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Positron emission tomography (PET) is a preclinical and clinical imaging technique extensively used to study and visualize biological and physiological processes in vivo. Fluorine-18 (18F) is the most frequently used positron emitter for PET imaging due to its convenient 109.8 min half-life, high yield production on small biomedical cyclotrons, and well-established radiofluorination chemistry. The presence of fluorine atoms in many drugs opens new possibilities for developing radioligands labelled with fluorine-18. The trifluoromethyl group (CF3) represents a versatile structural motif in medicinal and pharmaceutical chemistry to design and synthesize drug molecules with favourable pharmacological properties. This fact also makes CF3 groups an exciting synthesis target from a PET tracer discovery perspective. Early attempts to synthesize [18F]CF3-containing radiotracers were mainly hampered by low radiochemical yields and additional challenges such as low radiochemical purity and molar activity. However, recent innovations in [18F]trifluoromethylation chemistry have significantly expanded the chemical toolbox to synthesize fluorine-18-labelled radiotracers. This review presents the development of significant [18F]trifluoromethylation chemistry strategies to apply [18F]CF3-containing radiotracers in preclinical and clinical PET imaging studies. The continuous growth of PET as a crucial functional imaging technique in biomedical and clinical research and the increasing number of CF3-containing drugs will be the primary drivers for developing novel [18F]trifluoromethylation chemistry strategies in the future. [ABSTRACT FROM AUTHOR]

Background: The radiometal gallium-68 (68Ga) is increasingly used in diagnostic positron emission tomography (PET), with 68Ga-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional 99mTc agents. In precision medicine, PET applications of 68Ga are widespread, with 68Ga radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin. Main body: These 68Ga radiopharmaceuticals include agents such as [68Ga]Ga-macroaggregated albumin for myocardial perfusion evaluation, [68Ga]Ga-PLED for assessing renal function, [68Ga]Ga-t-butyl-HBED for assessing liver function, and [68Ga]Ga-PSMA for tumor imaging. The short half-life, favourable nuclear decay properties, ease of radiolabeling, and convenient availability through germanium-68 (68Ge) generators and cyclotron production routes strongly positions 68Ga for continued growth in clinical deployment. This progress motivates the development of a set of common guidelines and standards for the 68Ga radiopharmaceutical community, and recommendations for centers interested in establishing 68Ga radiopharmaceutical production. Conclusion: This review outlines important aspects of 68Ga radiopharmacy, including 68Ga production routes using a 68Ge/68Ga generator or medical cyclotron, standardized 68Ga radiolabeling methods, quality control procedures for clinical 68Ga radiopharmaceuticals, and suggested best practices for centers with established or upcoming 68Ga radiopharmaceutical production. Finally, an outlook on 68Ga radiopharmaceuticals is presented to highlight potential challenges and opportunities facing the community. [ABSTRACT FROM AUTHOR]

Lanthanum radiometals are well positioned to serve as theranostic PET radiometals for targeted radionuclide therapy. The positron emitters 132La and 133La show promise to serve as unique PET imaging agents for 225Ac targeted alpha-particle therapy, the 134Ce/134La pair has PET imaging potential with both 225Ac and 227Th, and 135La has potential in targeted Auger-Meitner electron therapy. With easily accessible cyclotron production routes, effective and efficient chemical separations, and robust chelation chemistry, these radionuclides are well poised for additional preclinical and clinical PET and targeted radionuclide therapy studies. This review summarizes recent advances in radiolanthanum production and preclinical applications that demonstrate the strong potential of these radionuclides