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This meeting report summarizes a consultants meeting that was held at International Atomic Energy Agency Headquarters, Vienna, in July 2022 to provide an update on the development of multimodality imaging by combining nuclear medicine imaging agents with other nonradioactive molecular probes and/or biomedical imaging techniques.
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Imagem Multimodal , Medicina Nuclear , Medicina Nuclear/métodos , Medicina Nuclear/tendências , Imagem Multimodal/métodos , HumanosRESUMO
Natural-abundance phosphomolybdic acid (H3(Mo12PO40) â§12H2O, 0.181-0.552 g Mo/mL) solutions were irradiated with 12.9 MeV protons on a GE PETtrace cyclotron using an adapted standard liquid target. Technetium-94m (94mTc) was produced through the 94Mo(p,n)94mTc nuclear reaction with saturation yields of up to 53 ± 6 MBq/µA. End of bombardment activities of 161 ± 17 MBq and 157 ± 7 MBq were achieved for the 0.552 g Mo/mL solution (10 µA for 30 min) and 0.181 g Mo/mL solution (15 µA for 60 min), respectively. No visible degradation of the niobium target body and foil were seen during the irradiations of up to 15 µA for 60 min. The produced 94mTc was separated from the target phosphomolybdic acid solution with >98% recovery using an aqueous biphasic extraction resin. Compared to previous reported liquid target methods for 94mTc production, the better production yield, in-target solution stability during irradiation and 94mTc separation recovery of phosphomolybdic acid makes it a very promising target material for routine clinical 94mTc production at medical facilities with liquid targets already installed for 18F production.
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The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists. However, AMD3100 has not been shown to be effective in cancer treatment as an individual agent. Configurational restriction and transition metal complex formation increases receptor binding affinity and residence time. In the present study, we have synthesized novel trans-IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.
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Complexos de Coordenação , Ciclamos , Compostos Heterocíclicos , Benzilaminas , Complexos de Coordenação/farmacologia , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/química , Receptores CXCR4/antagonistas & inibidoresRESUMO
INTRODUCTION: The chemokine receptor CXCR4 has been shown to be over-expressed in multiple types of cancer and is usually associated with aggressive phenotypes and poor prognosis. Successfully targeting and imaging the expression level of this receptor in tumours could inform treatment selection and facilitate patient stratification. METHODS: Known conjugates of AMD3100 that are specific to CXCR4 have been radiolabelled with gallium-68 and evaluated in naïve and tumour-bearing mice. Tumour uptake of the radiotracers was compared to the known CXCR4-specific PET imaging agent, [68Ga]Pentixafor. RESULTS: Ex vivo biodistribution in naïve animals showed CXCR4-mediated uptake in the liver with both radiotracers, confirmed by blocking experiments with the high affinity CXCR4 antagonist Cu2CB-Bicyclam (IC50 = 3 nM). PET/CT imaging studies revealed one tracer to have a higher accumulation in the tumour (SUVMean of 0.89 ± 0.14 vs 0.32 ± 0.11). CXCR4-specificity of the best performing tracer was confirmed by administration of a blocking dose of Cu2CB-Bicyclam, showing a 3- and 6-fold decrease in tumour and liver uptake, respectively. CONCLUSION AND ADVANCES IN KNOWLEDGE: This initial study offers some interesting insights on the impact of some structural features on the pharmacokinetics and metabolic stability of the radiotracer. Additionally, as Pentixafor only binds to human CXCR4, the development of CXCR4-targeted imaging agents that bind to the receptor across different species could significantly help with preclinical evaluation of new CXCR4-specific therapeutics.
