Radiopharmaceuticals Research Articles

New Imaging Modality of COVID-19 Pneumonia Developed on the Basis of Alzheimer's Disease Research.

Viral pneumonia caused by highly infectious SARS-CoV-2 poses a higher risk to older people and those who have underlying health conditions, including Alzheimer’s disease. In this work we present newly designed tacrine-based radioconjugates with physicochemical and biological properties that are crucial for the potential application as diagnostic radiopharmaceuticals. A set of ten tacrine derivatives was synthesized, labelled with gallium-68 and fully characterized in the context of their physicochemical properties. Based on these results, the final two most promising radioconjugates, [68Ga]Ga-NODAGA-Bn-NH(CH2)9Tac and [68Ga]Ga-THP-NH(CH2)9Tac, were selected for biodistribution studies. The latter compound was proven to be a good inhibitor of cholinesterases with significant affinity toward the lungs, according to the biodistribution studies. On the basis of molecular modelling combined with in vitro studies, we unraveled which structural properties of the developed tacrine derivatives are crucial for high affinity toward acetylcholinesterase, whose increased levels in lung tissues in the course of coronavirus disease indicate the onset of pneumonia. The radiopharmaceutical [68Ga]Ga-THP-NH(CH2)9Tac was ultimately selected due to its increased accuracy and improved sensitivity in PET imaging of lung tissue with high levels of acetylcholinesterase, and it may become a novel potential diagnostic modality for the determination of lung perfusion, including in inflammation after COVID-19.

Individualization of Radionuclide Therapies: Challenges and Prospects.

Simple SummaryCurrently, patient-specific treatment plans and dosimetry calculations are not routinely performed for radionuclide therapies. In external beam radiotherapy, it is quite the opposite. As a result, a small fraction of patients receives optimal radioactivity. This conservative approach provides “radiation safety” to healthy tissues but delivers a lower than indicated absorbed dose to the tumors, resulting in a lower response rate and a higher disease relapse rate. Evidence shows that better and more predictable outcomes can be achieved with patient-individualized dose assessment. Therefore, the incorporation of individual planning into radionuclide therapies is a high priority for nuclear medicine physicians and medical physicists alike. Internal dosimetry is used in tumor therapy to optimize the absorbed dose to the target tissue. The main reasons for the difficulties in incorporating patients’ internal dosimetry into routine clinical practice are discussed. The article presents the prospects for the routine implementation of personalized radionuclide therapies.The article presents the problems of clinical implementation of personalized radioisotope therapy. The use of radioactive drugs in the treatment of malignant and benign diseases is rapidly expanding. Currently, in the majority of nuclear medicine departments worldwide, patients receive standard activities of therapeutic radiopharmaceuticals. Intensively conducted clinical trials constantly provide more evidence of a close relationship between the dose of radiopharmaceutical absorbed in pathological tissues and the therapeutic effect of radioisotope therapy. Due to the lack of individual internal dosimetry (based on the quantitative analysis of a series of diagnostic images) before or during the treatment, only a small fraction of patients receives optimal radioactivity. The vast majority of patients receive too-low doses of ionizing radiation to the target tissues. This conservative approach provides “radiation safety” to healthy tissues, but also delivers lower radiopharmaceutical activity to the neoplastic tissue, resulting in a low level of response and a higher relapse rate. The article presents information on the currently used radionuclides in individual radioisotope therapies and on radionuclides newly introduced to the therapeutic market. It discusses the causes of difficulties with the implementation of individualized radioisotope therapies as well as possible changes in the current clinical situation.