in PET and targeted radionuclide therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Molecular imaging probes enable the early and accurate detection of disease-specific biomarkers and facilitate personalized treatment of many chronic diseases, including cancer. Among current clinically used functional imaging modalities, positron emission tomography (PET) plays a significant role in cancer detection and in monitoring the response to therapeutic interventions. Several preclinical and clinical studies have demonstrated the crucial involvement of cyclooxygenase-2 (COX-2) isozyme in cancer development and progression, making COX-2 a promising cancer biomarker. A variety of COX-2-targeting PET radioligands has been developed based on anti-inflammatory drugs and selective COX-2 inhibitors. However, many of those suffer from non-specific binding and insufficient metabolic stability. This article highlights examples of COX-2-targeting PET radioligands labelled with the short-lived positron emitter 18F, including radiosynthesis and PET imaging studies published in the last decade (2012–2021). [ABSTRACT FROM AUTHOR]

Simple Summary: Being able to detect and image tumors is extremely important for proper diagnosis and treatment. The most sensitive technique, positron emission tomography (PET), is widely applied for such a purpose. Additionally, fluorescence imaging can be used to visually see the margins between healthy and cancerous tissue during surgery. These two techniques can be combined to optimize patient outcomes by ensuring maximum tumor removal. This review will discuss the work that has been done recently to combine these two imaging capabilities into one imaging agent. Dual probes that possess positron emission tomography (PET) and fluorescence imaging (FI) capabilities are precision medicine tools that can be used to improve patient care and outcomes. Detecting tumor lesions using PET, an extremely sensitive technique, coupled with fluorescence-guided surgical resection of said tumor lesions can maximize the removal of cancerous tissue. The development of novel molecular probes is important for targeting different biomarkers as every individual case of cancer has different characteristics. This short review will discuss some aspects of dual PET/FI probes and explore the recently reported examples. [ABSTRACT FROM AUTHOR]

• Gasdermin D (GSDMD) activation occurs in oligodendrocytes and CNS macrophages. • GDSMD and Ninjurin 1 are induced in neuroinflammatory demyelination. • GSDMD genetic deletion reduces neuroinflammatory demyelination and axonal injury. • GSDMD activation represents a potential therapeutic target for progressive MS. Neuroinflammation coupled with demyelination and neuro-axonal damage in the central nervous system (CNS) contribute to disease advancement in progressive multiple sclerosis (P-MS). Inflammasome activation accompanied by proteolytic cleavage of gasdermin D (GSDMD) results in cellular hyperactivation and lytic death. Using multiple experimental platforms, we investigated the actions of GSDMD within the CNS and its contributions to P-MS. Brain tissues from persons with P-MS showed significantly increased expression of GSDMD, NINJ1, IL-1β, and −18 within chronic active demyelinating lesions compared to MS normal appearing white matter and nonMS (control) white matter. Conditioned media (CM) from stimulated GSDMD+/+ human macrophages caused significantly greater cytotoxicity of oligodendroglial and neuronal cells, compared to CM from GSDMD-/- macrophages. Oligodendrocytes and CNS macrophages displayed increased Gsdmd immunoreactivity in the central corpus callosum (CCC) of cuprizone (CPZ)-exposed Gsdmd+/+ mice, associated with greater demyelination and reduced oligodendrocyte precursor cell proliferation, compared to CPZ-exposed Gsdmd-/- animals. CPZ-exposed Gsdmd+/+ mice exhibited significantly increased G-ratios and reduced axonal densities in the CCC compared to CPZ-exposed Gsdmd-/- mice. Proteomic analyses revealed increased brain complement C1q proteins and hexokinases in CPZ-exposed Gsdmd-/- animals. [18F]FDG PET imaging showed increased glucose metabolism in the hippocampus and whole brain with intact neurobehavioral performance in Gsdmd-/- animals after CPZ exposure. GSDMD activation in CNS macrophages and oligodendrocytes contributes to inflammatory demyelination and neuroaxonal injury, offering mechanistic and potential therapeutic insights into P-MS pathogenesis. [ABSTRACT FROM AUTHOR]

