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1.
J Chromatogr A ; 1632: 461611, 2020 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-33086153

RESUMO

Chiral column chromatography (CCC) is a revolutionary analytical methodology for the enantioseparation of novel positron emission tomography (PET) tracers in the primary stages of drug development. Due to the different behaviors of tracer enantiomers (e.g. toxicity, metabolism and side effects) in administrated subjects, their separation and purification is a challenging endeavor. Over the last three decades, different commercial chiral columns have been applied for the enantioseparation of PET-radioligand (PET-RL) or radiotracers (PET-RT), using high-performance liquid chromatography (HPLC). The categorization and reviewing of them is a vital topic. This review presents a brief overview of advances, applications, and future prospectives of CCC in radiopharmaceutical approaches. In addition, the effective chromatographic parameters and degravitation trends to enhance enantioseparation resolution are addressed. Moreover, the application and potential of chiral super fluidical chromatography (CSFC) as an alternative for enantioseparation in the field of radiopharmaceutical is discussed. Finally, the crucial application challenges of CCC are explained and imminent tasks are suggested.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Compostos Radiofarmacêuticos/química , Ligantes , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/isolamento & purificação , Estereoisomerismo , Temperatura
2.
J Med Chem ; 63(20): 12008-12022, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32946235

RESUMO

The non-natural cyclic amino acids (1S,3R,4S)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([18F]9) and (1S,3S,4R)-1-amino-3-fluoro-4-(fluoro-18F)cyclopentane-1-carboxylic acid ([18F]28) have been prepared in 10 and 1.7% decay corrected radiochemical yield, respectively, and in greater than 99% radiochemical purity. Cell assays in rat 9L gliosarcoma, human U87 ΔEGFR glioblastoma, and human DU145 androgen-independent prostate carcinoma tumor cells indicated that both compounds are substrates for amino acid transport primarily by system L, with some transport taking place via system ASC. In rats with 9L gliosarcoma, [18F]9 and [18F]28 provided high tumor to normal brain tissue ratios, with maximal ratios of 3.5 and 4.1, respectively. Biodistribution studies in healthy rats confirmed that both compounds are BBB permeable and that bladder accumulation is low until at least 5 min post injection.


Assuntos
Ácidos Carboxílicos/química , Ciclopentanos/química , Glioblastoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos/química , Animais , Ácidos Carboxílicos/síntese química , Ciclopentanos/síntese química , Relação Dose-Resposta a Droga , Radioisótopos de Flúor , Humanos , Masculino , Conformação Molecular , Estrutura Molecular , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual , Células Tumorais Cultivadas
3.
Int J Nanomedicine ; 15: 6137-6152, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884268

RESUMO

Background: Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve risk assessment and clinical management in high-risk patients. To identify inflamed atherosclerotic lesions by molecular imaging in vivo, we studied the specificity of our radiotracer based on maleylated (Mal) human serum albumin (HSA), which targets key features of unstable atherosclerotic lesions. Materials and Methods: Mal-HSA was radiolabeled with a positron-emitting metal ion, zirconium-89 (89Zr4+). The targeting potential of this probe was compared with unspecific 89Zr-HSA and 18F-FDG in an experimental model of atherosclerosis (Apoe-/- mice, n=22), and compared with wild-type (WT) mice (C57BL/6J, n=21) as controls. Results: PET/MRI, gamma counter measurements, and autoradiography showed the accumulation of 89Zr-Mal-HSA in the atherosclerotic lesions of Apoe-/- mice. The maximum standardized uptake values (SUVmax) for 89Zr-Mal-HSA at 16 and 20 weeks were 26% and 20% higher (P<0.05) in Apoe-/- mice than in control WT mice, whereas no difference in SUVmax was observed for 18F-FDG in the same animals. 89Zr-Mal-HSA uptake in the aorta, as evaluated by a gamma counter 48 h postinjection, was 32% higher (P<0.01) for Apoe-/- mice than in WT mice, and the aorta-to-blood ratio was 8-fold higher (P<0.001) for 89Zr-Mal-HSA compared with unspecific 89Zr-HSA. HSA-based probes were mainly distributed to the liver, spleen, kidneys, bone, and lymph nodes. The phosphor imaging autoradiography (PI-ARG) results corroborated the PET and gamma counter measurements, showing higher accumulation of 89Zr-Mal-HSA in the aortas of Apoe-/- mice than in WT mice (9.4±1.4 vs 0.8±0.3%; P<0.001). Conclusion: 89Zr radiolabeling of Mal-HSA probes resulted in detectable activity in atherosclerotic lesions in aortas of Apoe-/- mice, as demonstrated by quantitative in vivo PET/MRI. 89Zr-Mal-HSA appears to be a promising diagnostic tool for the early identification of macrophage-rich areas of inflammation in atherosclerosis.


