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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]

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]

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]

Neuroimaging assessment of motor neuron disease has turned into a cornerstone of its clinical workup. Amyotrophic lateral sclerosis (ALS), as a paradigmatic motor neuron disease, has been extensively studied by advanced neuroimaging methods, including molecular imaging by MRI and PET, furthering finer and more specific details of the cascade of ALS neurodegeneration and symptoms, facilitated by multicentric studies implementing novel methodologies. With an increase in multimodal neuroimaging data on ALS and an exponential improvement in neuroimaging technology, the need for harmonization of protocols and integration of their respective findings into a consistent model becomes mandatory. Integration of multimodal data into a model of a continuing cascade of functional loss also calls for the best attempt to correlate the different molecular imaging measurements as performed at the shortest inter-modality time intervals possible. As outlined in this perspective article, simultaneous PET/MRI, nowadays available at many neuroimaging research sites, offers the perspective of a one-stop shop for reproducible imaging biomarkers on neuronal damage and has the potential to become the new gold standard for characterizing motor neuron disease from the clinico-radiological and neuroscientific perspectives. [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]

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]

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]

Molecular imaging using PET/CT or PET/MRI has evolved from an experimental imaging modality at its inception in 1972 to an integral component of diagnostic procedures in oncology, and, to lesser extent, in cardiology and neurology, by successfully offering in-vivo imaging and quantitation of key pathophysiological targets or molecular signatures, such as glucose metabolism in cancerous disease. Apart from metabolism probes, novel radiolabeled peptide and antibody PET tracers, including radiolabeled monoclonal antibodies (mAbs) have entered the clinical arena, providing the in-vivo capability to collect target-specific quantitative in-vivo data on cellular and molecular pathomechanisms on a whole-body scale, and eventually, extract imaging biomarkers possibly serving as prognostic indicators. The success of molecular imaging in mapping disease severity on a whole-body scale, and directing targeted therapies in oncology possibly could translate to the management of Coronavirus Disease 2019 (COVID-19), by identifying, localizing, and quantifying involvement of different immune mediated responses to the infection with SARS-COV2 during the course of acute infection and possible, chronic courses with long-term effects on specific organs. The authors summarize current knowledge for medical imaging in COVID-19 in general with a focus on molecular imaging technology and provide a perspective for immunologists interested in molecular imaging research using validated and immediately available molecular probes, as well as possible future targets, highlighting key targets for tailored treatment approaches as brought up by key opinion leaders. [ABSTRACT FROM AUTHOR]

The butyric acid scaffold is the base structure of several human metabolites that serve diverse and prominent biochemical roles including as oxidative sources of cellular energy and as substrates for biosynthesis. Derivatization of metabolites through incorporation of fluorine often alters bioactivity and can facilitate detection and analysis by nuclear magnetic resonance or positron emission tomography depending upon the fluorine isotope employed. We describe the synthesis of two new fluorinated butyric acids (and three related esters) that are derivatives of the metabolites acetoacetic acid and 3-hydroxybutyric acid. 4-Fluoro-3-hydroxybutyric acid is prepared from epoxy ester precursors via ring opening by triethylamine trihydrofluoride. 2-Fluoroacetoacetic acid is prepared by electrophilic fluorination of an acid-labile β-keto ester. The gradual pH-dependent decarboxylation of 2-fluoroacetoacetic acid is investigated by19 F NMR spectroscopy. [ABSTRACT FROM AUTHOR]