This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It evaluates the strengths and limitations of each potential imaging surrogate. Thirteen surrogates for TAT are explored: 133La, 132La, 134Ce/134La, and 226Ac for 225Ac TAT; 203Pb for 212Pb TAT; 131Ba for 223Ra and 224Ra TAT; 123I, 124I, 131I and 209At for 211At TAT; 134Ce/134La for 227Th TAT; and 155Tb and 152Tb for 149Tb TAT. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several new drugs into the clinic over the past decade, inspiring the need for novel therapeutics. We investigate targeting melanin pigment, which causes melanoma, with protein molecules called antibodies, which carry a radioactive payload to visualize or treat melanoma tumors. In this study, we imaged and treated melanoma in mice using a c8C3 antibody to melanin and two radioisotopes of lead—Lead-203 for imaging and Lead-212 for therapy. Imaging with Lead-203-bound antibodies allowed for visualization of the tumors in mice, while treatment with Lead-212-bound antibodies slowed down the growth of these aggressive tumors. The treatment was not toxic to mice. We concluded that the melanin-targeting Lead-203/Lead-212-bound c8C3 antibody is a promising agent for imaging and therapy of metastatic melanoma (so-called theranostic), which warrants further investigation. Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several immunotherapeutic agents into the clinic over the past decade, inspiring the development of novel therapeutics and the exploration of combination therapies. Our investigations target melanin pigment with melanin-specific radiolabeled antibodies as a strategy to treat metastatic melanoma. In this study, a theranostic approach was applied by first labeling a chimeric antibody targeting melanin, c8C3, with the SPECT radionuclide 203Pb for microSPECT/CT imaging of C57Bl6 mice bearing B16-F10 melanoma tumors. Imaging was followed by radioimmunotherapy (RIT), whereby the c8C3 antibody is radiolabeled with a 212Pb/212Bi "in vivo generator", which emits cytotoxic alpha particles. Using microSPECT/CT, we collected sequential images of B16-F10 murine tumors to investigate antibody biodistribution. Treatment with the 212Pb/212Bi-labeled c8C3 antibody demonstrated a dose-response in tumor growth rate in the 5–10 µCi dose range when compared to the untreated and radiolabeled control antibody and a significant prolongation in survival. No hematologic or systemic toxicity of the treatment was observed. However, administration of higher doses resulted in a biphasic tumor dose response, with the efficacy of treatment decreasing when the administered doses exceeded 10 µCi. These results underline the need for more pre-clinical investigation of targeting melanin with 212Pb-labeled antibodies before the clinical utility of such an approach can be assessed. [ABSTRACT FROM AUTHOR]

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[18F]FDF will specifically image microglia following neuroinflammatory insult. 6-[18F]FDF and, for comparison, [18F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo. In LPS-injected rats, increased accumulation of 6-[18F]FDF was observed at 48 h post-LPS injection, with plateaued uptake (60–120 min) that was significantly higher in the ipsilateral vs. contralateral striatum (0.985 ± 0.047 and 0.819 ± 0.033 SUV, respectively; p = 0.002, n = 4M/3F). The ipsilateral–contralateral difference in striatal 6-[18F]FDF uptake expressed as binding potential (BPSRTM) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [18F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (BPSRTM = 0.25 ± 0.06, n = 4M). Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes, respectively, in ipsilateral striatum. This proof-of-concept study revealed an early response of 6-[18F]FDF to neuroinflammatory stimuli in rat brain. 