Accumulation Of Radioactivity Research Articles

Pharmacokinetic Positron Emission Tomography Imaging of an Optimized CD38-Targeted 68Ga-Labeled Peptide in Multiple Myeloma: A Pilot Study.

Multiple myeloma (MM) is an incurable disease characterized by its clinical and prognostic heterogeneity. Despite conventional chemotherapy and autologous hematopoietic stem cell transplantation, the management of relapsed and refractory MM disease poses significant challenges, both medically and socioeconomically. CD38, highly expressed on the surface of MM cells, serves as a distinct tumor biological target in MM. Peptides offer advantages over antibodies, enabling precise tumor imaging and facilitating early tumor diagnosis and dynamic immunotherapy monitoring. In this study, we developed PF381, a CD38-targeted peptide, and investigated its role in diagnosis, biodistribution, and dosimetry through 68Ga-labeling for preclinical evaluation in tumor-bearing models. We screened a microchip-based combinatorial chemistry peptide library to obtain the amino acid sequence of PF381. Affinity for human CD38 was evaluated by SPRi. PF381 was conjugated with DOTA for radiolabeling with 68Ga, and the complex was characterized by HPLC. PET imaging was performed in murine tumor models after the administration of [68Ga]Ga-DOTA-PF381. Biodistribution analysis compared CD38-positive H929 and CD38-negative U266 tumors, and human radiation dosimetry was estimated. Tumor sections were stained for CD38 expression. SPRi showed that PF381 had a high affinity for CD38 with a KD of 2.49 × 10-8 M. HPLC measured a radiolabeling efficiency of 78.45 ± 7.91% for [68Ga]Ga-DOTA-PF381, with >98% radiochemical purity. PET imaging revealed rapid and persistent accumulation of radioactivity in CD38-positive H929 tumors, contrasting with negligible uptake in CD38-negative U266 tumors. Biodistribution confirmed higher uptake in H929 tumors (0.75 ± 0.03%ID/g) vs U266 (0.26 ± 0.08%ID/g, P < 0.001). The kidney received the highest radiation dose (3.57 × 10-02 mSv/MBq), with an effective dose of 1.41 × 10-02 mSv/MBq. Immunofluorescence imaging supported PET and biodistribution findings. We developed a novel peptide targeting CD38 and proved that 68Ga-labeled PF381 had rapid targeting and good tumor penetration capabilities. Therefore, 68Ga-labeled PF381 could achieve high sensitivity in vivo imaging for CD38-positive hematological malignancies.

Immuno-PET/CT Imaging of Trop2 with [18F]AlF-RESCA-T4 Differentiates Lung Cancer from Inflammation.

Immuno-PET/CT imaging, a branch of molecular imaging, can noninvasively and specifically visualize biomarker expression across the body. Trophoblast cell surface antigen 2 (Trop2) is a pan-cancer biomarker and plays a crucial role in tumorigenesis through multiple signaling pathways. The study aims to develop and translate novel Trop2 single-domain antibody (sdAb) tracers for clinical use. Methods: Two sdAbs (i.e., His-tagged T4 and His-tag-free RT4) are recombinantly expressed in Chinese hamster ovary cells. The purities and binding kinetics are determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, high-performance liquid chromatography, and surface plasmon resonance assays. The AlF restrained complexing agent (RESCA) method is applied to develop 18F-labeled sdAb tracers ([18F]AlF-RESCA-T4 and [18F]AlF-RESCA-RT4), followed by thorough preclinical imaging and blocking studies on tumor-bearing mice and a pilot clinical trial evaluating the clinical imaging safety and feasibility of [18F]AlF-RESCA-T4 immuno-PET/CT. Results: [18F]AlF-RESCA-T4 and [18F]AlF-RESCA-RT4 possess high radiochemical purities. Preclinical imaging in the T3M-4 tumor model revealed prominent uptake (percentage injected dose/g) of [18F]AlF-RESCA-T4 (11.13 ± 1.53, n = 4) and [18F]AlF-RESCA-RT4 (8.83 ± 1.22, n = 4), which were significantly reduced by coinjection of unlabeled T4 and RT4 in blocking studies. The His-tag removal strategy further optimized the probe's invivo pharmacokinetics and reduced renal radioactivity accumulation without significantly decreasing tumor uptake. In a pilot clinical trial, [18F]AlF-RESCA-T4 immuno-PET/CT showed promising potency in annotating Trop2 expression and differentiating tumors from inflammatory diseases such as tuberculosis. Conclusion: [18F]AlF-RESCA-T4 and [18F]AlF-RESCA-RT4 can specifically annotate Trop2 expression. Clinical [18F]AlF-RESCA-T4 immuno-PET/CT imaging can screen patients for Trop2-targeted therapies and differentiate lung inflammation from cancer.