Assuntos
Aterosclerose/diagnóstico por imagem , Maleatos/química , Imagem Molecular/métodos , Radioisótopos , Albumina Sérica Humana/química , Zircônio , Animais , Aorta/diagnóstico por imagem , Aorta/patologia , Aterosclerose/patologia , Autorradiografia , Modelos Animais de Doenças , Feminino , Fluordesoxiglucose F18 , Humanos , Marcação por Isótopo , Macrófagos/patologia , Imagem por Ressonância Magnética , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Distribuição Tecidual , Zircônio/química , Zircônio/farmacocinética
4.
Sci Rep ; 10(1): 13593, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788595

RESUMO

Folate receptor ß (FR-ß), a marker expressed on macrophages, is a promising target for imaging of inflammation. Here, we report the radiosynthesis and preclinical evaluation of [68Ga]Ga-NOTA-folate (68Ga-FOL). After determining the affinity of 68Ga-FOL using cells expressing FR-ß, we studied atherosclerotic mice with 68Ga-FOL and 18F-FDG PET/CT. In addition, we studied tracer distribution and co-localization with macrophages in aorta cryosections using autoradiography, histology, and immunostaining. The specificity of 68Ga-FOL was assessed in a blocking study with folate glucosamine. As a final step, human radiation doses were extrapolated from rat PET data. We were able to produce 68Ga-FOL with high radiochemical purity and moderate molar activity. Cell binding studies revealed that 68Ga-FOL had 5.1 nM affinity for FR-ß. Myocardial uptake of 68Ga-FOL was 20-fold lower than that of 18F-FDG. Autoradiography and immunohistochemistry of the aorta revealed that 68Ga-FOL radioactivity co-localized with Mac-3-positive macrophage-rich atherosclerotic plaques. The plaque-to-healthy vessel wall ratio of 68Ga-FOL was significantly higher than that of 18F-FDG. Blocking studies verified that 68Ga-FOL was specific for FR. Based on estimations from rat data, the human effective dose was 0.0105 mSv/MBq. Together, these findings show that 68Ga-FOL represents a promising new FR-ß-targeted tracer for imaging macrophage-associated inflammation.


Assuntos
Receptor 2 de Folato/metabolismo , Ácido Fólico/química , Compostos Heterocíclicos com 1 Anel/química , Macrófagos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Animais , Células CHO , Cricetinae , Cricetulus , Fluordesoxiglucose F18/química , Fluordesoxiglucose F18/farmacocinética , Radioisótopos de Gálio/química , Radioisótopos de Gálio/farmacocinética , Humanos , Camundongos , Placa Aterosclerótica/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição Tecidual
5.
Int J Nanomedicine ; 15: 5017-5026, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764933

RESUMO

Background: Molecular imaging is of great benefit to early disease diagnosis and timely treatment. One of the most striking innovations is the development of multimodal molecular imaging technology, which integrates two or more imaging modalities, largely in view of making the best of the advantages of each modality while overcoming their respective shortcomings. Hence, engineering a versatile and easily prepared nanomaterial with integrating multimodal molecular imaging function holds great promise, but is still a great challenge. Materials and Methods: We firstly designed and synthesized a BDT-DPP conjugated polymer and then noncovalent self-assembly with phospholipid-polyethylene glycol endowed BDT-DPP with water solubility and biocompatibility. Followed by [Cu] labeling, the acquired multifunctional nanoparticles (NPs) were studied in detail for the photophysical property. The cytotoxicity and biocompatibility of DPP-BDT NPs were examined through MTT assay and H&E stained analysis. In addition, we investigated the accumulation of the NPs in HepG2 tumor models by positron emission tomography (PET) and photoacoustic (PA) dual-mode imaging. Results and Discussion: The DPP-BDT NPs exhibited excellent optical stability, strong near-infrared (NIR) light absorption as well as fine biocompatibility. After tail vein injection into the living mice, the PA signals in the neoplastic tissues were gradually increased and reached to the maximum at the 4-h post-injection, which was consistent with the PET analysis. Such strong PA and PET signals were attributed to the efficient NPs accumulation resulting from the enhanced permeability and retention (EPR) effect. Conclusion: The biocompatible DPP-BDT NPs demonstrated to be strong NIR absorption property and PAI sensitivity. Besides, these novel DPP-BDT NPs can act not only as a PA imaging contrast agent but also as an imaging agent for PET.