Purpose: Prostate-specific membrane antigen (PSMA) is an important biomarker expressed in the majority of prostate cancers. The favorable positron emission tomography (PET) imaging profile of the PSMA imaging agent 2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentane-dioic acid [18F]DCFPyL in preclinical prostate cancer models and in prostate cancer patients stimulated the development and validation of other fluorine-containing PSMA inhibitors to further enhance pharmacokinetics and simplify production methods. Here, we describe the synthesis and radiopharmacological evaluation of various F-18-labeled PSMA inhibitors which were prepared through different prosthetic group chemistry strategies.Procedures: Prosthetic groups N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB), 4-[18F]fluorobenzaldehyde, and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) were used for bioconjugation reactions to PSMA-binding lysine-urea-glutamate scaffold via acylation and oxime formation. All fluorine-containing PSMA inhibitors were tested for their PSMA inhibitory potency in an in vitro competitive binding assay in comparison to an established reference compound [125I]TAAG-PSMA. Tumor uptake and clearance profiles of three F-18-labeled PSMA inhibitors ([18F]4, [18F]7, and [18F]8) were studied with dynamic PET imaging using LNCaP tumor-bearing mice.Results: F-18-labeled PSMA inhibitors were synthesized in 32-69 % radiochemical yields using (1) acylation reaction at the primary amino group of the lysine residue with [18F]SFB and (2) oxime formation with 4-[18F]fluorobenzaldehyde and [18F]FDG using the respective aminooxy-functionalized lysine residue. Compound 7 displayed an IC50 value of 6 nM reflecting very high affinity for PSMA. Compounds 4 and 8 showed IC50 values of 13 and 62 nM, respectively. The IC50 value of reference compound DCFPyL was 13 nM. Dynamic PET imaging revealed the following SUV60min for radiotracer uptake in PSMA(+) LNCaP tumors: 0.98 ([18F]DCFPyL), 2.11 ([18F]7), 0.40 ([18F]4), and 0.19 ([18F]8).Conclusion: The observed tumor uptake and clearance profiles demonstrate the importance of the selected prosthetic group on the pharmacokinetic profile of analyzed PSMA-targeting radiotracers. Radiotracer [18F]7 displayed the highest uptake and retention in LNCaP tumors, which exceeded uptake values of reference compound [18F]DCFPyL by more than 100 %. Despite the higher kidney and liver uptake and retention of compound [18F]7, the simple radiosynthesis and the exceptionally high tumor uptake (SUV60min 2.11) and retention make radiotracer [18F]7 an interesting alternative to radiotracer [18F]DCFPyL for PET imaging of PSMA in prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific membrane antigen (PSMA) is frequently overexpressed and upregulated in prostate cancer. To date, various F- and Ga-labeled urea-based radiotracers for PET imaging of PSMA have been developed and entered clinical trials. Here, we describe an automated synthesis of [F]DCFPyL via direct radiofluorination and validation in preclinical models of prostate cancer. Methods: [F]DCFPyL was synthesized via direct nucleophilic heteroaromatic substitution reaction in a single reactor TRACERlab FX automated synthesis unit. Radiopharmacological evaluation of [F]DCFPyL involved internalization experiments, dynamic PET imaging in LNCaP (PSMA+) and PC3 (PSMA−) tumor-bearing BALB/c nude mice, biodistribution studies, and metabolic profiling. In addition, reversible two-tissue compartmental model analysis was used to quantify pharmacokinetics of [F]DCFPyL in LNCaP and PC3 tumor models. Results: Automated radiosynthesis afforded radiotracer [F]DCFPyL in decay-corrected radiochemical yields of 23 ± 5 % ( n = 10) within 55 min, including HPLC purification. Dynamic PET analysis revealed rapid and high uptake of radioactivity (SUV 0.95) in LNCaP tumors which increased over time (SUV 1.1). Radioactivity uptake in LNCaP tumors was blocked in the presence of nonradioactive DCFPyL (SUV 0.22). The muscle as reference tissue showed rapid and continuous clearance over time (SUV 0.06). Fast blood clearance of radioactivity resulted in tumor-blood ratios of 1.0 after 10 min and 8.3 after 60 min. PC3 tumors also showed continuous clearance of radioactivity over time (SUV 0.11). Kinetic analysis of PET data revealed the two-tissue compartmental model as best fit with K = 0.12, k = 0.18, k = 0.08, and k = 0.004 min, confirming molecular trapping of [F]DCFPyL in PSMA+ LNCaP cells. Conclusions: [F]DCFPyL can be prepared for clinical applications simply and in good radiochemical yields via a direct radiofluorination synthesis route in a single reactor automated synthesis unit. Radiopharmacological evaluation of [F]DCFPyL confirmed high PSMA-mediated tumor uptake combined with superior clearance parameters. Compartmental model analysis points to a two-step molecular trapping mechanism based on PSMA binding and subsequent internalization leading to retention of radioactivity in PSMA+ LNCaP tumors. [ABSTRACT FROM AUTHOR]

Background: Cyclooxygenase-2 (COX-2) is the inducible isoform of the cyclooxygenase enzyme family. COX-2 is involved in tumor development and progression, and frequent overexpression of COX-2 in a variety of human cancers has made COX-2 an important drug target for cancer treatment. Non-invasive imaging of COX-2 expression in cancer would be useful for assessing COX-2-mediated effects on chemoprevention and radiosensitization using COX-2 inhibitors as an emerging class of anti-cancer drugs, especially for colorectal cancer. Herein, we describe the radiopharmacological analysis of [F]Pyricoxib, a novel radiolabeled COX-2 inhibitor, for specific PET imaging of COX-2 in colorectal cancer. Methods: Uptake of [F]Pyricoxib was assessed in human colorectal cancer cell lines HCA-7 (COX-2 positive) and HCT-116 (COX-2 negative). Standard COX-2 inhibitors were used to test for specificity of [F]Pyricoxib for COX-2 binding in vitro and in vivo. PET imaging, biodistribution, and radiometabolite analyses were included into radiopharmacological evaluation of [F]Pyricoxib. Results: Radiotracer uptake in COX-2 positive HCA-7 cells was significantly higher than in COX-2 negative HCT-116 cells ( P < 0.05). COX-2 inhibitors, celecoxib, rofecoxib, and SC58125, blocked uptake of [F]Pyricoxib in HCA-7 cells in a concentration-dependent manner. The radiotracer was slowly metabolized in mice, with approximately 60 % of intact compound after 2 h post-injection. Selective COX-2-mediated tumor uptake of [F]Pyricoxib in HCA-7 xenografts was confirmed in vivo. Celecoxib (100 mg/kg) selectively blocked tumor uptake by 16 % (PET image analysis; P < 0.05) and by 51 % (biodistribution studies; P < 0.01). Conclusions: The novel PET radiotracer [F]Pyricoxib displays a promising radiopharmacological profile to study COX-2 expression in cancer in vivo. [ABSTRACT FROM AUTHOR]

