradiating liquid targets to produce radiometals appears as a fast, reliable, convenient and cost-efficient alternative to the conventional solid target techniques, characterized by complex and time-consuming pre- and post-irradiation target handling. Production of radiometals in liquid targets incorporated to complete manufacturing processes for daily routine is already recognized as a viable alternative and complementary supply methodology to existing solid target based infrastructures to satisfy growing clinical demands. For instance, several sites already use the approach to produce Ga-radiopharmaceuticals for clinical use. This review article covers the production of common radiometals with clinical potential through the irradiation liquid targets. A comparison with the traditional solid target irradiation methods is presented when relevant.

PubMed: 31925619
DOI: 10.1186/s41181-019-0088-x

Authors: Kaelyn V Becker, Eduardo Aluicio-Sarduy, Tyler Bradshaw...

Sc and Sc are both positron-emitting radioisotopes of scandium with suitable half-lives and favorable positron energies for clinical positron emission tomography (PET) imaging. Irradiation of isotopically enriched calcium targets has higher cross sections compared to titanium targets and higher radionuclidic purity and cross sections than natural calcium targets for reaction routes possible on small cyclotrons capable of accelerating protons and deuterons. In this work, we investigate the following production routes via proton and deuteron bombardment on CaCO and CaO target materials: Ca(d,n)Sc, Ca(p,n)Sc, Ca(d,n)Sc, Ca(p,n)Sc, and Ca(p,2n)Sc. Radiochemical isolation of the produced radioscandium was performed with extraction chromatography using branched DGA resin and apparent molar activity was measured with the chelator DOTA. The imaging performance of Sc and Sc was compared with F, Ga, and Cu on two clinical PET/CT scanners. The results of this work demonstrate that proton and deuteron bombardment of isotopically enriched CaO targets produce high yield and high radionuclidic purity Sc and Sc. Laboratory capabilities, circumstances, and budgets are likely to dictate which reaction route and radioisotope of scandium is chosen.

PubMed: 37179772
DOI: 10.3389/fchem.2023.1167783

Authors: C Shaun Loveless, Jose R Blanco, George L Diehl...

Theranostic strategies involve select radionuclides that allow diagnostic imaging and tailored radionuclide therapy in the same patient. An example of a Food and Drug Administration-approved theranostic pair is the Ga- and Lu-labeled DOTATATE peptides, which are used to image neuroendocrine tumors, predict treatment response, and treat disease. However, when using radionuclides of 2 different elements, differences in the pharmacokinetic and pharmacodynamic profile of the agent can occur. Theranostic agents that incorporate the matched-pair radionuclides of scandium-Sc/Sc or Sc/Sc-would guarantee identical chemistries and pharmacologic profiles. The aim of this study was to investigate production of Sc via proton-induced nuclear reactions on titanium nuclei using a 24-MeV cyclotron. Aluminum, niobium, and tantalum target holders were used with titanium foils and pressed TiO to produce scandium radionuclides with proton energies of up to 24 MeV. Irradiated targets were digested using NHHF and HCl in a closed perfluoroalkoxy alkane vessel in 90 min. Scandium radionuclides were purified via ion-exchange chromatography using branched -tetra-2-ethylhexyldiglycolamide. The titanium target material was recovered via alkali precipitation with ammonia solution. Titanium foil and TiO were digested with an average efficiency of 98% ± 3% and 95% ± 1%, respectively. The typical digestion time was 45 min for titanium foil and 75 min for TiO The average scandium recovery was 94% ± 3%, and the average titanium recoveries from digested titanium foil and TiO after precipitation as TiO were 108% ± 8% and 104% ± 5% of initial mass, respectively. This work demonstrated a robust method for the cyclotron production of scandium radionuclides that could be used with natural or enriched TiO target material.

Topics: Biological Transport; Cell Line, Tumor; Cyclotrons; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Prostate-Specific Antigen; Radiochemistry; Radioisotopes; Scandium; Titanium

PubMed: 32620699
DOI: 10.2967/jnumed.120.242941