Assuntos
Cetonas/química , Nanopartículas/química , Neoplasias Experimentais/diagnóstico por imagem , Técnicas Fotoacústicas/métodos , Tomografia por Emissão de Pósitrons/métodos , Pirróis/química , Animais , Meios de Contraste/química , Radioisótopos de Cobre/administração & dosagem , Radioisótopos de Cobre/farmacocinética , Feminino , Células Hep G2 , Humanos , Injeções , Camundongos , Camundongos Nus , Imagem Multimodal/métodos , Células NIH 3T3 , Nanopartículas/administração & dosagem , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Polímeros/química , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Med Chem ; 63(21): 12693-12706, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32787084

RESUMO

The ß-diketone moiety is commonly present in many anticancer drugs, antibiotics, and natural products. We describe a general method for radiolabeling ß-diketone-bearing molecules with fluoride-18. Radiolabeling was carried out via 18F-19F isotopic exchange on nonradioactive difluoro-dioxaborinins, which were generated by minimally modifying the ß-diketone as a difluoroborate. Radiochemistry was one-step, rapid (<10 min), and high-yielding (>80%) and proceeded at room temperature to accommodate the half-life of F-18 (t1/2 = 110 min). High molar activities (7.4 Ci/µmol) were achieved with relatively low starting activities (16.4 mCi). It was found that substituents affected both the solvolytic stability and fluorescence properties of difluoro-dioxaborinins. An F-18 radiolabeled difluoro-dioxaborinin probe that was simultaneously fluorescent showed sufficient stability for in vivo positron emission tomography (PET)/fluorescence imaging in mice, rabbits, and patients. These findings will guide the design of probes with specific PET/fluorescence properties; the development of new PET/fluorescence dual-modality reporters; and accurate in vivo tracking of ß-diketone molecules.


Assuntos
Boro/química , Flúor/química , Cetonas/química , Compostos Radiofarmacêuticos/química , Animais , Flúor/metabolismo , Radioisótopos de Flúor/química , Radioisótopos de Flúor/metabolismo , Meia-Vida , Marcação por Isótopo , Imagem por Ressonância Magnética , Camundongos , Tomografia por Emissão de Pósitrons , Coelhos , Compostos Radiofarmacêuticos/metabolismo , Imagem Corporal Total
7.
PLoS One ; 15(7): e0221241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634153

RESUMO

Radioluminescence microscopy (RLM) is an imaging technique that allows quantitative analysis of clinical radiolabeled drugs and probes in single cells. However, the modality suffers from slow data acquisition (15-30 minutes), thus critically affecting experiments with short-lived radioactive drugs. To overcome this issue, we suggest an approach that significantly accelerates data collection. Instead of using a single scintillator to image the decay of radioactive molecules, we sandwiched the radiolabeled cells between two scintillators. As proof of concept, we imaged cells labeled with [18F]FDG, a radioactive glucose popularly used in oncology to image tumors. Results show that the double scintillator configuration increases the microscope sensitivity by two-fold, thus reducing the image acquisition time by half to achieve the same result as the single scintillator approach. The experimental results were also compared with Geant4 Monte Carlo simulation to confirm the two-fold increase in sensitivity with only minor degradation in spatial resolution. Overall, these findings suggest that the double scintillator configuration can be used to perform time-sensitive studies such as cell pharmacokinetics or cell uptake of short-lived radiotracers.


Assuntos
Microscopia de Fluorescência/métodos , Compostos Radiofarmacêuticos/química , Análise de Célula Única/métodos , Linhagem Celular Tumoral , Fluordesoxiglucose F18/química , Humanos , Microscopia de Fluorescência/instrumentação , Método de Monte Carlo , Contagem de Cintilação
8.
Sci Rep ; 10(1): 9313, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518372

RESUMO

The clinical translation of theranostic 177Lu-radiopharmaceuticals based on inhibitors of the prostate-specific membrane antigen (PSMA) has demonstrated positive clinical responses in patients with advanced prostate cancer (PCa). However, challenges still remain, particularly regarding their pharmacokinetic and dosimetric properties. We developed a potential PSMA-immunotheranostic agent by conjugation of a single-chain variable fragment of the IgGD2B antibody (scFvD2B) to DOTA, to obtain a 177Lu-labelled agent with a better pharmacokinetic profile than those previously reported. The labelled conjugated 177Lu-scFvD2B was obtained in high yield and stability. In vitro, 177Lu-scFvD2B disclosed a higher binding and internalization in LNCaP (PSMA-positive) compared to PC3 (negative control) human PCa cells. In vivo studies in healthy nude mice revealed that 177Lu-scFvD2B present a favorable biokinetic profile, characterized by a rapid clearance from non-target tissues and minimal liver accumulation, but a slow wash-out from kidneys. Micro-SPECT/CT imaging of mice bearing pulmonary microtumors evidenced a slow uptake by LNCaP tumors, which steadily rose up to a maximum value of 3.6 SUV at 192 h. This high and prolonged tumor uptake suggests that 177Lu-scFvD2B has great potential in delivering ablative radiation doses to PSMA-expressing tumors, and warrants further studies to evaluate its preclinical therapeutic efficacy.