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Complexos de Coordenação , Ciclamos , Neoplasias , Humanos , Animais , Camundongos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de Gálio , Distribuição Tecidual , Tomografia por Emissão de Pósitrons/métodos , Peptídeos Cíclicos/farmacocinética , Receptores CXCR4/metabolismoRESUMO
The chelator Bn2DT3A was used to produce a novel 68Ga complex for positron emission tomography (PET). Unusually, this system is stabilized by a coordinated hydroxide in aqueous solutions above pH 5, which confers sufficient stability for it to be used for PET. Bn2DT3A complexes Ga3+ in a hexadentate manner, forming a mer-mer complex with log K([Ga(Bn2DT3A)]) = 18.25. Above pH 5, the hydroxide ion coordinates the Ga3+ ion following dissociation of a coordinated amine. Bn2DT3A radiolabeling displayed a pH-dependent speciation, with [68Ga][Ga(Bn2DT3A)(OH)]- being formed above pH 5 and efficiently radiolabeled at pH 7.4. Surprisingly, [68Ga][Ga(Bn2DT3A)(OH)]- was found to show an increased stability in vitro (for over 2 h in fetal bovine serum) compared to [68Ga][Ga(Bn2DT3A)]. The biodistribution of [68Ga][Ga(Bn2DT3A)(OH)]- in healthy rats showed rapid clearance and excretion via the kidneys, with no uptake seen in the lungs or bones.
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Quelantes , Radioisótopos de Gálio , Animais , Ratos , Radioisótopos de Gálio/química , Quelantes/química , Distribuição Tecidual , Tomografia por Emissão de Pósitrons/métodos , Hidróxidos , Compostos Radiofarmacêuticos/químicaRESUMO
Sporopollenin exine capsules (SpECs) are microcapsules derived from the outer shells (exines) of plant spore and pollen grains. This work reports the first clinical study on healthy volunteers to show enhanced bioavailability of vitamin D encapsulated in SpECs from Lycopodium clavatum L. spore grains vs vitamin D alone, and the first evidence (in vitro, ex vivo and in vivo) of mechanisms to account for the enhancement and release of the active in the small intestine. Evidence for mucoadhesion of the SpECs contributing to the mechanism of the enhancement is based on: (i) release profile over time of vitamin D in a double blind cross-over human study showing significant release in the small intestine; (ii) in vivo particle counting data in rat showing preferred retention of SpECs vs synthetic beads; (iii) ex vivo99mTc labelling and counting data using rat small intestine sections showing preferred retention of SpECs vs synthetic beads; (iv) in vitro mucoadhesion data. Triggered release by bile in the small intestine was shown in vitro using solid state NMR and HPLC.
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Bile , Vitamina D , Animais , Disponibilidade Biológica , Biopolímeros , Cápsulas , Carotenoides , Estudos Cross-Over , Método Duplo-Cego , Humanos , Ratos , Esporos , VitaminasRESUMO
The aluminium-[18F]fluoride ([18F]AlF) radiolabelling method combines the favourable decay characteristics of fluorine-18 with the convenience and familiarity of metal-based radiochemistry and has been used to parallel gallium-68 radiopharmaceutical developments. As such, the [18F]AlF method is popular and widely implemented in the development of radiopharmaceuticals for the clinic. In this review, we capture the current status of [18F]AlF-based technology and reflect upon its impact on nuclear medicine, as well as offering our perspective on what the future holds for this unique radiolabelling method.
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OBJECTIVE: Neoadjuvant chemoradiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whist in vitro miR-187 overexpression enhanced radiosensitivity and upregulated PTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC. METHODS: The effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and Western blotting. PTEN expression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in two-dimensional and three-dimensional OAC models in vitro and as a single agent in vivo. Radiation response in vitro was assessed via clonogenic assay. RESULTS: PTEN expression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulated PTEN expression and inhibited downstream PI3K signalling in vitro. GDC-0941 significantly reduced viability and enhanced radiation response in vitro and led to tumour growth inhibition as a single agent in vivo. CONCLUSION: Targeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT. ADVANCES IN KNOWLEDGE: This is the first study evaluating the effect of PI3K inhibition on radiosensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the first time that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.
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Adenocarcinoma/terapia , Neoplasias Esofágicas/terapia , Terapia Neoadjuvante , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Feminino , Humanos , Camundongos , Resultado do TratamentoRESUMO
The CXCR4 chemokine receptor is an important biomolecular target in cancer diagnostics and therapeutics. In a new multivalent approach, iron oxide nanoparticles were conjugated with multiple binding units of a low affinity azamacrocylic CXCR4 antagonist. The silica coated nanostructure has good suspension stability, a mode size of 72 nm and high affinity for CXCR4, showing >98% inhibition of anti-CXCR4 mAb binding in a receptor binding competition assay on Jurkat cells.