Site-Specific Modification of Native IgGs with Flexible Drug-Load.

Homogeneous, site-specifically conjugated antibodies have shown to result in antibody-drug conjugates (ADCs) with improved efficacy and tolerability compared to stochastically conjugated ADCs. However, precisely controlling the drug load as well as attaching multiple payload moieties to the antibody remains challenging. Here, we demonstrate the simple and direct modification of native IgG-antibodies at the residue glutamine 295 (Q295) without the need for any protein engineering with flexible drug-to-antibody ratios of one or multiple payloads. The conjugation is enabled through short, positively charged lysine containing peptides and native, commercially available microbial transglutaminase. In proof-of-concept studies, HER2-targeting ADCs based on trastuzumab were generated with drug-to-antibody ratios (DARs) of 2 and 4 of the same or different payloads using orthogonal conjugation chemistries. Quantitative biodistribution studies performed with 111In-radiolabeled conjugates showed high tumour uptake and low accumulation of radioactivity in non-targeted tissues. A single dose study of trastuzumab conjugated to the highly potent payload α-Amanitin demonstrated complete and long-lasting tumour remission and was well-tolerated at all dose levels tested.

Influence of PEGylation on HER2-targeting retro A9 peptide analogue

Elevated levels of HER2 receptor in breast cancer can be targeted through receptor-specific peptides for precise detection and therapy by nuclear medicine approach. Previously reported retro analogue of A9 peptide had shown HER2-specificity with promising pharmacokinetic features. Hence, with an aim of further improving the circulation time of rL-A9 radiopeptide, long polyethylene glycol chain (PEG12) was introduced at the N-terminus of the peptide during solid phase synthesis and influence of PEGylation on biological profile was studied. [177Lu]Lu-DOTA-PEG12-rL-A9 demonstrated high specific cellular uptake (5.94 ± 0.09 %) in HER2-expressing human breast carcinoma SKBR3 cells and low nanomolar binding affinity (Kd = 34.58 ± 12.78 nM). Uptake in SKBR3 tumors induced in female SCID mice was higher at all the time points investigated (3, 24, 48 h) in comparison to the non-PEGylated radiopeptide, [177Lu]Lu-DOTA-rL-A9. Blocking studies led to 51 % reduction in accumulation of radioactivity in the tumor indicating specificity of the radiopeptide. Improved tumor-to-stomach and tumor-to-intestine ratios for [177Lu]Lu-DOTA-PEG12-rL-A9 compared to [177Lu]Lu-DOTA-rL-A9 at 48 h shall pave the way for better contrast and delineation of metastatic sites.

Safety assessment of introducing radioactive waste incineration facilities in Korea: An off-site resident dose evaluation

As nuclear power technology advances, radioactive waste accumulation rises, necessitating measures to alleviate strain on disposal facilities and minimize waste management costs. Analysis of radioactive waste composition revealed that combustible waste comprised the largest proportion (45 %), with incineration demonstrating high reduction efficiency for this fraction. In order for a radioactive waste incineration facility to be introduced, it is necessary to evaluate the safety of gas radioactive effluent generated during city operation. Evaluation criteria have already been established and methodologies also exist, but these results greatly depend on the area where the incineration facilities are located, the waste to be treated, the operation method of the facilities. Accordingly, this study assumed annual throughput and radionuclide concentrations based on the radioactive waste stored and generated in Korea. The centralized operation method at a specific site was compared with the decentralized operation method employed at all sites. Post-incineration, the impact of radionuclides released from the facilities was analyzed against Nuclear Safety and Security Commission standards, confirming the discharge standards and doses for single facilities and entire sites.