The study describes the Sonogashira cross-coupling reaction with 4-[18F]fluoroiodobenzene ([18F]FIB) as novel and efficient method for rapid labelling of peptides with the short-lived positron emitter fluorine-18. [ABSTRACT FROM AUTHOR]

The radiometal 64Cu is now widely used in the development of diagnostic imaging agents for positron emission tomography (PET). The present study has led to the development and evaluation of a novel chelating agent for 64Cu: the new monothiourea tripodal ligand 1-benzoyl-3-{6-[(bis-pyridin-2-ylmethyl-amino)-methyl]-pyridin-2-yl}-thiourea (MTUBo). X-ray crystallographic analysis has shown this ligand forms a mononuclear complex with copper(ii) and co-ordinates via a trigonal bipyramidal N4S array of donor atoms. Promisingly, cell uptake studies revealed that 64Cu-MTUBo selectively accumulates in EMT-6 cells incubated under hypoxic conditions which may result from its relatively high CuII/I redox potential. Small-animal PET imaging and ex vivo biodistribution studies in EMT-6 tumor bearing BALB/c mice revealed significant tumor uptake after 1 h p.i., yielding tumor-to-muscle (T/M) and tumor-to-blood (T/B) ratios of 8.1 and 1.1, respectively. However, injection of 64Cu-acetate resulted in similar uptake indicating that the observed uptake was most likely non-specific. Despite showing high in vitro stability, it is likely that in vivo the complex undergoes transchelation to proteins within the blood in a relatively short timeframe. For comparison, the hypoxia imaging agent 64Cu-ATSM was also evaluated in the same murine tumor model and showed about 60% higher tumor uptake than 64Cu-MTUBo. [ABSTRACT FROM AUTHOR]

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]

The use of radiopharmaceuticals for molecular imaging of biochemical and physiological processes in vivo has evolved into an important diagnostic tool in modern nuclear medicine and medical research. Positron emission tomography (PET) is currently the most sophisticated molecular imaging methodology, mainly due to the unrivalled high sensitivity which allows for the studying of biochemistry in vivo on the molecular level. The most frequently used radionuclides for PET have relatively short half-lives (e.g. 11C: 20.4 min; 18F: 109.8 min) which may limit both the synthesis procedures and the time frame of PET studies. Iodine-124 (124I, t1/2 = 4.2 d) is an alternative long-lived PET radionuclide attracting increasing interest for long term clinical and small animal PET studies. The present review gives a survey on the use of 124I as promising PET radionuclide for molecular imaging. The first part describes the production of 124I. The second part covers basic radiochemistry with 124I focused on the synthesis of 124I-labeled compounds for molecular imaging purposes. The review concludes with a summary and an outlook on the future prospective of using the long-lived positron emitter 124I in the field of organic PET chemistry and molecular imaging. [ABSTRACT FROM AUTHOR]

Abstract: The radiosynthesis of [N-methyl-11C]Org 34850 as a potential brain glucocorticoid receptor (GR)-binding radiotracer is described. The radiosynthesis was accomplished via N-methylation of the corresponding desmethyl precursor with [11C]methyl triflate in a remotely controlled synthesis module to give the desired compound in a radiochemical yield of 23±5% (decay-corrected, based upon [11C]CO2) at a specific activity of 47±12GBq/μmol (n=15) at the end-of-synthesis (EOS). The radiochemical purity after semi-preparative HPLC purification exceeded 95%. The total synthesis time was 35–40min after end-of-bombardment (EOB). The radiotracer is rapidly metabolized in rat plasma leading to the formation of two more hydrophilic metabolites as the major metabolites. Radiopharmacological evaluation involving biodistribution and small animal PET imaging in normal Wistar rats showed that the compound [N-methyl-11C]Org 34850 is not able to sufficiently penetrate the blood–brain barrier. Therefore, compound [N-methyl-11C]Org 34850 seems not to be a suitable PET radiotracer for imaging rat brain GRs. However, involvement of Pgp or species differences requires further clarification to establish whether the radiotracer [N-methyl-11C]Org 34850 may still represent a suitable candidate for imaging GRs in humans. [Copyright &y& Elsevier]