Assessment and Registration of Effective Doses Used in Diagnostic Nuclear Medicine Examinations

Over the recent period, the Russian healthcare system has been undertaking a nation-wide renewal of equipment for nuclear medicine, which, in turn, opens a gate to new diagnostic radiopharmaceuticals (DRPs) to routine practice. The market welcomed a new class of targeted DRPs. Dozens of PET centres and diagnostic rooms where DRPs with ultrashort-lived radionuclides are used for medical examination have been put into operation. All this dictates the need to modify the existing guidelines that govern this area. In 2021, there was an update in the procedural guidelines (PGs) MU 2.6.1.3700-21 “Assessment and registration of effective doses used in diagnostic nuclear medicine examinations”. The document presented the dose coefficients for new DRPs based on the latest data from the International Commission on Radiological Protection and the literature. This included calculation of the effective doses (using tissue weighting factors) from 1 MBq of radioactivity for approximately 280 DRPs used across five different age groups, as per ICRP Publication 60. These PGs apply to diagnostic nuclear medicine examinations performed using DRPs, scintigraphy, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) alone or in combination with X-ray computed tomography (SPECT/CT; PET/CT). The guidelines do not apply to radionuclide therapies that involve DRP administration that require individual planning and assessment of the absorbed doses across the target regions, critical organs and other radiosensitive organs and tissues.

Predicting response of micrometastases with MIRDcell V3: proof of principle with 225Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids.

The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (225Ac-liposomes) and uses these data in MIRDcellV3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses. Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were R-A-, R-A+, R+A-, and R+A+. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) or 225Ac. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into mean 225Ac decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment with 225Ac-liposomes. The biological responses of the multicellular clusters treated with 225Ac-liposomes with physicochemical properties R+A+, R-A+, and R-A- were predicted by MIRDcell with statistically significant accuracy. The prediction for R+A- was not predicted accurately. In most instances, MIRDcell predicts responses of spheroids treated with 225Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.

PROSPECTS FOR THE DEVELOPMENT OF NUCLEAR MEDICINE IN THE REPUBLIC OF KAZAKHSTAN: REACTOR ISOTOPES OF RARE EARTH ELEMENTS FOR THERAPY

Radioactive isotopes of rare earth elements have effective nuclear-physical properties and are promising for the development of new therapeutic radiopharmaceuticals. Rare earth elements (REE) include 17 elements of the secondary subgroup of group III of the periodic table of chemical elements of D.I. Mendeleev with atomic numbers 21, 39, 57, 58–71: scandium, yttrium, lanthanum and 14 lanthanides. Some radioactive isotopes of these elements are already used in medicine, as a radioactive component of approved medicines, for example, the isotopes of 153Sm and 177Lu, and for some the possibility of their use in medicine is only being studied. Thus, the isotope scandium – 47Sc is being studied as a potential radioisotope for cancer diagnosis, holmium – 166Ho as an isotope for radiosynovectomy and brachytherapy, praseodymium – 142Pr is promising for brachytherapy. The ability of rare earth elements to form chemical bonds with organic molecules, including peptides of natural and synthetic origin, is the basis for the development of new drugs for targeted therapy of breast and prostate cancer, neuroendocrine tumors, disseminated lung cancer and other types of diseases. To determine the list of the most promising for irradiation at the rector of the WWR-K REE in order to develop radioactive isotopes, an assessment of the ways of developing radioactive isotopes and an analysis of their nuclear physical characteristics according to literature data was carried out. Isotopes such as: 166Ho, 165Dy, 90Y, 175Yb, 153Sm, 177Lu, 147Nd, 170Tm, 159Gd and 141Ce can be used in the treatment of oncological diseases. This research work makes it possible to evaluate the possibility of obtaining REE radioisotopes by reaction (n, γ) at the WWR-K reactor, and reflects the prospects for using these isotopes in the development of new-generation radiopharmaceuticals for the treatment of oncological diseases.