6-[18F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the CNS. Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. Human autopsied CNS tissues (male and female), human cell cultures, and cuprizonemediated demyelination mice (female) were examined by RT-PCR, Western blotting, and immunolabeling. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo. White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared with non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-a-exposed microglia displayed reduced immunolabeling of peroxisomal proteins, PMP70 and PEX11β, which was prevented with 4-PBA. In human myeloid cells exposed to TNF-a or nigericin, suppression of PEX11β and catalase protein levels were observed to be dependent on NLRP3 expression. Hindbrains from cuprizoneexposed mice showed reduced Abcd1, Cat, and Pex5l transcript levels, with concurrent increased Nlrp3 and Il1b transcript levels, which was abrogated by 4-PBA. In the central corpus callosum, Iba-1 in CNS-associated macrophages and peroxisomal thiolase immunostaining after cuprizone exposure was increased by 4-PBA. 4-PBA prevented decreased myelin basic protein and neurofilament heavy chain immunoreactivity caused by cuprizone exposure. Cuprizone-induced neurobehavioral deficits were improved by 4-PBA treatment. Peroxisome injury in CNS-associated macrophages contributed to neuroinflammation and demyelination that was prevented by 4-PBA treatment. A peroxisome-targeted therapy might be valuable for treating inflammatory demyelination and neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

• Nine novel pyridinyl amide derivatives. • Amide location and spacer role critical for activity. • Compound 3 demonstrated good antiproliferative activity against K562 and HepG2 cells. • Molecular docking reveals targeted mechanism of action with bcr/abl tyrosine, EGFR, HER2. • Notable cancer cell selectivity over normal cells and low cytotoxicity towards HDFa. A novel series of secondary pyridinyl amides, reinforced with the methylsulfonyl pharmacophore unit, was designed and synthesized. Further, we determined the antiproliferative activities of these compounds through experimental assays and analyzed their interactions with Breakpoint Cluster Region/Abelson (bcr/abl), Epidermal Growth Factor Receptor (EGFR), and Human Epidermal Growth Factor Receptor 2 (HER2) tyrosine kinases using molecular autodocking techniques. We grouped these amides into three categories, classified by the type of spacer that binds the pyridine ring to the amide nitrogen atom. Additionally, within each group, we strategically positioned the amide moiety at the ortho, meta , or para position on the pyridyl ring. Among the studied amides, compound 3 exhibited the best overall antiproliferative activity against human immortalized myelogenous leukemia (K562) (IC 50 = 26 µM), human leukemia monocytic cell line (THP-1) (IC 50 = 81 µM), and human hepatocellular carcinoma (HepG2) (IC 50 = 210 µM). Molecular docking studies revealed that compound 3 binds effectively to bcr/abl, EGFR, and HER2 tyrosine kinases, demonstrating strong interactions with crucial active site amino acids, indicative of its targeted antiproliferative mechanism. All investigated compounds showed either very minor or no cytotoxicity against human dermal fibroblast adult cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Tissue hypoxia is a pathological condition characterized by reducing oxygen supply. Hypoxia is a hallmark of tumor environment and is commonly observed in many solid tumors. Non-invasive imaging techniques like positron emission tomography (PET) are at the forefront of detecting and monitoring tissue hypoxia changes in vivo. Results: We have developed a novel 18F-labeled radiotracer for hypoxia PET imaging based on cytotoxic agent benznidazole. Radiotracer N-(4-[18F]fluorobenzyl)-2-(2-nitro-1H-imidazol-1-yl)acetamide ([18F]FBNA) was synthesized through acylation chemistry with readily available 4-[18F]fluorobenzyl