Potential Radiopharmaceuticals Research Articles

Radiolabeled Probes from Derivatives of Natural Compounds Used in Nuclear Medicine.

Natural compounds are important precursors for the synthesis of new drugs. The development of novel molecules that are useful for various diseases is the main goal of researchers, especially for the diagnosis and treatment of many diseases. Some pathologies need to be treated with radiopharmaceuticals, and, for this reason, radiopharmaceuticals that use the radiolabeling of natural derivates molecules are arousing more and more interest. Radiopharmaceuticals can be used for both diagnostic and therapeutic purposes depending on the radionuclide. β+- and gamma-emitting radionuclides are used for diagnostic use for PET or SPECT imaging techniques, while α- and β--emitting radionuclides are used for in metabolic radiotherapy. Based on these assumptions, the purpose of this review is to highlight the studies carried out in the last ten years, to search for potentially useful radiopharmaceuticals for nuclear medicine that use molecules of natural origin as lead structures. In this context, the main radiolabeled compounds containing natural products as scaffolds are analyzed, in particular curcumin, stilbene, chalcone, and benzofuran. Studies on structural and chemical modifications are emphasized in order to obtain a collection of potential radiopharmaceuticals that exploit the biological properties of molecules of natural origin. The radionuclides used to label these compounds are 68Ga, 44Sc, 18F, 64Cu, 99mTc, and 125I for diagnostic imaging.

Radiosynthesis of 99MTc-Montelukast as a Novel Potential Radiopharmaceutical Model for Lung Scanning

Radiosynthesis of 99MTc-Montelukast as a Novel Potential Radiopharmaceutical Model for Lung Scanning

Synthesis of a [18F]F Estradiol Derivative via Click Chemistry Using an Automated Synthesis Module: In Vitro Evaluation as Potential Radiopharmaceutical for Breast Cancer Imaging.

"Click reactions" are a very useful tool for the selective conjugation of different molecular subunits to produce complex structures in a simple way. In this paper, we present the application of Cu(I)-catalyzed biorthogonal reactions between alkynes and azides to the indirect radiofluorination of an estradiol derivative with potential applications in estrogen receptor imaging. The procedure was fully developed on an automated synthesis platform, and conditions were optimized to achieve the desired product with a reasonable yield without precipitation. Although the biological results were not adequate for a potential radiopharmaceutical, the outcome of this work is valuable since the use of automated platforms is required for the reliable and reproducible preparation of PET radiopharmaceuticals in GMP conditions while limiting the radiation dose rates to the personnel.

Co-Catalyzed Hydrofluorination of Alkenes: Photocatalytic Method Development and Electroanalytical Mechanistic Investigation.

The hydrofluorination of alkenes represents an attractive strategy for the synthesis of aliphatic fluorides. This approach provides a direct means to form C(sp3)-F bonds selectively from readily available alkenes. Nonetheless, conducting hydrofluorination using nucleophilic fluorine sources poses significant challenges due to the low acidity and high toxicity associated with HF and the poor nucleophilicity of fluoride. In this study, we present a new Co(salen)-catalyzed hydrofluorination of simple alkenes utilizing Et3N·3HF as the sole source of both hydrogen and fluorine. This process operates via a photoredox-mediated polar-radical-polar crossover mechanism. We also demonstrated the versatility of this method by effectively converting a diverse array of simple and activated alkenes with varying degrees of substitution into hydrofluorinated products. Furthermore, we successfully applied this methodology to 18F-hydrofluorination reactions, enabling the introduction of 18F into potential radiopharmaceuticals. Our mechanistic investigations, conducted using rotating disk electrode voltammetry and DFT calculations, unveiled the involvement of both carbocation and CoIV-alkyl species as viable intermediates during the fluorination step, and the contribution of each pathway depends on the structure of the starting alkene.

The Potential of Radiolabeled Bisphosphonates in SPECT and PET for Bone Imaging.