Implementation of the failure modes and effects analysis in a Hospital Radiopharmacy Unit

AimThe aim of this study is the implementation in a Hospital Radiopharmacy Unit of a risk analysis methodology in order to proactively identify possible failure modes and prioritize corrective measures. Materials and methodsBy means of the failure modes and effects analysis (FMEA), the possible failure modes of each of the stages of the processes of prescription, preparation, and administration of radiopharmaceuticals for diagnostic and therapy were identified. From the variables of severity, probability and detectability, the risk was quantified using the Risk Priority Number (RPN) for each failure mode, sub-process, and type of radiopharmaceutical. Improvement measures were established and the reduction in the RPN value was calculated. ResultsA total of 96 failure modes were identified (58 for diagnostic radiopharmaceuticals and 38 for therapy). Biunivocal identification of the patient with the radiopharmaceutical is the failure mode with the highest RPN (60) and the radiolabeling cell sub-process the one that has the highest risk (RPN 286). As a result of the improvement measures, the overall RPN was reduced by 22% for diagnostic radiopharmaceuticals and 20% for therapy. This reduction would be 46% and 31% respectively if radiopharmacy software and a barcode technology in the administration were implemented. ConclusionsThe application of the FMEA methodology as a risk analysis tool allows to identify the critical points of the processes related to radiopharmaceuticals and prioritize measures to reduce the risk.

Porphyrins as Chelating Agents for Molecular Imaging in Nuclear Medicine.

Porphyrin ligands, showing a significant affinity for cancer cells, also have the ability to chelate metallic radioisotopes to form potential diagnostic radiopharmaceuticals. They can be applied in single-photon emission computed tomography (SPECT) and positron emission tomography (PET) to evaluate metabolic changes in the human body for tumor diagnostics. The aim of this paper is to present a short overview of the main metallic radionuclides complexed by porphyrin ligands and used in these techniques. These chelation reactions are discussed in terms of the complexation conditions and kinetics and the complex stability.

The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide, Bifunctional Chelator, and Pharmacokinetics Modifying Linker.

Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater versatility for clinical translation compared to non-metal radionuclides. This paper comprehensively discusses various components commonly used as chemical scaffolds to build radiopharmaceutical agents, i.e., radionuclides, pharmacokinetic-modifying linkers, and chelators, whose characteristics are explained and can be used as a guide for the researcher.

P-272 - Development of novel PSMA target therapeutic radiopharmaceuticals by modification with albumin binder

P-272 - Development of novel PSMA target therapeutic radiopharmaceuticals by modification with albumin binder

P-207 - Synthesis of gold nanoparticles labeled with Auger electron emitters: 197Hg/197mHg as potential therapeutic radiopharmaceuticals

P-207 - Synthesis of gold nanoparticles labeled with Auger electron emitters: 197Hg/197mHg as potential therapeutic radiopharmaceuticals

Potential Theranostic Boron Neutron Capture Therapy Agents as Multimodal Radiopharmaceuticals.

Boron neutron capture therapy (BNCT) has been extant for decades and continues to be practiced in many centers around the globe. Most of the active clinical trials utilize boronophenylalanine as the drug containing boron atoms. The important aspect that has been added to the BNCT practice is the use of an F-18 radiolabeled analog for ascertaining targeting and monitoring follow-up studies. The recent widespread application of therapeutic radiopharmaceuticals, especially peptides (somatostatin analogs), prostate-specific antigen-binding ligands, or immunomolecules, offers the ambit for invention of new tumor-specific BNCT agents, especially for BNCT-susceptible tumors, that is, locoregional cancers such as head and neck cancer. Such BNCT agents, when radiolabeled, can enable simultaneous imaging and/or therapeutic applications (depending on the radionuclide used) through multimodal approaches. Development of boron-rich moieties such as sodium borocaptate and neutral carboranes combined with tumor-targeting moieties can lead to a new horizon in BNCT. The review covers various aspects of drug design, tumor targeting, and possible future radiopharmaceutical development for multimodal theranostic application in humans.