Assuntos
Antígenos de Superfície/metabolismo , Antineoplásicos Imunológicos/farmacocinética , Glutamato Carboxipeptidase II/metabolismo , Imunoconjugados/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Compostos Radiofarmacêuticos/farmacocinética , Animais , Antígenos de Superfície/imunologia , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Glutamato Carboxipeptidase II/imunologia , Compostos Heterocíclicos com 1 Anel/química , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Região Variável de Imunoglobulina/química , Lutécio/farmacocinética , Masculino , Camundongos Nus , Células PC-3 , Medicina de Precisão/métodos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/química , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Anticorpos de Cadeia Única/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
9.
PLoS One ; 15(6): e0234772, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555746

RESUMO

Glioblastoma is the most aggressive primary brain tumor leading to death in most of patients. It comprises almost 50-55% of all gliomas with an incidence rate of 2-3 per 100,000. Despite its rarity, overall mortality of glioblastoma is comparable to the most frequent tumors. The current standard treatment combines surgical resection, radiotherapy and chemotherapy with temozolomide. In spite of this aggressive multimodality protocol, prognosis of glioblastoma is poor and the median survival remains about 12-14.5 months. In this regard, new therapeutic approaches should be developed to improve the life quality and survival time of the patient after the initial diagnosis. Before switching to clinical trials in humans, all innovative therapeutic methods must be studied first on a relevant animal model in preclinical settings. In this regard, we validated the feasibility of intratumoral delivery of a holmium (Ho) microparticle suspension to an induced U87 glioblastoma model. Among the different radioactive beta emitters, 166Ho emits high-energy ß(-) radiation and low-energy γ radiation. ß(-) radiation is an effective means for tumor destruction and γ rays are well suited for imaging (SPECT) and consequent dosimetry. In addition, the paramagnetic Ho nucleus is a good asset to perform MRI imaging. In this study, five minipigs, implanted with our glioblastoma model were used to test the injectability of 165Ho (stable) using a bespoke injector and needle. The suspension was produced in the form of Ho microparticles and injected inside the tumor by a technique known as microbrachytherapy using a stereotactic system. At the end of this trial, it was found that the 165Ho suspension can be injected successfully inside the tumor with absence or minimal traces of Ho reflux after the injections. This injection technique and the use of the 165Ho suspension needs to be further assessed with radioactive 166Ho in future studies.


Assuntos
Neoplasias Encefálicas/radioterapia , Glioblastoma/radioterapia , Hólmio/química , Compostos Radiofarmacêuticos/administração & dosagem , Siloxanas/química , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Humanos , Masculino , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Suínos , Porco Miniatura , Tomografia Computadorizada de Emissão de Fóton Único , Transplante Heterólogo
10.
Proc Natl Acad Sci U S A ; 117(23): 12991-12999, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32439710

RESUMO

Malignant melanoma has one of the highest mortality rates of any cancer because of its aggressive nature and high metastatic potential. Clinical staging of the disease at the time of diagnosis is very important for the prognosis and outcome of melanoma treatment. In this study, we designed and synthesized the 18F-labeled pyridine-based benzamide derivatives N-(2-(dimethylamino)ethyl)-5-[18F]fluoropicolinamide ([18F]DMPY2) and N-(2-(dimethylamino)ethyl)-6-[18F]fluoronicotinamide ([18F]DMPY3) to detect primary and metastatic melanoma at an early stage and evaluated their performance in this task. [18F]DMPY2 and [18F]DMPY3 were synthesized by direct radiofluorination of the bromo precursor, and radiochemical yields were ∼15-20%. Cell uptakes of [18F]DMPY2 and [18F]DMPY3 were >103-fold and 18-fold higher, respectively, in B16F10 (mouse melanoma) cells than in negative control cells. Biodistribution studies revealed strong tumor uptake and retention of [18F]DMPY2 (24.8% injected dose per gram of tissue [ID/g] at 60 min) and [18F]DMPY3 (11.7%ID/g at 60 min) in B16F10 xenografts. MicroPET imaging of both agents demonstrated strong tumoral uptake/retention and rapid washout, resulting in excellent tumor-to-background contrast in B16F10 xenografts. In particular, [18F]DMPY2 clearly visualized almost all metastatic lesions in lung and lymph nodes, with excellent image quality. [18F]DMPY2 demonstrated a significantly higher tumor-to-liver ratio than [18F]fluorodeoxyglucose ([18F]FDG) and the previously reported benzamide tracers N-[2-(diethylamino)-ethyl]-5-[18F]fluoropicolinamide ([18F]P3BZA) and N-[2-(diethylamino)-ethyl]-4-[18F]fluorobenzamide ([18F]FBZA) in B16F10-bearing or SK-MEL-3 (human melanoma)-bearing mice. In conclusion, [18F]DMPY2 might have strong potential for the diagnosis of early stage primary and metastatic melanoma using positron emission tomography (PET).