Preclinical Evaluation of a Radiolabeled Pan-RAF Inhibitor for RAF-Specific PET/CT Imaging.

Abnormalities in the RAS-RAF signaling pathway occur in many solid tumors, leading to aberrant tumor proliferation, invasion, and metastasis. Due to the elusive pharmacology of RAS, RAF inhibitors have become the main targeted therapeutic drugs. Naporafenib (LXH-254) is a high-affinity pan-RAF inhibitor with FDA Fast Track Qualification. We sought to develop an 18F-labeled molecular probe from LXH-254 for PET imaging of tumors overexpressing RAF to noninvasively screen patients for susceptibility to targeted RAF therapy. To reduce the lipid solubility, LXH-254 was designed with triethylene glycol di(p-toluenesulfonate) (TsO-PEG3-OTs) to obtain the precursor (LXH-254-OTs) and a nucleophilic substitution reaction with 18F to obtain the tracer ([18F]F-LXH-254). [18F]F-LXH-254 exhibited good molar activity (7.16 ± 0.81 GBq/μmol), radiochemical purity (>95%), and stability. Micro-PET imaging revealed distinct radioactivity accumulation of [18F]F-LXH-254 in tumors in the imaging groups, whereas in the blocked group, the tumor radioactivity level was consistent with the background tissue, illustrating the affinity and specificity of [18F]F-LXH-254 in targeting RAF. Overall, [18F]F-LXH-254 is a promising radiotracer for screening and diagnosing patients with RAF-related disease and monitoring their treatment. This is the first attempt at using an 18F-labeled RAF-specific radiotracer.

Ways to reduce radioactivity accumulation in the kidney during targeted therapy using small molecules, peptides and antibody fragments

Administration of pharmaceuticals containing radioactive isotopes and capable of specific binding to certain proteins is one of the approaches used in the treatment or diagnosis of malignant tumors. High renal accumulation of radioactive compounds after administration of radioconjugates with molecular mass less than 70 KDa is of the challenges that need to be solved. The purpose of the study was to identify the most effective approaches to reduce the accumulation of radioactivity in the kidneys after administration of radioconjugates used for diagnostic imaging and targeted therapy for cancer. Material and Methods. We conducted a literature search on the topic of the review in the electronic databases PubMed, Scopus and Web of Science from 1987 to 2023, 82 articles were used for writing the review. Results. The review presents a description of approaches used to improve the biodistribution of radioconjugates, mainly in preclinical studies. The advantages and disadvantages of such techniques have been described. Conclusion. Reducing renal radioactivity using radioconjugates of molecules with molecular masses less than 70 KDa is a challenging but achievable task. It is concluded that the use of cleavable linkers in such radioconjugates is highly promising, since this approach does not change the pharmacokinetics of such drugs. It is noted that the advantage of introducing concomitant substances compared to changing the structure of radioconjugates is a lesser dependence on the characteristics of a particular radiopharmaceutical. This approach also does not require prior work to modify the radioconjugate, but has limited efficiency.

Detection of lipid radicals generated via cerebral ischemia/reperfusion injury using a radiolabeled nitroxide probe