Fluorine-18 Fluorodeoxyglucose Isolation Using Graphene Oxide for Alternative Radiopharmaceutical Spillage Decontamination in PET Scan

Radiopharmaceuticals (RPC) used for diagnostic and therapeutic purposes in nuclear medicine may contaminate surface areas due to spillage during its preparation or accident during RPC transfer from laboratory to the treatment room. Fluorine-18 Fluorodeoxyglucose (18F-FDG) is the most common RPC for positron emission tomography (PET) scan in nuclear medicine due to its ideal annihilation converted energy at 511 keV and short half-life at 109.8 min. Ineffective medical waste management of 18F-FDG may pose a risk to the environment or cause unnecessary radiation doses to the personnel and public. Depending on the incident rate of these events, simple decontamination methods such as the use of chemicals and swabs might not be cost-effective and sustainable in the environment. This study aims to propose an alternative method to decontaminate 18F-FDG by using graphene oxide (GO). GO was synthesised using the Hummers method while the physical morphology was analysed using a field emission scanning electron microscope (FESEM). 18F-FDG adsorption efficiency rate using GO nanolayers was analysed based on the kinetic study of the GO:18F-FDG mixtures. The chemical adsorbability of the material was analysed via UV–vis spectrophotometer to interlink the microstructures of GO with the sorption affinity interaction. Resultantly, the adsorption rate was effective at a slow decay rate and the optical adsorption of GO with 18F-FDG was dominated by the π → π* plasmon peak, which was near 230 nm. By elucidating the underlining GO special features, an alternative technique to isolate 18F-FDG for the decontamination process was successfully proven.

Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma.

Simple SummaryThe current routine treatment for glioblastoma (GB), the most lethal high-grade brain tumor in adults, aims to induce DNA damage in the tumor. However, the tumor cells might be able to repair that damage, which leads to therapy resistance. Fortunately, DNA repair defects are common in GB cells, and their survival is often based on a sole backup repair pathway. Hence, targeted drugs inhibiting essential proteins of the DNA damage response have gained momentum and are being introduced in the clinic. This review gives a perspective on the use of radiopharmaceuticals targeting DDR kinases for imaging in order to determine the DNA repair phenotype of GB, as well as for effective radionuclide therapy. Finally, four new promising radiopharmaceuticals are suggested with the potential to lead to a more personalized GB therapy.Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

Possibilities of brain SPECT with perfusion radiopharmaceuticals for the quantitative assessment of cognitive changes in patients with hypertensive encephalopathy

Background. Vascular diseases of the brain, which lead to encephalopathy, are a significant medical and social problem. The main clinical tool for diagnosing cognitive impairments is a neuropsychological testing. Its disadvantages are a big number of different tests, which are used in clinical institutions, and thus, make it extremely complicated to compare the data; in monitoring studies, patients can learn answers, which somewhat distorts the results; there is also a possibility of a non-objective doctor’s impact on the results of the conducted test. Therefore, the development of methods for assessing the neuropsychological and cognitive state of patients based on objective data is an urgent task. Besides, to this date, it is not completely known which segments of the brain directly or indirectly affect this or that cognitive function. Purpose – to develop a methodology for assessing the scores of neuropsychological testing (NPT) in patients with atherosclerotic hypertensive encephalopathy (ATHE) based on data from single-photon emission computed tomography (SPECT) with perfusion radiopharmaceuticals (RPh). Materials and Methods. NPT and SPECT data of twenty patients with clinical diagnosis of atherosclerotic hypertensive encephalopathy were analyzed. The principal scales used during the study were the following: Montgomery – Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HARS), Schulte Table, O. Luria. Tomographic images of the brain were obtained on the gamma camera «E. Cam» (Siemens) using perfusion lipophilic radiopharmaceutical 99mTc-hexamethylpropyleneamineoxime (99mTc-HMPAO). Processing and analysis of the scintigraphic images were conducted in the original software «ScintiBrain», which is implemented in the Matlab-2018 environment. The quantitative characteristics of accumulation and spatial distribution of RPh in the brain were: specific accumulation of RPh (Upt) and parameter of intrahemispheric symmetry (IHS) of perfusion in the brain segments. Based on machine learning method, which can be attributed to regression methods, NPT data were compared with the ratio of Upt and IHS between different segments of the brain Results. As a result of the analysis (machine learning) of 190 Upt and IHS ratios between different segments of the brain with NPT values, the most informative ratios in terms of regression analysis were highlighted. The independence of Upt and IHS makes it possible to increase the accuracy of calculations of NPT values by algebraic averaging of calculations by Upt and IHS ratios.
 Machine learning results by both Upt and IHS values had one order of correlation and a mean squared error in the tests. The correlation coefficient of linear approximation of values between the SPECT and NPT data was in the range of 0.75–0.93 (p < 0.01), which corresponded to the average relative error in calculations of test values from 7–22%. Conclusions. For the first time, a method of quantitative assessment of the neuropsychological and cognitive state of patients was developed on the basis of an objective research method, namely SPECT. The average relative error in calculations of equivalent values of NPT was in the range of 7 – 22%. At the same time, it was shown that the neuropsychological and cognitive state of patients, in particular patients with ATHE, according to the analysis of effective brain perfusion, didn’t correspond to one specific segment of the brain, but instead to a group of three interrelations of RPh accumulation in the highlighted regions of interest. The presence of a sufficiently high correlation between the NPT data and the indicators of the specific accumulation of RPh and the IHS in the brain segments showed that the neuropsychological and cognitive state of the patient depended not only on the level of accumulation of RPh in segments, but also on its spatial distribution.