The cyclin-dependent kinase (Cdk)-cyclin D/retinoblastoma (pRb)/E2F cascade, which controls the G1/S transition of cell cycle, has been found to be altered in many neoplasias. Inhibition of this pathway by using, for example, selective Cdk4 inhibitors has been suggested to be a promising approach for cancer therapy. We hypothesized that appropriately radiolabeled Cdk4 inhibitors are suitable probes for tumor imaging and may be helpful studying cell proliferation processes in vivo by positron emission tomography. Herein, we report the synthesis and biological, biochemical, and radiopharmacological characterizations of two 124I-labeled small molecule Cdk4 inhibitors (8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]-pyrimidin-7-one (CKIA) and 8-cyclopentyl-6-iodo-5-methyl-2-(5-(piperazin-1-yl)-pyridin-2- yl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one (CKIB)). Our data demonstrate a defined and specific inhibition of tumor cell proliferation through CKIA and CKIB by inhibition of the Cdk4/pRb/E2F pathway emphasizing potential therapeutic benefit of CKIA and CKIB. Furthermore, radiopharmacological properties of [124I]CKIA and [124I]CKIB observed in human tumor cells are promising prerequisites for in vivo biodistribution and imaging studies. [ABSTRACT FROM AUTHOR]

Abstract: The radiosynthesis and radiopharmacological evaluation of 1-[11C]methoxy-4-(2-(4-(methanesulfonyl)phenyl)cyclopent-1-enyl)-benzene [ 11 C]5 as novel PET radiotracer for imaging of COX-2 expression is described. The radiotracer was prepared via O-methylation reaction with [11C]methyl iodide in 19% decay-corrected radiochemical yield at a specific activity of 20–25GBq/μmol at the end-of-synthesis within 35min. The radiotracer [ 11 C]5 was evaluated in vitro using various pro-inflammatory and tumor cell lines showing high functional expression of COX-2 at baseline or after induction. In vivo biodistribution of compound [ 11 C]5 was characterized in male Wistar rats. Compound [ 11 C]5 was rapidly metabolized in rat plasma, and more pronounced, in mouse plasma. In vivo kinetics and tumor uptake were demonstrated by dynamic small animal PET studies in a mouse tumor xenograft model. Tumor uptake of radioactivity was clearly visible overtime. However, radioactivity uptake in the tumor could not be blocked by the pre-injection of nonradioactive compound 5. Therefore, it can be concluded that radioactivity uptake in the tumor was not COX-2 mediated. [Copyright &y& Elsevier]

Abstract: The radiosynthesis and the radiopharmacological characterization of [ 11 C]AL-438 as a nonsteroidal ligand for the glucocorticoid receptor (GR) is described. Radiolabeling of the corresponding desmethyl precursor 10 with [11C]MeI gave [ 11 C]AL-438 in decay-corrected radiochemical yields of 30±4% (based upon [11C]CO2) within 35min at a specific radioactivity of 10–15GBq/μmol at the end-of-synthesis. The radiopharmacological evaluation of [ 11 C]AL-438 involved biodistribution and small animal PET imaging in rats, and autoradiography studies using rat brain sections. Biodistribution studies were performed in male Wistar rats and demonstrated high radioactivity uptake in pituitary and brain. However, the inability of high dose corticosterone to block binding would suggest that the radioactivity accumulation in the brain was not receptor-mediated. [Copyright &y& Elsevier]

Abstract: The novel thiol-group-selective bifunctional 18F-labeling agent N-[6-(4-[18F]fluoro-benzylidene)aminooxyhexyl]maleimide ([18F]FBAM) has been developed. The bifunctional labeling precursor N-(6-aminoxyhexyl)maleimide containing a thiol-reactive maleimide group and a carbonyl-group-reactive aminooxy group was prepared in only three steps in a total chemical yield of 59%. Subsequent radiolabeling with 4-[18F]fluorobenzaldehyde gave the bifunctional 18F-labeling agent [18F]FBAM in a radiochemical yield of 29%. In a typical experiment, 3.88 GBq of [18F]fluoride could be converted into 723 MBq of [18F]FBAM within 69 min. Conjugation of [18F]FBAM with thiol groups was exemplified with the cystein-containing tripeptide glutathione and with various apolipoproteins of human low-density lipoprotein (LDL) subfractions. The latter was evaluated with respect to the uptake of [18F]FBAM-LDL subfractions in human hepatoma cells (HepG2) in vitro. In vivo biodistribution studies in rats revealed high stability for [18F]FBAM-LDL subfractions. Moreover, the metabolic fate of [18F]FBAM-LDL subfractions in vivo was delineated by dynamic positron emission tomography studies using a dedicated small animal tomograph. Data were compared to former studies that used the NH2-reactive 18F-labeling agent N-succinimidyl-4-[18F]fluorobenzoate. The compound [18F]FBAM can be considered as an excellent prosthetic group for the selective and mild 18F labeling of thiol-group-containing biomolecules suitable for subsequent investigations in vitro and in vivo. [Copyright &y& Elsevier]

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]