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Nanopartículas Magnéticas de Óxido de Ferro/química , Receptores CXCR4/metabolismo , Humanos , Células Jurkat , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício/químicaRESUMO
BACKGROUND: Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18-fluorothymidine ([18F]FLT) with positron emission tomography/computed tomography (PET/CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion). METHODS AND RESULTS: Fourteen-week-old apolipoprotein E-knockout (ApoE-/-) mice received saline or AngII via osmotic mini-pumps for 14 (n = 7 and 5, respectively) or 28 (n = 3 and 4, respectively) days and underwent 90-minute dynamic [18F]FLT PET/CT. Organs were harvested from independent cohorts for gamma counting, ultrasound scanning, and western blotting. [18F]FLT uptake was significantly greater in 14- (n = 5) and 28-day (n = 3) AAA than in saline control aortae (n = 5) (P < 0.001), which reduced between days 14 and 28. Whole-organ gamma counting confirmed greater [18F]FLT uptake in 14-day AAA (n = 9) compared to saline-infused aortae (n = 4) (P < 0.05), correlating positively with aortic volume (r = 0.71, P < 0.01). Fourteen-day AAA tissue showed increased expression of thymidine kinase-1, equilibrative nucleoside transporter (ENT)-1, ENT-2, concentrative nucleoside transporter (CNT)-1, and CNT-3 than 28-day AAA and saline control tissues (n = 3 each) (all P < 0.001). CONCLUSIONS: [18F]FLT uptake is increased during the active growth phase of the AAA model compared to saline control mice and late-stage AAA.
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Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Proliferação de Células , Didesoxinucleosídeos/farmacocinética , Radioisótopos de Flúor/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Knockout para ApoERESUMO
The goal of "personalised" medicine has seen a growing interest in the development of theranostic agents. Bifunctional, and targeted-trifunctional, theranostic water-soluble porphyrins with a histidine-like chelating group have been synthesised via copper-catalysed azide-alkyne cycloaddition (CuAAC) "click" chemistry in high yield and purity. They are capable of photodynamic treatment and [99mTc(CO)3]+ complexation for single-photon emission computed tomography (SPECT) imaging, with a radiochemical yield of >95%. The toxicity and phototoxicity were evaluated on HT-29 cells, DU145, and DU145-PSMA cell lines, with the targeted theranostic showing more potent phototoxicity towards DU145-PSMA expressing cells.
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INTRODUCTION: Time-of-flight (TOF) positron emission tomography (PET) scanners can provide significant benefits by improving the noise properties of reconstructed images. In order to achieve this, the timing response of the scanner needs to be modelled as part of the reconstruction process. This is currently achieved using Gaussian TOF kernels. However, the timing measurements do not necessarily follow a Gaussian distribution. In ultra-fast timing resolutions, the depth of interaction of the γ-photon and the photon travel spread (PTS) in the crystal volume become increasingly significant factors for the timing performance. The PTS of a single photon can be approximated better by a truncated exponential distribution. Therefore, we computed the corresponding TOF kernel as a modified Laplace distribution for long crystals. The obtained (CTR) kernels could be more appropriate to model the joint probability of the two in-coincidenceγ-photons. In this paper, we investigate the impact of using a CTR kernel vs. Gaussian kernels in TOF reconstruction using Monte Carlo generated data. MATERIALS AND METHODS: The geometry and physics of a PET scanner with two timing configurations, (a) idealised timing resolution, in which only the PTS contributed in the CTR, and (b) with a range of ultra-fast timings, were simulated. In order to assess the role of the crystal thickness, different crystal lengths were considered. The evaluation took place in terms of Kullback-Leibler (K-L) distance between the proposed model and the simulated timing response, contrast recovery (CRC) and spatial resolution. The reconstructions were performed using STIR image reconstruction toolbox. RESULTS: Results for the idealised scanner showed that the CTR kernel was in excellent agreement with the simulated time differences. In terms of K-L distance outperformed the a fitted normal distribution for all tested crystal sizes. In the case of the ultra-fast configurations, a convolution kernel between the CTR and a Gaussian showed the best agreement with the simulated data below 40 ps timing resolution. In terms of CRC, the CTR kernel demonstrated improvements, with values that ranged up to 3.8% better CRC for the thickest crystal. In terms of spatial resolution, evaluated at the 60th iteration, the use of CTR kernel showed a modest improvement of the peek-to-valley ratios up to 1% for the 10-mm crystal, while for larger crystals, a clear trend was not observed. In addition, we showed that edge artefacts can appear in the reconstructed images when the timing kernel used for the reconstruction is not carefully optimised. Further iterations, can help improve the edge artefacts.