Production of positron-emitting radionuclide yttrium-86 with a computer-aided design target for positron emission tomography

Yttrium-86 (86Y, t1/2 = 14.7 h, 33% β+) is a nonstandard medical nuclide with a longer half-life than other standard nuclides such as gallium-68 for radiolabelling for PET (positron emission computed tomography) imaging. 86Y is compatible with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and can be used to evaluate DOTA-chelated radiopharmaceuticals with long clearance half-lives, particularly therapeutic radiopharmaceuticals in several days. 86Y can be produced through 86Sr(p, n)86Y reaction, in which 86Sr-enriched SrCO3 powder is bombarded with low-energy protons. To handle the SrCO3 powder, a powder target for 86Y production in 14.6 MeV proton cyclotron was designed while maximizing yield, reliability and efficiency. To that end, the target's primary design parameters were traversed, simulated and optimized using computer algorithms to obtain advantageous parameter combinations. In this way, 86Y was produced on the powder target with high yield and successfully isolated with high purity (>97%) by solid-phase extraction via DGA resin for high-quality PET imaging and drug screening.

Implementación del análisis modal de fallos y efectos en una Unidad de Radiofarmacia Hospitalaria

AimThe aim of this study is the implementation in a Hospital Radiopharmacy Unit of a risk analysis methodology in order to proactively identify possible failure modes and prioritize corrective measures. Materials and methodsBy means of the failure modes and effects analysis (FMEA), the possible failure modes of each of the stages of the processes of prescription, preparation, and administration of radiopharmaceuticals for diagnostic and therapy were identified. From the variables of severity, probability and detectability, the risk was quantified using the Risk Priority Number (RPN) for each failure mode, sub-process, and type of radiopharmaceutical. Improvement measures were established and the reduction in the RPN value was calculated. ResultsA total of 96 failure modes were identified (58 for diagnostic radiopharmaceuticals and 38 for therapy). Biunivocal identification of the patient with the radiopharmaceutical is the failure mode with the highest RPN (60) and the radiolabeling cell sub-process the one that has the highest risk (RPN 286). As a result of the improvement measures, the overall RPN was reduced by 22% for diagnostic radiopharmaceuticals and 20% for therapy. This reduction would be 46% and 31% respectively if radiopharmacy software and a barcode technology in the administration were implemented. ConclusionsThe application of the FMEA methodology as a risk analysis tool allows to identify the critical points of the processes related to radiopharmaceuticals and prioritize measures to reduce the risk.

MIRD Pamphlet No. 27: MIRDcell V3, a Revised Software Tool for Multicellular Dosimetry and Bioeffect Modeling.