amine. Radiotracer [18F]FBNA was obtained in good radiochemical yields (47.4 ± 5.3%) and high radiochemical purity (> 95%). The total synthesis time was 100 min, including HPLC purification and the molar activity was greater than 40 GBq/µmol. Radiotracer [18F]FBNA was stable in saline and mouse serum for 6 h. [18F]FBNA partition coefficient (logP = 1.05) was found to be more lipophilic than [18F]EF-5 (logP = 0.75), [18F]FMISO (logP = 0.4) and [18F]FAZA (logP = − 0.4). In vitro studies showed that [18F]FBNA accumulates in gastric cancer cell lines AGS and MKN45 under hypoxic conditions. Conclusions: Hence, [18F]FBNA represents a novel and easy-to-prepare PET radioligand for imaging hypoxia. [ABSTRACT FROM AUTHOR]

Deregulation and changes in energy metabolism are emergent and important biomarkers of cancer cells. The uptake of hexoses in cancer cells is mediated by a family of facilitative hexose membrane-transporter proteins known as Glucose Transporters (GLUTs). In the clinic, numerous breast cancers do not show elevated glucose metabolism (which is mediated mainly through the GLUT1 transporter) and may use fructose as an alternative energy source. The principal fructose transporter in most cancer cells is GLUT5, and its mRNA was shown to be elevated in human breast cancer. This offers an alternative strategy for early detection using fructose analogs. In order to selectively scout GLUT5 binding-pocket requirements, we designed, synthesized and screened a new class of fructose mimics based upon the 2,5-anhydromannitol scaffold. Several of these compounds display low millimolar IC50 values against the known high-affinity 18F-labeled fructose-based probe 6-deoxy-6-fluoro-D-fructose (6-FDF) in murine EMT6 breast cancer cells. In addition, this work used molecular docking and molecular dynamics simulations (MD) with previously reported GLUT5 structures to gain better insight into hexose–GLUT interactions with selected ligands governing their preference for GLUT5 compared to other GLUTs. The improved inhibition of these compounds, and the refined model for their binding, set the stage for the development of high-affinity molecular imaging probes targeting cancers that express the GLUT5 biomarker. [ABSTRACT FROM AUTHOR]

Copper-64 (64Cu, t 1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy. 64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg 68Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T. Maximum purified activity of 4.9 GBq [64Cu]CuCl 2 was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl 2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUV mean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUV mean of 0.76 ± 0.14 after 60 min post-injection. 64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction. Our 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Tumour hypoxia is associated with increased metastasis, invasion, poor therapy response and prognosis. Most PET radiotracers developed and used for clinical hypoxia imaging belong to the 2-nitroimidazole family. Recently we have developed novel 2-nitroimidazole-derived PET radiotracer [18F]FBNA (N -(4-[18F]fluoro-benzyl)-2-(2-nitro-1 H -imidazol-1-yl)-acet-amide), an 18F-labeled analogue of antiparasitic drug benznidazole. The present study aimed to analyze its radio-pharmacological properties and systematically compare its PET imaging profiles with [18F]FMISO and [18F]FAZA in preclinical triple-negative (MDA-MB231) and estrogen receptor-positive (MCF-7) breast cancer models. In vitro cellular uptake experiments were carried out in MDA-MB321 and MCF-7 cells under normoxic and hypoxic conditions. Metabolic stability in vivo was determined in BALB/c mice using radio-TLC analysis. Dynamic PET experiments over 3 h post-injection were performed in MDA-MB231 and MCF-7 tumour-bearing mice. Those PET data were used for kinetic modelling analysis utilizing the reversible two-tissue-compartment model. Autoradiography was carried out in tumour tissue slices and compared to HIF-1α immunohistochemistry. Detailed ex vivo biodistribution was accomplished in BALB/c mice, and this