Skeletal-related events due to bone metastases can be prevented by early diagnosis using radiological or nuclear imaging techniques. Nuclear medicine techniques such as Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been used for diagnostic imaging of bone for decades. Although it is widely recognized that conventional diagnostic imaging techniques such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) have high sensitivity, low cost and wide availability, the specificity of both techniques is rather low compared to nuclear medicine techniques. Nuclear medicine techniques, on the other hand, have improved specificity when introduced as a hybrid imaging modality, as they can combine physiological and anatomical information. Two main radiopharmaceuticals are used in nuclear medicine: [99mTc]-methyl diphosphonate ([99mTc]Tc-MDP) from the generator and [18F]sodium fluoride ([18F]NaF) from the cyclotron. The former is used in SPECT imaging, while the latter is used in PET imaging. However, recent studies show that the role of radiolabeled bisphosphonates with gallium-68 (68Ga) and fluorine-18 (18F) may have a potential role in the future. This review, therefore, presents and discusses the brief method for producing current and future potential radiopharmaceuticals for bone metastases.

Development and Characterization of 99mTc-scFvD2B as a Potential Radiopharmaceutical for SPECT Imaging of Prostate Cancer.

Previously, we demonstrated that the 177Lu-labeled single-chain variable fragment of an anti-prostate-specific membrane antigen (PSMA) IgG D2B antibody (scFvD2B) showed higher prostate cancer (PCa) cell uptake and tumor radiation doses compared to 177Lu-labeled Glu-ureide-based PSMA inhibitory peptides. To obtain a 99mTc-/177Lu-scFvD2B theranostic pair, this research aimed to synthesize and biochemically characterize a novel 99mTc-scFvD2B radiotracer. The scFvD2B-Tag and scFvD2B antibody fragments were produced and purified. Then, two HYNIC derivatives, HYNIC-Gly-Gly-Cys-NH2 (HYNIC-GGC) and succinimidyl-HYNIC (S-HYNIC), were used to conjugate the scFvD2B-Tag and scFvD2B isoforms, respectively. Subsequently, chemical characterization, immunoreactivity tests (affinity and specificity), radiochemical purity tests, stability tests in human serum, cellular uptake and internalization in LNCaP(+), PC3-PIP(++) or PC3(-) PCa cells of the resulting unlabeled HYNIC-scFvD2B conjugates (HscFv) and 99mTc-HscFv agents were performed. The results showed that incorporating HYNIC as a chelator did not affect the affinity, specificity or stability of scFvD2B. After purification, the radiochemical purity of 99mTc-HscFv radiotracers was greater than 95%. A two-sample t-test of 99mTc-HscFv1 and 99mTc-HscFv1 uptake in PC3-PIP vs. PC3 showed a p-value < 0.001, indicating that the PSMA receptor interaction of 99mTc-HscFv agents was statistically significantly higher in PSMA-positive cells than in the negative controls. In conclusion, the results of this research warrant further preclinical studies to determine whether the in vivo pharmacokinetics and tumor uptake of 99mTc-HscFv still offer sufficient advantages over HYNIC-conjugated peptides to be considered for SPECT/PSMA imaging.

Synthesis and Evaluation of 177Lu-DOTA-PD-L1-i and 225Ac-HEHA-PD-L1-i as Potential Radiopharmaceuticals for Tumor Microenvironment-Targeted Radiotherapy.