Reactive oxygen species generated via reperfusion cause lipid damage and induce lipid peroxidation, leading to cerebral ischemia/reperfusion injury and exacerbation of cerebral infarction. Lipid radicals are key molecules generated during lipid peroxidation. Therefore, understanding the spatiotemporal behavior of lipid radicals is important to improve the therapeutic outcomes of cerebral infarction. However, the behaviors of lipid radicals in the brain remain unclear. In this study, we aimed to evaluate the distribution of radioactivity in a transient middle cerebral artery occlusion (tMCAO) model using lipid radical detection probe [125I]1 to assess the behaviors of lipid radicals after cerebral ischemia/reperfusion. The tMCAO model administered [125I]1 exhibited significant differences in the timing and location of radioactivity accumulation between the ischemic and non-ischemic regions. Liquid chromatography/mass spectrometry analysis identified the lipid radical adducts formed by the reaction of 1 with the lipid radicals generated after reperfusion. More adducts were detected in the ischemic region samples than in the non-ischemic region samples. Therefore, 1 successfully detected the lipid radicals generated after cerebral ischemia/reperfusion. Overall, this study demonstrates the potential of nuclear medical imaging using radiolabeled 1 to detect the lipid radicals generated after cerebral ischemia/reperfusion. Our approach can aid in the development of new therapeutic agents scavenging lipid radicals after cerebral reperfusion by facilitating the determination of therapeutic efficacy and optimal administration period.

Accumulation of Environmental Radioactivity on the Surface of a High Arctic Ice Cap (Flade Isblink, NE Greenland).

Under climatic warming, glaciers are becoming a secondary source of atmospheric contaminants originally released into the environment decades ago. This phenomenon has been well-documented for glaciers near emission sources. However, less is known about polar ice sheets and ice caps. Radionuclides are one of the contaminants that can be remobilised through ice melting and accumulate in cryoconite material on the surface of glaciers. To understand the cycling of radionuclides in polar glacial contexts, we evaluate the radioactivity of cryoconite samples from Flade Isblink, a High Arctic ice cap in northeast Greenland. The measured radioactivity is among the highest reported across the High Arctic and the highest from Greenland. The high variability observed among the samples is explained by considering the different macroscopic features of single cryoconite deposits. The radioactivity source is compatible with the stratospheric reservoir established during atmospheric nuclear tests and with weapons-grade fissile fuel, likely originating from Novaya Zemlya proving grounds. This study shows that the ability of cryoconite to accumulate radioactivity in remote areas is undisputed, highlighting the need for a deeper understanding of the remobilisation of radioactive species in polar glacial contexts.

A detailed simulation study on radionuclide dispersion under spent fuel road transportation conditions: Effects of vessel type and coniferous vegetation growth

Vegetation barriers are an important environmental characteristic of spent fuel road transportation accidents. Spent fuel vessels may be affected by force majeure factors during transportation, which leads to damage to spent fuel assemblies and containers and can cause radionuclides to gradually release from assemblies to vessels to the external environment. In this work, considering the growth periods of coniferous vegetation barriers and vessel type, a radionuclide dispersion model based on computational fluid dynamics (CFD) was established by adding a decay term and a pressure loss term. The simulations showed that, first, compared to the small (Type-II) vessel, the effects of fluid flow around the large vessel (Type-I) have a more significant impact on radionuclide dispersion. The backflow around the Type-I vessel causes leaked radionuclides to disperse towards the vessel, and the larger the vessel is, the more significant the rise of the leaked radionuclide plume tail will be due to the increased negative pressure gradient area. Moreover, the area contaminated exceeding the maximum allowable concentration by radioactivity for the Type-I vessel is reduced gradually with the growth of coniferous vegetation barriers due to the weakening of the backflow effect by growing vegetation. Second, compared to vegetation barriers of 15 years and 23 years, the horizontal distance exceeding the maximum allowable concentration of the leaked 131I dispersion from Type II vessels near vegetation barriers for 12 years is the longest. The older the vegetation barrier is, the shorter the horizontal dispersion range, and the shape of radionuclide dispersion gradually transforms from flat to semicircular with vegetation barrier growth, but this could cause a greater radioactive accumulation effect near the leakage point, and the maximum concentration of leaked 131I reached 0.54 kBq·m−3 for leaked radionuclides from the Type II vessel under vegetation barriers of 23 years. In addition, improvement suggestions based on the proposed method are presented, which will enable the Standards Institutes to apply the research methodologies described herein across various scenarios. Environmental ImplicationCompared to nonradioative pollutants, radioactive pollutants are intercepted by vegetation barriers and then migrate to the soil through leaves, stems, and roots, which can contaminate the surrounding environment. Considering the effects of vessel type and coniferous vegetation growth, a radionuclide dispersion model based on CFD was established. Suggestions for decontaminating radioactive pollution areas have been proposed based on the simulation results of hypothetical scenarios. The scenario applicability improvements based on the proposed model could assist relevant Standards Institutes to making improving measures.