biodistribution data were used for dosimetry calculation. Under hypoxic conditions in vitro cellular uptake was elevated in both cell lines, MCF-7 and MDA-MB231, for all three radiotracers. After intravenous injection, [18F]FBNA formed two radiometabolites, resulting in a final fraction of 65 ± 9 % intact [18F]FBNA after 60 min p.i. After 3 h p.i., [18F]FBNA tumour uptake reached SUV values of 0.78 ± 0.01 in MCF-7 and 0.61 ± 0.04 in MDA-MB231 tumours (both n = 3), representing tumour-to-muscle ratios of 2.19 ± 0.04 and 1.98 ± 0.15, respectively. [18F]FMISO resulted in higher tumour uptakes (SUV 1.36 ± 0.04 in MCF-7 and 1.23 ± 0.08 in MDA-MB231 (both n = 4; p < 0.05) than [18F]FAZA (0.66 ± 0.11 in MCF-7 and 0.63 ± 0.14 in MDA-MB231 (both n = 4; n.s.)), representing tumour-to-muscle ratios of 3.24 ± 0.30 and 3.32 ± 0.50 for [18F]FMISO, and 2.92 ± 0.74 and 3.00 ± 0.42 for [18F]FAZA, respectively. While the fraction per time of radiotracer entering the second compartment (k3) was similar within uncertainties for all three radiotracers in MDA-MB231 tumours, it was different in MCF-7 tumours. The ratios k3/(k3 + k2) and K1*k3/(k3 + k2) in MCF-7 tumours were also significantly different, indicating dissimilar fractions of radiotracer bound and trapped intracellularly: K1*k3/(k2 + k3) [18F]FMISO (0.0088 ± 0.001)/min, n = 4; p < 0.001) > [18F]FAZA (0.0052 ± 0.002)/min, n = 4; p < 0.01) > [18F]FBNA (0.003 ± 0.001)/min, n = 3). In contrast, in MDA-MB231 tumours, only K1 was significantly elevated for [18F]FMISO. However, this did not result in significant differences for K1*k3/(k2 + k3) for all three 2-nitroimidazoles in MDA-MB231 tumours. Novel 2-nitroimidazole PET radiotracer [18F]FBNA showed uptake into hypoxic breast cancer cells and tumour tissue presumably associated with elevated HIF1-α expression. Systematic comparison of PET imaging performance with [18F]FMISO and [18F]FAZA in different types of preclinical breast cancer models revealed a similar tumour uptake profile for [18F]FBNA with [18F]FAZA and, despite its higher lipophilicity, still a slightly higher muscle tissue clearance compared to [18F]FMISO. [Display omitted] [ABSTRACT FROM AUTHOR]

Radioligand [18F]ONO-8430506 ([18F]8) was prepared and tested as a novel autotaxin (ATX) PET imaging agent derived from highly potent ATX inhibitor ONO-8430506. [Display omitted] We have prepared and tested radioligand [18F]ONO-8430506 ([18F]8) as a novel ATX PET imaging agent derived from highly potent ATX inhibitor ONO-8430506. Radioligand [18F]8 could be prepared in good and reproducible radiochemical yields of 35 ± 5% (n = 6) using late-stage radiofluorination chemistry. ATX binding analysis showed that 9-benzyl tetrahydro- b -carboline 8 has about five times better inhibitory potency than clinical candidate GLPG1690 and somewhat less inhibitory potency than ATX inhibitor PRIMATX. The binding mode for compound 8 inside the catalytic pocket of ATX using computational modelling and docking protocols revealed that compound 8 resembled a comparable binding mode to that of ATX inhibitor GLPG1690. However, PET imaging studies with radioligand [18F]8 showed only relatively low tumour uptake and retention (SUV 60min 0.21 ± 0.03) in the tested 8305C human thyroid tumour model reaching a tumour-to-muscle ratio of ∼ 2.2 after 60 min. [ABSTRACT FROM AUTHOR]

203Pb (t 1/2 = 51.9 h, 279 keV (81 %)) is a diagnostic SPECT imaging radionuclide ideally suited for theranostic applications in combination with 212Pb for targeted alpha particle therapy. Our objectives were to develop a high-yield solid target 203Pb cyclotron production route using isotopically enriched 205Tl target material and the 205Tl(p,3n)203Pb reaction as an alternative to lower energy production via the 203Tl(p,n)203Pb reaction. 