Radiopharmaceutical therapy is growing rapidly. However, yet to be addressed is the implementation of methods to plan treatments for circulating tumor cells, disseminated tumor cells, and micrometastases. Given the capacity of radiopharmaceuticals to specifically target and kill single cells and multicellular clusters, a quality not available in chemotherapy and external-beam radiation therapy, it is important to develop dosimetry and bioeffect modeling tools that can inform radiopharmaceutical design and predict their effect on microscopic disease. This pamphlet describes a new version of MIRDcell, a software tool that was initially released by the MIRD committee several years ago. Methods: Version 3 (V3) of MIRDcell uses a combination of analytic and Monte Carlo methods to conduct dosimetry and bioeffect modeling for radiolabeled cells within planar colonies and multicellular clusters. A worked example is provided to assist users to learn old and new features of MIRDcell and test its capacity to recapitulate published responses of tumor cell spheroids to radiopharmaceutical treatments. Prominent capabilities of the new version include radially dependent activity distributions, user-imported activity distributions, cold regions within the cluster, complex bioeffect modeling that accounts for radiation type and subcellular distribution, and a rich table of output data for subsequent analysis. Results: MIRDcell V3 effectively reproduces experimental responses of multicellular spheroids to uniform and nonuniform distributions of therapeutic radiopharmaceuticals. Conclusion: MIRDcell is a versatile software tool that can be used for educational purposes and design of radiopharmaceutical therapies.

A method to prevail false positive responses due to excess cations and viscous nature of Radiopharmaceuticals in Limulus Amebocyte Lysate Gel Clot test

Objective(s):Bacterial endotoxin test (BET) for detection and quantification of endotoxin in radiopharmaceuticals (RPs), used for therapy or diagnosis, is prerequisite to administration in patients. Out of the two established methods used for this purpose (Kinetic Chromogenic Assay: KCM and Gel Clot Bacterial Endotoxin Test: GC-BET), GC-BET is recommended by pharmacopeias to evaluate the interferences exhibited during the assay due to presence of various ingredients in samples. In the present study, the influence of excess of cations in [177Lu]Lu-DOTATATE, used for Peptide Receptor Radionuclide Therapy (PRRT), were studied and a protocol to negate the enhancement observed was developed. Additionally, a protocol for carrying out GC-BET for extremely viscous [131I]I-Lipiodol was standardized.Methods:GC-BET was performed for [177Lu]Lu-DOTATATE and [131I]I-Lipiodol at maximum valid dilution (MVD), using LRW as a diluent. To negate the false positivity observed in case of [177Lu]Lu-DOTATATE, various concentrations of calcium chloride (CaCl2) were added and evaluated for the reversal of the interference observed initially. To prevail the difficulty in performing GC-BET for [131I]I-Lipiodol various modification in the protocols like orbital vortexing at different rpm and time intervals were performed. KCM assays were also performed for studied RPs at MVD.Results:It was observed that at MVD, [177Lu]Lu-DOTATATE exhibited false positivity in GC-BET. However, all the individual reagents used in labeling of [177Lu]Lu-DOTATATE did not show any false positivity. Finally, performing the assay with an addition of 2mM CaCl2 (final concentration) nullified the false positivity. Further, intricacy in performing GC-BET for [131I]I-Lipiodol due to its viscosity was resolved by orbital vortexing at 3000 rpm for 5 minutes.Conclusions:Our study proved that false positivity was observed in GC-BET for [177Lu]Lu-DOTATATE due to the presence excess M3+ ions. Further, our study is the first of its kind which demonstrated methods for negating these false positive results by using modified protocol and hypothesizing the reason behind the enhancement. Additionally, ours is the first study which proved that a simple step of vortexing the viscous RPs like [131I]I-Lipiodol can resolved the problems encountered during performing GC-BET due to viscosity of RPs.

3p-C-NETA: A versatile and effective chelator for development of Al18F-labeled and therapeutic radiopharmaceuticals.