Radionuclide therapy of bevacizumab-based PNA-mediated pretargeting.

The radionuclide-labeled bevacizumab (BV) is a potential therapeutic approach for vascular endothelial growth factor overexpressed tumors. Because of its large molecular weight, BV is cleared slowly in vivo, which caused damage to healthy tissues and organs. On account of this situation, using the pretargeting strategy with DNA/RNA analogs, such as peptide nucleic acid (PNA), is an effective way of treating solid tumors. The BV-PNA conjugate (BV-PNA-1) was injected intravenously as the pretargeted probe, which was specifically accumulated in a solid tumor and gradually metabolically cleared. Then the [177Lu]Lu-labeled complementary PNA strand ([177Lu]Lu-PNA-2) as the second probe was injected, and bound with BV-PNA-1 by the base complementary pairing. In this study, the BV-based PNA-mediated pretargeting strategy was systematically studied, including stability of probes, specific binding ability, biodistribution in animal model, evaluation of single photon emission computed tomography/computed tomography imaging, and therapeutic effect. Compared with group A ([177Lu]Lu-BV), the group B (BV-PNA-1 + [177Lu]Lu-PNA-2) showed lower blood radiotoxicity (22.55 ±1.62 vs. 5.18 ± 0.40%, %ID/g, P < 0.05), and similar accumulation of radioactivity in tumor (5.32 ± 0.66 vs. 6.68 ± 0.79%, %ID/g, P > 0.05). Correspondingly, there was no significant difference in therapeutic effect between groups A and B. The PNA-mediated pretargeting strategy could increase the tumor-to-blood ratio, thereby reducing the damage to normal tissues, while having a similar therapeutic effect to solid tumor. All the experiments in this study showed the potential and effectiveness of pretargeting radioimmunotherapy.

Improving the In Vivo Stability of [52Mn]Mn(II) Complexes with 18-Membered Macrocyclic Chelators for PET Imaging.

We report the [natMn/52Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN [(41R,42R,101R,102R)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane]. The X-ray crystal structures of Mn-PYAN and Mn-CHXPYAN evidence distorted octahedral geometries through coordination of the nitrogen atoms of the macrocycles. Cyclic voltammetry studies evidence reversible processes due to the Mn(II)/Mn(III) pair, indicating that the complexes are resistant to oxidation. CHXPYAN forms a more thermodynamically stable and kinetically inert Mn(II) complex than PYAN. Radiochemical studies with the radioactive isotope manganese-52 (52Mn, t1/2 = 5.6 days) evidenced better radiochemical yields for CHXPYAN than for PYAN. Both [52Mn]Mn(II) complexes remained stable in mouse and human serum, so in vivo stability studies were carried out. Positron emission tomography/computed tomography scans and biodistribution assays indicated that [52Mn]Mn-PYAN has a distribution pattern similar to that of [52Mn]MnCl2, showing persistent radioactivity accumulation in the kidneys. Conversely, [52Mn]Mn-CHXPYAN remained stable in vivo, clearing quickly from the liver and kidneys.

Trend analysis of environmental radioactivity levels around Kaiga Generating Station, India

The study assessed the radiological impact of the Kaiga Generating Station (KGS) on the surrounding environment and the safety of the nearby population. Over a period of 15 years (2005–2020), the radiological monitoring detected only trace levels of 3H and 137Cs (attributed to fallout) in the surrounding environment. The study utilized the non-parametric Mann–Kendall test to analyze the long-term trends, identifying either decreasing or no trend in the radioactivity levels across various environmental matrices such as air, water, biota, and dietary items. These findings indicate no significant accumulation of radioactivity, confirming the minimal environmental impact of the KGS operations.