Current cancer therapies focus on reducing immunosuppression and remodeling the tumor microenvironment to inhibit metastasis, cancer progression, and therapeutic resistance. Programmed death receptor 1 (PD-1) is expressed on immune T cells and is one of the so-called checkpoint proteins that can suppress or stop the immune response. To evade the immune system, cancer cells overexpress a PD-1 inhibitor protein (PD-L1), which binds to the surface of T cells to activate signaling pathways that induce immune suppression. This research aimed to synthesize PD-L1 inhibitory peptides (PD-L1-i) labeled with lutetium-177 (177Lu-DOTA-PD-L1-i) and actinium-225 (225Ac-HEHA-PD-L1-i) and to preclinically evaluate their potential as radiopharmaceuticals for targeted radiotherapy at the tumor microenvironment level. Using PD-L1-i peptide as starting material, conjugation with HEHA-benzene-SCN and DOTA-benzene-SCN was performed to yield DOTA-PD-L1-i and HEHA-PD-L1-I, which were characterized by FT-IR, UV-vis spectroscopy, and HPLC. After labeling the conjugates with 225Ac and 177Lu, cellular uptake in HCC827 cancer cells (PD-L1 positive), conjugate specificity evaluation by immunofluorescence, radiotracer effect on cell viability, biodistribution, biokinetics, and assessment of radiation absorbed dose in mice with in duced lung micrometastases were performed. 225Ac-HEHA-PD-L1-i and 177Lu-DOTA-PD-L1-i, obtained with radiochemical purities of 95 ± 3% and 98.5 ± 0.5%, respectively, showed in vitro and in vivo specific recognition for the PD-L1 protein in lung cancer cells and high uptake in HCC287 lung micrometastases (>30% ID). The biokinetic profiles of 177Lu-DOTA-PD-L1-i and 225Ac-DOTA-PD-L1-i showed rapid blood clearance with renal and hepatobiliary elimination and no accumulation in normal tissues. 225Ac-DOTA-PD-L1-i produced a radiation dose of 5.15 mGy/MBq to lung micrometastases. In the case of 177Lu-DOTA-PD-L1-i, the radiation dose delivered to the lung micrometastases was ten times (43 mGy/MBq) that delivered to the kidneys (4.20 mGy/MBq) and fifty times that delivered to the liver (0.85 mGy/MBq). Therefore, the radiotherapeutic PD-L1-i ligands of 225Ac and 177Lu developed in this research could be combined with immunotherapy to enhance the therapeutic effect in various types of cancer.

The current role of nuclear medicine in breast cancer.

Breast cancer is the most common cancer in females worldwide. Nuclear medicine plays an important role in patient management, not only in initial staging, but also during follow-up. Radiopharmaceuticals to study breast cancer have been used for over 50 years, and several of these are still used in clinical practice, according to the most recent guideline recommendations.In this critical review, an overview of nuclear medicine procedures used during the last decades is presented. Current clinical indications of each of the conventional nuclear medicine and PET/CT examinations are the focus of this review, and are objectively provided. Radionuclide therapies are also referred, mainly summarising the methods to palliate metastatic bone pain. Finally, recent developments and future perspectives in the field of nuclear medicine are discussed. In this context, the promising potential of new radiopharmaceuticals not only for diagnosis, but also for therapy, and the use of quantitative imaging features as potential biomarkers, are addressed.Despite the long way nuclear medicine has gone through, it looks like it will continue to benefit clinical practice, paving the way to improve healthcare provided to patients with breast cancer.

Synthesis and Preclinical Evaluation of 18F-Labeled Ketoprofen Methyl Esters for Cyclooxygenase-1 Imaging in Neuroinflammation.