Gallium-68 is an important radionuclide for positron emission tomography (PET) with steadily increasing applications of 68Ga-based radiopharmaceuticals for clinical use. Current 68Ga sources are primarily 68Ge/68Ga-generators, along with successful attempts of 68Ga production using a cyclotron. This study evaluated cyclotron 68Ga production and automated separation using expeditiously manufactured solid targets, demonstrates an order of magnitude improvement in yield compared to 68Ge/68Ga generators, and presents a convenient alternative to existing cyclotron production processes. A comparison of radiolabeling and preclinical PET imaging was performed with both cyclotron and generator produced 68Ga. 100 mg enriched 68Zn (99.3% 68Zn, 0.48% 67Zn, 0.1% 66Zn) pellets pressed on silver discs were bombarded for 20–75 min using 12.5 MeV proton beam energies and 10–30 μA currents. 68Ga was separated using an automated TRASIS AllinOne synthesizer employing AG 50W-X8 and UTEVA resins. Post-separation recovery of the 68Zn by electrolysis yielded 76.7 ± 4.3%. Radionuclidic purity of cyclotron-produced 68Ga was investigated with gamma spectroscopy using a HPGe-detector. Radiolabeling was investigated using the macrocyclic chelator DOTA and the bombesin-derived peptide NOTA-BBN2. PET imaging was performed using [68Ga]Ga-NOTA-BBN2 in a PC3 xenograft model. 600 μA·min fresh and recycled quadruplet 68Zn target irradiations (n = 8) at 12.5 MeV and 30 μA yielded 13.9 ± 1.0 GBq 68Ga; 2200 μA·min irradiations (n = 3) yielded 37.5 ± 1.9 GBq 68Ga. HPGe analysis showed EOB 0.0074% and 0.0084% of total activity of 66Ga and 67Ga, respectively. Metal impurities were 0.06 ± 0.03 μg/GBq Zn, 0.13 ± 0.007 μg/GBq Fe, and 0.02 ± 0.01 μg/GBq Al for cyclotron 68Ga. Cyclotron and 68Ge/68Ga generator 68Ga respective DOTA and NOTA-BBN2 labeling incorporations were 99.4 ± 0.0% and 99.3 ± 0.2%, and 90.4 ± 1.5% and 93.0 ± 3.6% determined by radio-thin layer chromatography (radio-TLC). Preclinical PET imaging comparison between generator and cyclotron produced 68Ga showed identical radiotracer tumor uptake and biodistribution profiles in PC3 tumor bearing mice. Cyclotron 68Ga production provides highly scalable production with equivalent or superior quality 68Ga to a 68Ge/68Ga generator, while providing identical biodistribution and tumor uptake profiles. Our described targetry is simpler and more cost-effective than existing liquid and solid targetry, enabling a turnkey production system for multi-facility distribution of cyclotron produced 68Ga. The manufacturing simplicity described has potential applications for producing other radiometals such as 44Sc. Our cost-effective method of solid target 68Ga production can enhance 68Ga production capabilities to meet the high demand for 68Ga-radiopharmaceuticals for research and clinical use. [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]

Elevated growth in breast cancer (BC) activates hypoxia-inducible factor (HIF1α) and downstream, facilitative glucose transporter 1 (GLUT1), which can be visualized with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). GLUT5 (fructose) and GLUT2 (glucose/fructose) might provide alternative targets for BC imaging as to why effects of hypoxia on GLUT1/2/5 levels and function were examined in human BC models. GLUT1/2/5 and HIF1α mRNA was analyzed in BC patient biopsies. In MCF10A, MCF7, and MDA-MB231 cells, [18F]FDG, 6-deoxy-6-[18F]fluoro-d-fructose (6-[18F]FDF) and [18F]-fluoroazomycin arabinoside were used in radiotracer experiments, whereas GLUT1/2/5 mRNA was analyzed with real-time PCR and protein levels determined via Western blot/immunohistochemistry. Positron emission tomography imaging was performed in MCF7 and MDA-MB231 tumor-bearing mice. Glucose/fructose/cytochalasin B reduced cellular 6-[18F]FDF uptake by 50%, indicating functional involvement of GLUT2. With GLUT5 staining lower than GLUT1, 6-[18F]FDF revealed lower uptake than [18F]FDG [standardized uptake value (SUV)6-[18F]FDF, 120 min 0.77 ± 0.06 vs. SUV[18F]FDG, 120 min 1.08 ± 0.07] in MDA-MB231 tumors and was blocked by 20% with cytochalasin B after 10 min. Whereas correspondence between 6-[18F]FDF uptake and GLUT5 protein was low, high GLUT2 levels were detected in all cell lines and tumor models. Besides GLUT1, GLUT5 seems to be regulated under hypoxia on the molecular and functional level. Additionally, results strongly support a functional involvement of GLUT2 in fructose metabolism, possibly by compensating for the weaker expression and function of GLUT5 in BC. [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]