Synthesis and Preclinical Evaluation of Novel 68Ga-DOTA-RBB as Potential PET Radiotracer for Imaging CDK4/6 in Tumors.

Many malignant tumors, including breast cancer, exhibit amplification and overexpression of cyclin-dependent kinase 4 and 6 (CDK4/6). Ribociclib, approved and used in clinical treatment, acts as a highly selective CDK4/6 inhibitor for ER+/HER2- breast cancer. By modifying ribociclib with the chelator DOTA, we designed and synthesized a novel CDK4/6-positive PET imaging agent, which was radiolabeled by 68Ga for radioactive tagging. The radiotracer demonstrates high radiochemical purity, excellent stability in vitro and in vivo, and favorable pharmacokinetic characteristics. Cell uptake experiments using MCF-7 cells indicate that an excess of ribociclib (RBB) can inhibit cellular uptake of 68Ga-DOTA-RBB. Imaging and biodistribution experiments in MCF-7 tumor-bearing nude mice show significant radioactive accumulation in the tumor. However, preadministration of excess ribociclib results in a substantial reduction in radioactive accumulation within the tumor. On the basis of our explorations, 68Ga-DOTA-RBB, as a targeted imaging agent for CDK4/6-positive tumors, holds significant potential application values.

An intelligent and self-assembled nanoscale metal organic framework (99mTC-DOX loaded Fe3O4@FeIII-tannic acid) for tumor targeted chemo/chemodynamic theranostics

BackgroundRecent advances in clinical transformation research have focused on chemodynamic theranostics as an emerging strategy for tackling cancer. Nevertheless, its effectiveness is hampered by the tumor's glutathione antioxidant effect, poor acidic tumor microenvironment (TME) and inadequate endogenous H2O2. Hence, we designed an activatable theranostics (99mTc-DOX loaded AA-Fe3O4@FeIII-TA) that effectively boost the catalytic efficiency of the Fenton-reaction-induced ROS production and augment the chemotherapeutic efficacy combined with diagnostic action.ResultsA cross-linked matrix of tannic acid-ferric salt (FeIII-TA) as a pH-responsive shell onto ascorbic acid-decorated iron-oxide nanoparticles (AA-Fe3O4NPs) was prepared demonstrating a metal–organic- framework (MOF) nanostructure, followed by loading of 99mTc-labelled DOX. The platform (99mTc-DOX loaded AA-Fe3O4@FeIII-TA) displayed suitable physical–chemical properties, including 69.8 nm particle size, 94.8 nm hydrodynamic size, − 21 mV zeta potential, effective FeIII-TA shell crosslinking onto AA-Fe3O4NPs and 94% loading efficiency for 99mTc-DOX. The results of the in-vitro release investigations showed that the platform exhibited a pH-dependent release manner with 98.3% of the 99mTc-DOX being released at pH 5 (simulating the tumor’s pH) and only 10% being released at the physiological pH (pH 7.4). This indicates that there was negligible payload leakage into the systemic circulation during the platform's passive accumulation inside tumor. Due to the acidic TME nature, the MOF shell might be degraded releasing free FeIII, TA and a sustained release of 99mTc-DOX. Besides its chemotherapeutic impact and capacity to raise intracellular H2O2 content, the released 99mTc-DOX might be used as SPECT imaging tracer for concurrent tumor diagnosis. Furthermore, the mild acidity of the tumor may be overcome by the released TA, which might raise the acidification level of cancer cells. The released FeIII, TA and the endogenous GSH could engage in a redox reaction that depletes GSH and reduces FeIII to FeII ions which subsequently catalyze the elevated concentration of H2O2 to reactive •OH via Fenton-like reaction, increasing the effectiveness of chemodynamic therapy. Moreover, the in-vivo evaluation in tumor-bearing mice showed significant radioactivity accumulation in the tumor lesion (16.8%ID/g at 1 h post-injection) with a potential target/non-target ratio of 8.ConclusionsThe 99mTc-DOX loaded AA-Fe3O4@FeIII-TA could be introduced as an effective chemo/chemodynamic theranostics.Graphical