250 mg 205Tl metal (99.9 % isotopic enrichment) was pressed using a hardened stainless steel die. Aluminum target discs were machined with a central depression and annulus groove. The flattened 205Tl pellet was placed into the central depression of the Al disc and a circle of indium wire was laid in the machined annulus surrounding the pellet. An aluminum foil cover was then pressed onto the target disc to create an airtight bond. Targets were irradiated at 23.3 MeV for up to 516 min on a TR-24 cyclotron at currents up to 60 μA to produce 203Pb via the 205Tl(p,3n)203Pb nuclear reaction. Following a cool-down period of >12 h, the target was removed and 205Tl dissolved in 4 M HNO 3. A NEPTIS Mosaic-LC synthesis unit performed automated separation using Eichrom Pb resin, and 203Pb was eluted using 8 M HCl or 1 M NH 4 OAc. 205Tl was diverted to a vial for recovery in an electrolytic cell. 203Pb product radionuclidic purity was assessed by HPGe gamma spectroscopy, while elemental purity was assessed by ICP-OES. Radiolabeling and stability studies were performed with PSC, TCMC, and DOTA chelators, and 203Pb incorporation was verified by radio-TLC analysis. Cyclotron irradiations performed at 60 μA proton beam current and 23.3 MeV (205Tl incident energy) had a 203Pb saturated yield of 4658 ± 62 MBq/μA (n = 3). Automated NEPTIS separation took <4 h from the start of target dissolution to product elution, yielding >85 % decay-corrected [203Pb]PbCl 2 with a radionuclidic purity of >99.9 %. Purified [203Pb]PbCl 2 yields of up to 12 GBq 203Pb were attained (15.8 GBq at EOB). The [203Pb]PbCl 2 and [203Pb]Pb(OAc) 2 products contained no detectable radionuclidic impurities besides 201Pb (<0.1 %), and <0.4 ppm stable Pb. 205Tl metal was recovered with a 92 % batch yield. Aliquots of 100 μL [203Pb]Pb(OAc) 2 were used for radiolabeling PSC-Bn-NCS, TCMC-NCS, and DOTA-NCS chelators at pH 4.5 and 22 °C for 30 min, with maximum respective molar activities of 461 ± 30 GBq/μmol, 195 ± 37 GBq/μmol, and 83 ± 12 GBq/μmol. PSC, TCMC, and DOTA chelators exhibited >99.9 % incorporation after a 120-hour incubation in human serum at 37 °C. Nuclear medicine centers with access to higher energy cyclotrons can produce large 203Pb activities sufficient for clinical applications, with a convenient separation technique producing highly pure [203Pb]PbCl 2 or [203Pb]Pb(OAc) 2 for direct radiolabeling. This represents an attractive route to produce 203Pb for diagnostic SPECT imaging alongside 212Pb targeted alpha particle therapy. Our high-yield 203Pb production technique significantly enhances 203Pb production capabilities to meet the growing preclinical and clinical demand for 203Pb radiopharmaceuticals alongside 212Pb target alpha particle therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel series of 1,5-disubstituted tetrazoles were designed and synthesized. • In vitro bioassay data of the novel azoles as COX-1/COX-2 inhibitors were shown. • In vitro antiproliferative data were described. • Selected probes were docked in COX-1, COX-2, and bcr/abl kinase enzymes. • The structural modifications improved the biological activities of the new probes. A unique class of 1,5-disubstituted tetrazoles was designed and synthesized, and their biological activities as cyclooxygenase (COX) inhibitors and anti-cancer agents were determined experimentally and assessed with molecular docking studies for two isoenzymes COX-1 and COX-2, as well as oncogenic tyrosine kinase bcr/abl enzymes. The structural modifications of this study comprised five different substitutions at the hydroxy group of our model compound 1. All new compounds showed an enhanced inhibition potency toward COX-2 enzyme with no significant inhibition toward COX-1 enzyme. Tetrazole 4 showed not only the highest desirable inhibition potency for both COX-2 enzyme (IC 50 = 0.086 µM,) and COX-1 isoenzyme (IC 50 = 61 µM), but also the best selectivity for COX-2 enzyme (SI = 714). Azoles 2, 3 , and 5 showed a moderate activity against the human breast cancer cell line (MCF-7; IC 50 = 40.68 µM, 70.71 µM, and 13.52 µM, respectively), while among the studied compounds only azole 5 showed anti-cancer activity against the human immortalized myelogenous leukemia (K562), (IC 50 = 26.88 µM). All investigated compounds displayed no cytotoxicity for the HDFa (Human Dermal Fibroblasts Adult) cell lines (IC 50 = >100 µM). [Display omitted] [ABSTRACT FROM AUTHOR]