Introduction Receptor tyrosine kinase (RTK) platelet-derived growth factor receptor-alpha (PDGFRα) was recently identified as a molecular switch for dedifferentiation in thyroid cancer that predicts resistance to therapy as well as recurrence of disease in papillary thyroid cancer. Here we describe the radiolabeling and functional characterization of an imaging probe based on a PDGFRα-specific monoclonal antibody (mAb) for immuno-PET imaging of PDGFRα in papillary thyroid cancer. Methods Antibody D13C6 (Cell Signaling) was decorated with chelator NOTA using bioconjugation reaction with 2-( p -NCS-Bz)-NOTA. Radiolabeling was carried out using 40 μg of antibody-NOTA conjugate with 143–223 MBq of [ 64 Cu]CuCl 2 in 0.25 M NaOAc (pH 5.5) at 30 °C for 1 h. The reaction mixture was purified with size-exclusion chromatography (PD-10 column). PDGFRα and mock transfected B-CPAP thyroid cancer cells lines for validation of 64 Cu-labeled immuno-conjugates were generated using LVX-Tet-On technology. PET imaging was performed in NSG mice bearing bilaterally-induced PDGFRα (+/−) B-CPAP tumors. Results Bioconjugation of NOTA chelator to monoclonal antibody D13C6 resulted in 2.8 ± 1.3 chelator molecules per antibody as determined by radiometric titration with 64 Cu. [ 64 Cu]Cu-NOTA-D13C6 was isolated in high radiochemical purity (>98%) and good radiochemical yields (19–61%). The specific activity was 0.9–5.1 MBq/μg. Cellular uptake studies revealed a specific radiotracer uptake in PDGFRα expressing cells compared to control cells. PET imaging resulted in SUV mean values of ~5.5 for PDGFRα (+) and ~2 for PDGFRα (−) tumors, after 48 h p.i.. After 1 h, radiotracer uptake was also observed in the bone marrow (SUV mean ~5) and spleen (SUV mean ~8.5). Conclusion Radiolabeled antibody [ 64 Cu]Cu-NOTA-D13C6 represents a novel and promising radiotracer for immuno-PET imaging of PDGFRα in metastatic papillary thyroid cancer. Advances in knowledge and implications for patient care The presented work has the potential to allow physicians to identify papillary thyroid cancer patients at risk of metastases by using the novel immuno-PET imaging assay based on PDGFRα-targeting antibody [ 64 Cu]Cu-NOTA-D13C6. [ABSTRACT FROM AUTHOR]

A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo[3,2,1-hi]indole and pyrrolo[3,2,1-hi]indole core structures has been designed and was synthesized by a modular sequence of Friedel-Crafts acylation, amide formation, and McMurry cyclization. This synthesis route represents a novel and versatile access toward dihydropyrrolo[3,2,1-hi]indoles and is characterized by good chemical yields and high modularity. From a set of 19 derivatives, 11 candidates were selected for determination of their COX inhibition potency and were found to be selective inhibitors with high affinity to COX-2 (IC50 ranging from 20-2500 nM and negligible inhibition of COX-1). The binding mode of the novel inhibitors in the active side of COX-2 was calculated in silico using the protein-ligand docking program GOLD by application of the molecular structures of two compounds derived from X-ray crystallography. Two novel compounds with high affinity to COX-2 (6k = 70 nM, 8e = 60 nM) have a fluoro substituent, making them promising candidates for the development of 18F-radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET). [ABSTRACT FROM AUTHOR]

Introduction 18 F-labeled amino acids are important PET radiotracers for molecular imaging of cancer. This study describes synthesis and radiopharmacological evaluation of 2-amino-5-(4-[ 18 F]fluorophenyl)pent-4-ynoic acid ([ 18 F]FPhPA) as a novel amino acid radiotracer for oncologic imaging. Methods 18 F]FPhPA was prepared using Pd-mediated S onogashira cross-coupling reaction between 4-[ 18 F]fluoroiodobenzene ([ 18 F]FIB) and propargylglycine. The radiopharmacological profile of [ 18 F]FPhPA was evaluated in comparison with O -(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]FET) using the murine breast cancer cell line EMT6 involving cellular uptake studies, radiotracer uptake competitive inhibition experiments and small animal PET imaging. Results 18 F]FPhPA was prepared in 42 ± 10% decay-corrected radiochemical yield with high radiochemical purity >95% after semi-preparative HPLC purification. Cellular uptake of L-[ 18 F]FPhPA reached a maximum of 58 ± 14 % radioactivity/mg protein at 90 min. Lower uptake was observed for racemic and D-[ 18 F]FPhPA. Radiotracer uptake inhibition studies by synthetic and naturally occurring amino acids suggested that Na + -dependent system ASC, especially ASCT2, and Na + -independent system L are important amino acid transporters for [ 18 F]FPhPA uptake into EMT6 cells. Small animal PET studies demonstrated similar high tumor uptake of [ 18 F]FPhPA in EMT6 tumor-bearing mice compared to [ 18 F]FET reaching a maximum standardized uptake value (SUV) of 1.35 after 60 min p.i.. Muscle uptake of [ 18 F]FPhPA was higher (SUV 30min = 0.65) compared to [ 18 F]FET (SUV 30min = 0.40), whereas [ 18 F]FPhPA showed a more rapid uptake and clearance from the brain compared to [ 18 F]FET. Conclusion L-[ 18 F]FPhPA is the first 18 F-labeled amino acid prepared through Pd-mediated cross-coupling reaction. Advances in Knowledge and Implications for patient Care L-[ 18 F]FPhPA displayed promising properties as a novel amino acid radiotracer for molecular imaging of system ASC and system L amino acid transporters in cancer. [ABSTRACT FROM AUTHOR]