Cyclooxygenase (COX) is a rate-limiting enzyme in the synthesis of proinflammatory prostanoids from arachidonic acid. In vivo imaging of COX by PET is a potentially powerful tool for assessing the inflammatory response to injury, infection, and disease. We previously reported on a promising PET probe for COX imaging, 11C-labeled ketoprofen methyl ester, which can detect COX-1 activation in models of neuroinflammation and neurodegenerative disorders. In the current study, we aimed to design a fluorine-substituted benzoyl group of ketoprofen (FKTP) and to evaluate its racemate and enantiomers (18F-labeled ketoprofen methyl ester, [18F]FKTP-Me) as PET proradiotracers, potential radiopharmaceuticals for invivo PET study of COX-1. Methods: We performed nucleophilic aromatic 18F-fluorination to obtain the desired racemic radiolabeled probe, (RS)-[18F]FKTP-Me, at a radiochemical yield of 11%-13%. Subsequent high-performance liquid chromatography separation with a chiral column yielded the desired enantiomerically pure (R)- and (S)-[18F]FKTP-Me. We examined the invivo properties of (RS)-, (R)-, and (S)-[18F]FKTP-Me in PET studies using rats in which hemispheric inflammation was induced by intrastriatally injecting a lipopolysaccharide. Results: Racemic (RS)-[18F]FKTP-Me and enantiomeric (R)- or (S)-[18F]FKTP-Me were synthesized with radiochemical and chemical purities of more than 99%. The metabolite analysis revealed that the racemic (RS)-[18F]FKTP-Me crossed the blood-brain barrier and entered the brain, where it was subsequently hydrolyzed to its pharmacologically active acid form. PET images revealed a high accumulation of (R)-, (S)-, and (RS)-[18F]FKTP in the inflamed regions in rat brain. Moreover, the accumulated radioactivity of (S)-[18F]FKTP-Me was higher than that of (RS)-[18F]FKTP-Me and (R)-[18F]FKTP-Me, which was correlated with the stereospecific inhibitory activity of FKTP against COX-1. Conclusion: From the results of this study, we conclude that racemic (RS)-[18F]FKTP-Me and its enantiomers could act as proradiotracers of neuroinflammation in rat brain by the association of their hydrolyzed acid forms with COX-1 in inflamed regions. In particular, (S)-[18F]FKTP-Me demonstrated suitable properties as a COX-1-specific probe in PET imaging of neuroinflammation.

The application of FAPI-targeted theranostics in pancreatic cancer: a narrative review

Pancreatic cancer is one of the most lethal malignancies in the world. Cancer-associated fibroblasts are one of the main components of tumor microenvironment in pancreatic cancer and play an essential role in tumor progression. Fibroblast activation protein that is expressed in specific subtypes of cancer-associated fibroblasts promotes tumor growth and is related to poor survival. Recent researches have preliminarily demonstrated a promising potential of radiopharmaceuticals targeting fibroblast activation protein in diagnosis and therapy of pancreatic cancer. This article comprehensively reviews the current development and clinical translation of fibroblast activation protein inhibitor-targeting radiopharmaceuticals in pancreatic cancer and provides significant perspectives for future investigations.

Treatment with Radiopharmaceuticals and Radionuclides in Breast Cancer: Current Options.

Radiopharmaceutical therapy (RPT) is an effective and safe treatment for many types of cancer. RPT acts by binding radioactive atoms to tumor-associated antigens, monoclonal antibodies, nanoparticles, peptides, and small molecules. These treatments ensure that a concentrated dose is delivered to the targeted tumor tissue while preserving the normal tissues surrounding the tumor. Given these features, RPT is superior to traditional methods. This review article aimed to performa comprehensive review and evaluation of the potential of radionuclides and radiopharmaceuticals used in breast cancer treatment in preclinical studies conducted in the last five years.

Preparation and Characterization of a Novel Nanocellulose-Derivative as a Potential Radiopharmaceutical Agent

Preparation and Characterization of a Novel Nanocellulose-Derivative as a Potential Radiopharmaceutical Agent

Advances in Development of Radiometal Labeled Amino Acid-Based Compounds for Cancer Imaging and Diagnostics.

Radiolabeled biomolecules targeted at tumor-specific enzymes, receptors, and transporters in cancer cells represent an intensively investigated and promising class of molecular tools for the cancer diagnosis and therapy. High specificity of such biomolecules is a prerequisite for the treatment with a lower burden to normal cells and for the effective and targeted imaging and diagnosis. Undoubtedly, early detection is a key factor in efficient dealing with many severe tumor types. This review provides an overview and critical evaluation of novel approaches in the designing of target-specific probes labeled with metal radionuclides for the diagnosis of most common death-causing cancers, published mainly within the last three years. Advances are discussed such traditional peptide radiolabeling approaches, and click and nanoparticle chemistry. The progress of radiolabeled peptide based ligands as potential radiopharmaceuticals is illustrated via novel structure and application studies, showing how the molecular modifications reflect their binding selectivity to significant onco-receptors, toxicity, and, by that, practical utilization. The most impressive outputs in categories of newly developed structures, as well as imaging and diagnosis approaches, and the most intensively studied oncological diseases in this context, are emphasized in order to show future perspectives of radiometal labeled amino acid-based compounds in nuclear medicine.