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Rigid and topologically constrained ethylene cross-bridged tetraazamacrocycles have been increasingly utilised for thirty years as they form remarkably stable transition metal complexes for catalysis, biomedical imaging, and inorganic drug molecule applications. Extending these benefits to pentaazamacrocycles has been achieved and a first transition metal complex prepared and structurally characterized.
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The miniaturisation of positron emission tomography (PET) radiotracer production is facilitating a move towards a dose-on-demand strategy that would enable a stratified approach to patient diagnostics, but while the on-chip synthesis steps have been demonstrated, the subsequent quality control (QC) testing steps have received much less attention. As part of the development of an integrated QC platform for PET tracers, we have developed two microfluidic electrochemical detectors for the pulsed amperometric detection (PAD) of carbohydrate-based radiotracers, with a particular view to the QC testing of the most important tracer, [18F]2-fluoro-2-deoxy-d-glucose ([18F]FDG). The first device employed a commercial screen-printed electrode (SPE) to enable a single-use format, while the second device incorporated wire electrodes for use as a more permanent fixture in a QC instrument. A flow-injection analysis (FIA)-style setup was used to inject boluses of d-glucose into the chips in a proxy for intended chromatographic separations prior to PAD. In proof-of-concept testing of the devices, the chips featuring the SPE and the wire electrodes yielded limits of detection of 0.1 ppm and 9 ppm, respectively, each below the required limits for [18F]FDG, and thus making both methodologies viable for the QC testing of PET radiotracers in a dose-on-demand format.
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Reaction of [ReOCl3(PPh3)2] or [ReO2I(PPh3)2] with 2,2'-diphenylglycine (dpgH2) in refluxing ethanol afforded the air-stable complex [ReO(dpgH)(dpg)(PPh3)] (1). Treatment of [ReO(OEt)I2(PPh3)2] with 1,2,3-triaza-7-phosphaadamantane (PTA) afforded the complex [ReO(OEt)I2(PTA)2] (2). Reaction of [ReOI2(PTA)3] with dpgH2 led to the isolation of the complex [Re(NCPh2)I2(PTA)3]·0.5EtOH (3·0.5EtOH). A similar reaction but using [ReOX2(PTA)3] (X = Cl, Br) resulted in the analogous halide complexes [Re(NCPh2)Cl2(PTA)3]·2EtOH (4·2EtOH) and [Re(NCPh2)(PTA)3Br2]·1.6EtOH (5·1.6EtOH). Using benzilic acid (2,2'-diphenylglycolic acid, benzH) with 2 afforded the complex [ReO(benz)2(PTA)][PTAH]·EtOH (6·EtOH). The potential for the formation of complexes using radioisotopes with relatively short half-lives suitable for nuclear medicine applications by developing conditions for [Re(NCPh2)(dpg)I(PTA)3] (7)[ReO4]- in a 4 h time scale was investigated. A procedure for the technetium analog of complex [Re(NCPh2)I2(PTA)3] (3) from 99mTc[TcO4]- was then investigated. The molecular structures of 1-7 are reported; complexes 3-7 have been studied using in vitro cell assays (HeLa, HCT116, HT-29, and HEK 293) and were found to have IC50 values in the range of 29-1858 µM.