PET/CT with &lt;sup&gt;18&lt;/sup&gt;F-FDG for TENIS Syndrome in a Patient with Bone Metastasis of Hurthle Cell Thyroid Cancer: a Clinical Case Report

A significant role in improving the prognosis of differentiated thyroid cancer (DTC) in the presence of bone metastases is determined by early diagnosis of metastases, timely and correctly selected treatment tactics for the patient. During dynamic follow-up of patients with DTC after combined treatment (thyroidectomy with radioiodine therapy) are determination of the level of oncomarkers (serum thyroglobulin and antibodies to thyroglobulin) and ultrasound diagnostic of the neck, scanning with radioactive iodine (if clinically indicated). In some cases, patients have TENIS-syndrome (Thyroglobulin Elevated Negative Iodine Scintigraphy, hereinafter TENIS-syndrome), characterized by high serum thyroglobulin level in blood and absence of radioactive iodine accumulation on post therapeutic scintigraphy. According to the research studies, PET/CT with 18F-FDG has high sensitivity and specificity (89 % and 72 %, respectively) in visualization of metastatic radioiodine refractory foci in TENIS-syndrome.This article presents a clinical case of a patient, a 52-year-old woman with Gurtle cell thyroid cancer (pT3aN0M0, stage I) with established TENIS syndrome. Thyroidectomy was performed in September 2019 and radioiodine therapy was performed in January 2022 due to suspected disease progression given high thyroglobulin levels. Given the absence of pathologic accumulation of 131I according to post-therapy radioiodine scanning, PET/CT with 18F-FDG was performed, which revealed a solitary metastasis in the left iliac bone (41×35×42 mm with SUVmax 17.25). In November 2022, radical treatment of the solitary bone metastasis was performed in the scope of resection of the left iliac bone with reconstructive-plastic component. According to the data of control examinations in June 2023, the patient has a complete biochemical and radiologic remission of the disease.

Synthesis and biological evaluation of radioiodinated benzoxazole and benzothiazole derivatives for imaging myelin in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that results from destruction of the myelin sheath. Due to heterogeneity of the symptoms and course of MS, periodic monitoring of disease activity is important for diagnosis and treatment. In the present study, we synthesized four radioiodinated benzoxazole (BO) and benzothiazole (BT) derivatives, and evaluated their utility as novel myelin imaging probes for single photon emission computed tomography (SPECT). In a biodistribution study using normal mice, three compounds ([125I]BO-1, [125I]BO-2, and [125I]BT-2) displayed moderate brain uptake (2.7, 2.9, and 2.8% ID/g, respectively) at 2 min postinjection. On ex vivo autoradiography using normal mice, [125I]BO-2 showed the most preferable ratio of radioactivity accumulation in white matter (myelin-rich region) versus gray matter (myelin-deficient region). In addition, the radioactivity of [125I]BO-2 was reduced in the lysophosphatidylcholine-induced demyelination region. In conclusion, [123I]BO-2 demonstrated the fundamental characteristics of a myelin imaging probe for SPECT.

89Zr-ImmunoPET for the Specific Detection of EMP2-Positive Tumors.