Environmental Effect of Potential Radiopharmaceuticals Residuals

Abstract Driven by the current development of quantitative structure-properties relationship (QSPR) methods in the environmental science, we proposed an approach based on chemometric tools for selection of appropriate physicochemical parameters of radiopharmaceuticals residuals for predicting of partitioning, hazards and biodegradation of such compounds into the environment or into wastewater treatment plant. The present scheme was successfully applied for prediction of missing values for 24 different physicochemical and assessment response of the environmental fate descriptors for 11 tetrazine derivatives and 12 cyclooctene derivatives. The multivariate statistics was also proved to be useful in the evaluation of the obtained modelling results for identification of the ecological effect of radiopharmaceuticals residuals. The presented approach can be one of the first steps and support tools in the assessment of chemicals in terms of their environmental impact. The problem studies are significant since it allows a special point of view to the underestimated radiopharmaceutical pollutants.

Radionuclides: medicinal products or rather starting materials?

The EU directive 2001/83 describes the community code for medicinal products for human use including radiopharmaceuticals. In its current definition, also radionuclide precursors, such as fluorine-18, need to hold a marketing authorization before being placed on the market. The potential of novel radiopharmaceuticals for nuclear medicine is, although encouraged by European legislation and its respective guidance documents, therefore hampered by the regulatory framework. An update of EU directive 2001/83 would be beneficial for the development of novel radiopharmaceuticals and a safe advance in nuclear medicine.

Chelators and metal complex stability for radiopharmaceutical applications

Abstract Diagnostic and therapeutic nuclear medicine relies heavily on radiometal nuclides. The most widely used and well-known radionuclide is technetium-99m (99mTc), which has dominated diagnostic nuclear medicine since the advent of the 99Mo/99mTc generator in the 1960s. Since that time, many more radiometals have been developed and incorporated into potential radiopharmaceuticals. One critical aspect of radiometal-containing radiopharmaceuticals is their stability under in vivo conditions. The chelator that is coordinated to the radiometal is a key factor in determining radiometal complex stability. The chelators that have shown the most promise and are under investigation in the development of diagnostic and therapeutic radiopharmaceuticals over the last 5 years are discussed in this review.

Baeyer-Villiger oxidation tuned to chemoselective conversion of non-activated [18 F]fluorobenzaldehydes to [18 F]fluorophenols.

A reaction pathway via oxidation of [18 F]fluorobenzaldehydes offers a very useful tool for the no-carrier-added radiosynthesis of [18 F]fluorophenols, a structural motive of several potential radiopharmaceuticals. A considerably improved chemoselectivity of the Baeyer-Villiger oxidation (BVO) towards phenols was achieved, employing 2,2,2-trifluoroethanol as reaction solvent in combination with Oxone or m-CPBA as oxidation agent. The studies showed the necessity of H2 SO4 addition, which appears to have a dual effect, acting as catalyst and desiccant. For example, 2-[18 F]fluorophenol was obtained with a RCY of 97% under optimised conditions of 80°C and 30-minute reaction time. The changed performance of the BVO, which is in agreement with known reaction mechanisms via Criegee intermediates, provided the best results with regard to radiochemical yield (RCY) and chemoselectivity, i.e. formation of [18 F]fluorophenols rather than [18 F]fluorobenzoic acids. Thus, after a long history of the BVO, the new modification now allows an almost specific formation of phenols, even from electron-deficient benzaldehydes. Further, the applicability of the tuned, chemoselective BVO to the n.c.a. level and to more complex compounds was demonstrated for the products n.c.a. 4-[18 F]fluorophenol (RCY 95%; relating to 4-[18 F]fluorobenzaldehyde) and 4-[18 F]fluoro-m-tyramine (RCY 32%; relating to [18 F]fluoride), respectively.