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Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Células HEK293 , Humanos , Estrutura Molecular , Compostos de Organotecnécio/síntese química , Compostos de Organotecnécio/química , Fosfinas/síntese química , Fosfinas/química , Fosfinas/toxicidade , Rênio/química , Solubilidade , Água/químicaRESUMO
A series of six different 1,8-naphthalimide conjugated dipicolylamine ligands (L1-6) have been synthesised and characterised. The ligands possess a range of different linker units between the napthalimide fluorophore and dipcolylamine chelator which allow the overall lipophilicity to be tuned. A corresponding series of Re(i) complexes have been synthesised of the form fac-[Re(CO)3(L1-6)]BF4. The absorption and luminescence properties of the ligands and Re(i) complexes were dominated by the intramolecular charge transfer character of the substituted fluorophore (typically absorption ca. 425 nm and emission ca. 520 nm). Photophysical assessments show that some of the variants are moderately bright. Radiolabelling experiments using a water soluble ligand variant (L5) were successfully undertaken and optimised with fac-[99mTc(CO)3(H2O)3]+. Confocal fluorescence microscopy showed that fac-[Re(CO)3(L5)]+ localises in the mitochondria of MCF-7 cells. SPECT/CT imaging experiments on naïve mice showed that fac-[99mTc(CO)3(L5)]+ has a relatively high stability in vivo but did not show any cardiac uptake, demonstrating rapid clearance, predominantly via the biliary system along with a moderate amount cleared renally.
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Meios de Contraste/química , Complexos de Coordenação/química , Mitocôndrias/patologia , Naftalimidas/química , Compostos de Organotecnécio/química , Aminas/química , Animais , Sistema Biliar/diagnóstico por imagem , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/farmacologia , Feminino , Humanos , Marcação por Isótopo , Ligantes , Células MCF-7 , Camundongos , Camundongos Nus , Microscopia Confocal , Ácidos Picolínicos/química , Rênio/química , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios XRESUMO
The role of MRI differs considerably between the three main groups of hematological malignancies: lymphoma, leukemia, and myeloma. In myeloma, whole-body MRI (WB-MRI) is recognized as a highly sensitive test for the assessment of myeloma, and is also endorsed by clinical guidelines, especially for detection and staging. In lymphoma, WB-MRI is presently not recommended, and merely serves as an alternative technique to the current standard imaging test, [18 F]FDG-PET/CT, especially in pediatric patients. Even for lymphomas with variable FDG avidity, such as extranodal mucosa-associated lymphoid tissue lymphoma (MALT), contrast-enhanced computed tomography (CT), but not WB-MRI, is presently recommended, despite the high sensitivity of diffusion-weighted MRI and its ability to capture treatment response that has been reported in the literature. In leukemia, neither MRI nor any other cross-sectional imaging test (including positron emission tomography [PET]) is currently recommended outside of clinical trials. This review article discusses current clinical applications as well as the main research topics for MRI, as well as PET/MRI, in the field of hematological malignancies, with a focus on functional MRI techniques such as diffusion-weighted imaging and dynamic contrast-enhanced MRI, on the one hand, and novel, non-FDG PET imaging probes such as the CXCR4 radiotracer [68 Ga]Ga-Pentixafor and the amino acid radiotracer [11 C]methionine, on the other hand. Level of Evidence: 5 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1325-1335.
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Neoplasias Hematológicas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Criança , Fluordesoxiglucose F18 , Neoplasias Hematológicas/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Imagem Corporal TotalRESUMO
Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell-based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability 64Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. Methods: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-bicyclam. In vivo dynamic PET studies were performed on mice bearing U87 (CXCR4 low-expressing) and U87.CXCR4 (human-CXCR4 high-expressing) tumors. Biodistribution and receptor blocking studies were performed on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction, and Western blot. Results:64Cu-CuCB-bicyclam has a high affinity for both the human and the murine variants of the CXCR4 receptor (half-maximal inhibitory concentration, 8 nM [human]/2 nM [murine]) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4-expressing cells that can be blocked by more than 90% using a higher-affinity antagonist, with limited uptake in non-CXCR4-expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. Conclusion: The tetraazamacrocyclic small molecule 64Cu-CuCB-bicyclam has been shown to be an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models.