Epithelial membrane protein-2 (EMP2) is upregulated in a number of tumors and therefore remains a promising target for mAb-based therapy. In the current study, image-guided therapy for an anti-EMP2 mAb was evaluated by PET in both syngeneic and immunodeficient cancer models expressing different levels of EMP2 to enable a better understanding of its tumor uptake and off target accumulation and clearance. The therapeutic efficacy of the anti-EMP2 mAb was initially evaluated in high- and low-expressing tumors, and the mAb reduced tumor load for the high EMP2-expressing 4T1 and HEC-1-A tumors. To create an imaging agent, the anti-EMP2 mAb was conjugated to p-SCN-Bn-deferoxamine (DFO) and radiolabeled with 89Zr. Tumor targeting and tissue biodistribution were evaluated in syngeneic tumor models (4T1, CT26, and Panc02) and human tumor xenograft models (Ramos, HEC-1-A, and U87MG/EMP2). PET imaging revealed radioactive accumulation in EMP2-positive tumors within 24 hours after injection, and the signal was retained for 5 days. High specific uptake was observed in tumors with high EMP2 expression (4T1, CT26, HEC-1-A, and U87MG/EMP2), with less accumulation in tumors with low EMP2 expression (Panc02 and Ramos). Biodistribution at 5 days after injection revealed that the tumor uptake ranged from 2 to approximately 16%ID/cc. The results show that anti-EMP2 mAbs exhibit EMP2-dependent tumor uptake with low off-target accumulation in preclinical cancer models. The development of improved anti-EMP2 Ab fragments may be useful to track EMP2-positive tumors for subsequent therapeutic interventions.

18F]pFBC, a Covalent CLIP-Tag Radiotracer for Detection of Viral Reporter Gene Transfer in the Murine Brain.

Preclinical models of neurological diseases and gene therapy are essential for neurobiological research. However, the evaluation of such models lacks reliable reporter systems for use with noninvasive imaging methods. Here, we report the development of a reporter system based on the CLIP-tag enzyme and [18F]pFBC, an 18F-labeled covalent CLIP-tag-ligand synthesized via a DoE-optimized and fully automated process. We demonstrated its specificity using a subcutaneous xenograft model and a model of viral vector-mediated brain gene transfer by engineering HEK293 cells and striatal neurons to express membrane-tethered CLIP-tag protein. After in vitro characterization of the reporter, mice carrying either CLIP-tag expressing or control subcutaneous xenografts underwent dynamic [18F]pFBC PET imaging. The CLIP-tag expressing xenografts showed a significantly higher uptake than control xenografts (tumor-to-muscle ratio 5.0 vs 1.7, p = 0.0379). In vivo, metabolite analysis by radio-HPLC from plasma and brain homogenates showed only one radio-metabolite in plasma and none in the brain. In addition, [18F]pFBC showed fast uptake and rapid clearance from the brain in animals injected with adeno-associated virus (AAV)-CLIP in the right striatum but no right-to-left (R-L) uptake difference in the striata in the acquired PET data. In contrast, autoradiography showed a clear accumulation of radioactivity in the AAV-CLIP-injected right striatum compared to the sham-injected left striatum control. CLIP-tag expression and brain integrity were verified by immunofluorescence and light sheet microscopy. In conclusion, we established a novel reporter gene system for PET imaging of gene expression in the brain and periphery and demonstrated its potential for a wide range of applications, particularly for neurobiological research and gene therapy with viral vectors.

Synthesis and biological evaluation of novel 18F-labeled 2,4-diaminopyrimidine derivatives for detection of ghrelin receptor in the brain

The ghrelin receptor (GHSR) is known to regulate various physiological processes including appetite, food intake, and growth hormone release. Its expression is mainly observed in the brain, pancreas, stomach, and intestine. However, the functions of the receptor have not been fully elucidated. GHSR imaging with positron emission tomography (PET) is expected to further understanding of the functions and pathologies of the receptor. In this study, we newly designed and synthesized diaminopyrimidine derivatives ([18F]BPP-1 and [18F]BPP-2) and evaluated their utility as novel PET probes targeting GHSR. In in vitro competitive binding assays, the binding affinity of BPP-2 for GHSR (Ki = 274 nM) was comparable to that of the diaminopyimidine lead compound Abb8a (Ki = 109 nM). In a biodistribution study using normal mice, [18F]BPP-2 displayed low uptake in the brain and moderate uptake in the pancreas, but high radioactivity accumulation in bone was observed due to its defluorination in vivo. Taken together, although further improvement of the pharmacokinetics is needed, the diaminopyrimidine scaffold has potential for the development of useful GHSR-targeting PET probes.