Enhanced tumor retention of NTSR1-targeted agents by employing a hydrophilic cysteine cathepsin inhibitor

We explored the approach of using an analog of E−64, a well-known and hydrophilic cysteine cathepsin (CC) inhibitor, as a potent cysteine cathepsin-trapping agent (CCTA) to improve the tumor retention of low-molecular-weight, receptor-targeted radiopharmaceuticals. The synthesized hydrophilic CCTA-incorporated, NTSR1-targeted agents demonstrated a substantial increase in cellular retention upon uptake into the NTRS1-positive HT-29 human colon cancer cell line. Similarly, biodistribution studies using HT-29 xenograft mice revealed a significant and substantial increase in tumor retention for the CCTA-incorporated, NTSR1-targeted agent. The intracellular trapping mechanism of the CCTA-incorporated agents by macromolecular adduct formation was confirmed using multiple in vitro and in vivo techniques. Furthermore, utilization of the more hydrophilic CCTA greatly increased the hydrophilicity of the resulting NTSR1-targeted constructs leading to substantial decreases in most non-target tissues in contrast to our previously reported dipeptidyl acyloxymethyl ketone (AOMK) constructs. This work further confirms that the CCTA trapping approach can make significant improvements in the clinical potential of NTSR1-and other receptor-targeted radiopharmaceuticals.

Radiopharmaceuticals for Relapsed or Refractory Leukemias.

Radiopharmaceuticals, meaning drugs that hold a radionuclide intended for use in cancer patients for treatment of their disease or for palliation of their disease-related symptoms, have gained new interest for clinical development in adult patients with relapsed or refractory leukemia. About one-third of adult patients outlive their leukemia, with the remainder unable to attain complete remission status following the first phase of treatment due to refractory bone marrow or blood residual microscopic disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 49 phase 1-1b trials in adult patients with leukemia between 1986 and 2017 in an effort to discover tolerated and effective therapeutic drug combinations intended to improve remission and mortality rates. None of these trials involved radiopharmaceuticals. In this article, the NCI perspective on the challenges encountered in and on the future potential of radiopharmaceuticals alone or in combination for adult patients with relapsed or refractory leukemia is discussed. An effort is underway already to build-up the NCI's clinical trial enterprise infrastructure for radiopharmaceutical clinical development.

Development and Evaluation of 99mTc-Amphotericin Complexes as Potential Diagnostic Agents in Nuclear Medicine

Background: Invasive fungal infections have become highly relevant due to the exponential increase in the population, whose immune non mycotic foci by gamma scintigraphy would allow the appropriate treatment of the patient and avoid the appearance of irreversible tissue damage. Objectives: The present study aimed at development and evaluation of amphotericin B and 99mTc complexes as potential radiopharmaceuticals for the diagnosis of fungal infections by gamma scintigraphy. Methods: Amphotericin was radiolabeled with 99mTc-tricarbonyl and 99mTc-nitride precursors. The complexes were assessed for in vitro stability, lipophilicity, plasma protein binding, plasma stability, and yeast union. Biological evaluation was conducted in 4 groups of CD1 female mice. G0 healthy animals and G1 were induced sterile inflammation with turpentine oil. G2 and G3 were infected with Candida albicans and Aspergillus niger. Results: 99mTc-amphotericin complexes were obtained with radiochemical purity (RCP) higher than 90%, and both were stable in labelling milieu for at least 20 hours and in plasma for 4 hours. Biodistributions of 99mTc(CO)3-amphotericin revealed that the complex was well tolerated by mice and showed mainly urinary excretion. Lesion uptake was 3 times higher in infected tissues with Candida albicans than in sterile inflammation. Conclusions: The 99mTc(CO)3-amphotericin complex is outlined as a potential diagnostic agent for fungal infections by gamma scintigraphy.