Abstract: The radiosynthesis of 3-(4-[18F]fluorophenyl)-2-(4-methylsulfonylphenyl)-1H-indole [18F]-3 as potential PET radiotracer for functional characterization of cyclooxygenase-2 (COX-2) in vitro and in vivo is described. [18F]-3 was prepared by McMurry cyclization of a 18F-labeled intermediate with low valent titanium and zinc via a two-step procedure in a remote controlled synthesizer unit including HPLC purification and solid phase extraction. In this way [18F]-3 was synthesized in 80min synthesis time in 10% total decay corrected yield from [18F]fluoride in radiochemical purity >98% and a specific activity of 74–91GBq/μmol (EOS). [18F]-3 was evaluated in vitro using pro-inflammatory stimulated THP-1 and COX-2 expressing tumor cell lines (FaDu, A2058, HT-29), where the radiotracer uptake was shown to be consistent with up regulated COX-2 expression. The stability of [18F]-3 was determined by incubation in rat whole blood and plasma in vitro and by metabolite analysis of arterial blood samples in vivo, showing with 75% of original compound after 60min an acceptable high metabolic stability. However, no substantial tumor accumulation of [18F]-3 could be observed by dynamic small animal PET studies on HT-29 tumor-bearing mice in vivo. This may be due to the only moderate COX-1/COX-2 selectivity of 3 as demonstrated by both cellular and enzymatic cyclooxygenase inhibition assay in vitro. Nevertheless, the new approach first using McMurry cyclization in 18F-chemistry gives access to 18F-labeled diarylsubstituted heterocycles that hold promise as radiolabeled COX-2 inhibitors. [Copyright &y& Elsevier]

Abstract: A new synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine [18F]FET was developed using a NanoTek® microfluidic synthesis system (Advion BioSciences, Inc.). Optimal reaction conditions were studied through screening different reaction parameters like temperature, flow rate, reaction time, concentration of the labeling precursor, and the applied volume ratio between the labeling precursor and [18F]fluoride. [18F]FET was obtained after HPLC purification with 50% decay-corrected radiochemical yield starting from as little as 40μg of labeling precursor. Small animal PET studies in EMT-6 tumor bearing mice showed radioactivity accumulation in the tumor (SUV60min 1.21±0.2) resulting in an slightly increasing tumor-to-muscle ratio over time. [Copyright &y& Elsevier]

Abstract: Introduction: Several clinical studies have shown low or no expression of GLUT1 in breast cancer patients, which may account for the low clinical specificity and sensitivity of 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) used in positron emission tomography (PET). Therefore, it has been proposed that other tumor characteristics such as the high expression of GLUT2 and GLUT5 in many breast tumors could be used to develop alternative strategies to detect breast cancer. Here we have studied the in vitro and in vivo radiopharmacological profile of 6-deoxy-6-[18F]fluoro-d-fructose (6-[18F]FDF) as a potential PET radiotracer to image GLUT5 expression in breast cancers. Methods: Uptake of 6-[18F]FDF was studied in murine EMT-6 and human MCF-7 breast cancer cells over 60 min and compared to [18F]FDG. Biodistribution of 6-[18F]FDF was determined in BALB/c mice. Tumor uptake was studied with dynamic small animal PET in EMT-6 tumor-bearing BALB/c mice and human xenograft MCF-7 tumor-bearing NIH-III mice in comparison to [18F]FDG. 6-[18F]FDF metabolism was investigated in mouse blood and urine. Results: 6-[18F]FDF is taken up by EMT-6 and MCF-7 breast tumor cells independent of extracellular glucose levels but dependent on the extracellular concentration of fructose. After 60 min, 30±4% (n=9) and 12±1% (n=7) ID/mg protein 6-[18F]FDF was found in EMT-6 and MCF-7 cells, respectively. 6-deoxy-6-fluoro-d-fructose had a 10-fold higher potency than fructose to inhibit 6-[18F]FDF uptake into EMT-6 cells. Biodistribution in normal mice revealed radioactivity uptake in bone and brain. Radioactivity was accumulated in EMT-6 tumors reaching 3.65±0.30% ID/g (n=3) at 5 min post injection and decreasing to 1.75±0.03% ID/g (n=3) at 120 min post injection. Dynamic small animal PET showed significantly lower radioactivity uptake after 15 min post injection in MCF-7 tumors [standard uptake value (SUV)=0.76±0.05; n=3] compared to EMT-6 tumors (SUV=1.23±0.09; n=3). Interestingly, [18F]FDG uptake was significantly different in MCF-7 tumors (SUV15 min 0.74±0.12 to SUV120 min 0.80±0.15; n=3) versus EMT-6 tumors (SUV 15 min 1.01±0.33 to SUV 120 min 1.80±0.25; n=3). 6-[18F]FDF was shown to be a substrate for recombinant human ketohexokinase, and it was metabolized rapidly in vivo. Conclusion: Based on the GLUT5 specific transport and phosphorylation by ketohexokinase, 6-[18F]FDF may represent a novel radiotracer for PET imaging of GLUT5 and ketohexokinase-expressing tumors. [Copyright &y& Elsevier]