Background: Radiolabeled somatostatin analogues (e.g. [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [18F]AlF-NOTA-octreotide, a promising 18F-labeled somatostatin analogue and potential alternative for 68Ga-DOTA-peptides, is under clinical evaluation. However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar (e.g. Al18F-method in combination with therapeutic radiometals 213Bi/177Lu) or identical (e.g. complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients. In this study we evaluated 3p-C-NETA, as potential theranostic Al18F-chelator and present first results of radiosynthesis and preclinical evaluation of [18F]AlF-3p-C-NETA-TATE.Methods: 3p-C-NETA was synthesized and radiolabeled with diagnostic (68Ga, Al18F) or therapeutic (177Lu, 161Tb, 213Bi, 225Ac and 67Cu) radionuclides at different temperatures (25-95 °C). The in vitro stability of the corresponding radiocomplexes was determined in phosphate-buffered saline (PBS) and human serum. 3p-C-NETA-TATE was synthesized using standard solid/liquid-phase peptide synthesis. [18F]AlF-3p-C-NETA-TATE was synthesized in an automated AllinOne® synthesis module and the in vitro stability of [18F]AlF-3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum. [18F]AlF-3p-C-NETA-TATE pharmacokinetics were evaluated using µPET/MRI in healthy rats, with [18F]AlF-NOTA-Octreotide as benchmark.Results: 3p-C-NETA quantitatively sequestered 177Lu, 213Bi and 67Cu at 25 °C while heating was required to bind Al18F, 68Ga, 161Tb and 225Ac efficiently. The [18F]AlF-, [177Lu]Lu- and [161Tb]Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over the study period. In contrast, [67Cu]Cu- and [225Ac]Ac-, [68Ga]Ga-3p-C-NETA were stable in PBS, but not in human serum. [18F]AlF-3p-C-NETA-TATE was obtained in good radiochemical yield and radiochemical purity. [18F]AlF-3p-C-NETA-TATE displayed good in vitro stability for 4 h in all tested conditions. Finally, [18F]AlF-3p-C-NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [18F]AlF-NOTA-Octreotide.Conclusions: 3p-C-NETA is a versatile chelator that can be used for both diagnostic applications (Al18F) and targeted radionuclide therapy (213Bi, 177Lu, 161Tb). It has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine.

Implications of physics, chemistry and biology for dosimetry calculations using theranostic pairs.

Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using radiopharmaceuticals that target identical molecular targets for both imaging (using emitted gamma rays) and radiopharmaceutical therapy (using emitted beta, alpha or Auger-electron particles) for the treatment of various diseases, such as cancer. If the therapeutic radiopharmaceutical cannot be imaged quantitatively, a “theranostic pair” imaging surrogate can be used to predict the absorbed radiation doses from the therapeutic radiopharmaceutical. However, theranostic dosimetry assumes that the pharmacokinetics and biodistributions of both radiopharmaceuticals in the pair are identical or very similar, an assumption that still requires further validation for many theranostic pairs. In this review, we consider both same-element and different-element theranostic pairs and attempt to determine if factors exist which may cause inaccurate dose extrapolations in theranostic dosimetry, either intrinsic (e.g. chemical differences) or extrinsic (e.g. injecting different amounts of each radiopharmaceutical) to the radiopharmaceuticals. We discuss the basis behind theranostic dosimetry and present common theranostic pairs and their therapeutic applications in oncology. We investigate general factors that could create alterations in the behavior of the radiopharmaceuticals or the quantitative accuracy of imaging them. Finally, we attempt to determine if there is evidence showing some specific pairs as suitable for theranostic dosimetry. We show that there are a variety of intrinsic and extrinsic factors which can significantly alter the behavior among pairs of radiopharmaceuticals, even if they belong to the same chemical element. More research is needed to determine the impact of these factors on theranostic dosimetry estimates and on patient outcomes, and how to correctly account for them.