Abstract: Tumor cells are characterized by their loss of growth control resulting from alterations in regulating pathways of the cell cycle, such as a deregulated cyclin-dependent kinase (Cdk) activity and/or Cdk expression. Appropriately radiolabeled Cdk4 inhibitors are discussed as promising molecular probes for imaging cell proliferation processes and tumor visualization by PET. This work describes the design, synthesis and radiopharmacological evaluation of two 124I-labeled Cdk4 inhibitors as potential radiotracers for imaging of Cdk4 in vivo. Treatment of a solution containing labeling precursors with [124I]NaI gave radiolabeled Cdk4 inhibitors [124I]CKIA and [124I]CKIB in radiochemical yields of up to 35%. 124I-labeled radiotracers [124I]CKIA and [124I]CKIB were used in cell uptake studies as well as biodistribution studies in Wistar rats and small-animal PET in tumor-bearing mice. In vitro radiotracer uptake studies in adherent tumor cells using [124I]CKIA showed substantial uptake in HT-29 and FaDu cells (750–850 %ID/mg protein [124I]CKIA and 900–1000 %ID/mg protein [124I]CKIB) after 1 h at 37 °C. Biodistribution of [124I]CKIA and [124I]CKIB showed rapid blood clearance of radioactivity and an accumulation as well as metabolization in the liver. Both radiotracers were administered intravenously to mouse FaDu xenograft tumor model and imaging studies were performed on a small-animal PET scanner. Both imaging techniques showed only little uptake of both radiotracers in the FaDu tumor xenografts. [Copyright &y& Elsevier]

Abstract: The radiosynthesis and radiopharmacological evaluation of 3-[4′-[18F]fluorobenzylidene]indolin-2-one, a derivative of tyrosine kinase inhibitor SU5416, is described. The radiosynthesis was accomplished by Knoevenagel condensation of 4-[18F]fluorobenzaldehyde with oxindole in a remotely controlled synthesis module. The reaction conditions were optimized through screening the influence of different bases on the radiochemical yield. The radiotracer was obtained after a two-step labelling procedure in 4% decay-corrected radiochemical yield at a specific activity of 48–61GBq/μmol within 90min. The radiochemical purity after semi-preparative HPLC purification exceeded 98%. The biodistribution was studied in Wistar rats. After distribution the radiotracer was rapidly accumulated in the adrenals, liver and kidneys, however, it was cleared from these and the most other organs. Only the adipose tissue remained the activity over 60min. Unexpected high transient uptake was observed in the brain, pancreas, heart and lung. The fast clearance of 3-[4′-[18F]fluorobenzylidene]indolin-2-one was caused by excretion, approximately one half each was renal and biliary excreted and the other part cleared by metabolic processes. In arterial blood plasma two more polar metabolites were found by radio-HPLC. After 20min post-injection, only 12% of intact radiotracer has been detected. Consequently, in small animal PET studies with FaDu tumour bearing mice no specific uptake in the tumours could be observed. [Copyright &y& Elsevier]

Abstract: This work involves the production, processing and imaging of the short-lived, rarely used positron emission tomography (PET) radionuclide technetium-94m (94mTc). Our procedures are an extension of methods reported in the literature and are detailed within. A key modification was the development of a single step that combines purification and concentration of an aqueous 94mTc-pertechnetate solution, which both reduces processing time and increases the final concentration of the solution. Additionally, a convenient method for the direct recovery of 94mTc into an organic solvent was developed, eliminating the solvent transfer step needed for organic syntheses using 94mTc. Each of these advances potentially extends the scope of syntheses possible with this short-lived radionuclide. To explore the imaging potential of 94mTc, we carried out phantom imaging studies on small-scale high-resolution PET scanners to estimate the limitations of detection associated with 94mTc and PET. Preliminary studies demonstrate that useful images can be obtained with modern image reconstruction algorithms when using a correction for the cascade gamma ray contamination. [Copyright &y& Elsevier]

Abstract: Oxidative modification of low-density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Assessing the metabolic fate of oxidized LDL (oxLDL) in vivo with radiotracer techniques is hindered by the lack of suitable sensitive and specific radiolabeling methods. We evaluated an improved methodology based on the radiolabeling of native LDL (nLDL) and oxLDL with the positron emitter fluorine-18 (18F) by conjugation with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB). We investigated whether radiolabeling of LDL induces adverse structural modifications. Results suggest that radiolabeling of both nLDL and oxLDL using [18F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively. Thus, radiolabeling of LDL using [18F]SFB could prove to be a promising approach for studying the kinetics of oxLDL in vivo. [Copyright &y& Elsevier]