Assuntos
Melanoma/diagnóstico por imagem , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Neoplasias Cutâneas/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Radioisótopos de Flúor/administração & dosagem , Humanos , Camundongos , Ácidos Picolínicos/administração & dosagem , Compostos Radiofarmacêuticos/química , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Commun ; 11(1): 1736, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269227

RESUMO

Carbon-11 (11C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce 11C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS) 11C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [11C]CO2 and [11C]CH3I into molecules with diversified structures. It provides facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology.


Assuntos
Radioisótopos de Carbono/química , Fluoretos/química , Compostos de Organossilício/química , Acetoacetatos/química , Metilação , Racloprida/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
12.
Inorg Chem ; 59(8): 5728-5741, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32242663

RESUMO

[44/47Sc]Sc3+, [68Ga]Ga3+, and [111In]In3+ are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the toolbox of nuclear medicine. In this study, all three of the metal ions are successfully chelated using a new oxine-based hexadentate ligand, H3glyox, which forms thermodynamically stable neutral complexes with exceptionally high pM values [pIn (34) > pSc (26) > pGa (24.9)]. X-ray diffraction single crystal structures with stable isotopes revealed that the ligand is highly preorganized and has a perfect fit to size cavity to form [Sc(glyox)(H2O)] and [In(glyox)(H2O)] complexes. Quantitative radiolabeling with gallium-68 (RCY > 95%, [L] = 10-5 M) and indium-111 (RCY > 99%, [L] = 10-8 M) was achieved under ambient conditions (RT, pH 7, and 15 min) with very high apparent molar activities of 750 MBq/µmol and 650 MBq/nmol, respectively. Preliminary quantitative radiolabeling of [44Sc]ScCl3 (RCY > 99%, [L] = 10-6 M) was fast at room temperature (pH 7 and 10 min). In vitro experiments revealed exceptional stability of both [68Ga]Ga(glyox) and [111In]In(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, H3glyox exhibits enhanced fluorescence, which was employed to determine the stability constants for Sc(glyox) in addition to the in-batch UV-vis spectrophotometric titrations; as a proof-of-concept these complexes were used to obtain fluorescence images of live HeLa cells using Sc(glyox) and Ga(glyox), confirming the viability of the cells. These initial investigations suggest H3glyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.


Assuntos
Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Corantes Fluorescentes/farmacologia , Oximas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Quelantes/síntese química , Complexos de Coordenação/sangue , Complexos de Coordenação/química , Estabilidade de Medicamentos , Corantes Fluorescentes/química , Radioisótopos de Gálio/química , Células HeLa , Humanos , Radioisótopos de Índio/química , Marcação por Isótopo , Ligantes , Microscopia de Fluorescência/métodos , Oximas/síntese química , Estudo de Prova de Conceito , Radioisótopos/química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/química , Escândio/química , Termodinâmica
13.
Molecules ; 25(6)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32245032

RESUMO

The α7 nicotinic acetylcholine receptor (α7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer's disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [125I]Iodo-ASEM [(3-(1,4-diazabycyclo[3.2.2]nonan-4-yl)-6-(125I-iododibenzo[b,d]thiopentene 5,5-dioxide)] in the mouse, rat and pig brain using autoradiography. The in vivo binding properties of [18F]ASEM were investigated using positron emission tomography (PET) in the pig brain. [125I]Iodo-ASEM showed specific and displaceable high affinity (~1 nM) binding in mouse, rat, and pig brain. Binding pattern overlapped with [125I]α-bungarotoxin, specific binding was absent in α7 nAChR gene-deficient mice and binding was blocked by a range of α7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in ß2 nAChR gene-deficient mice was lower for [125I]Iodo-ASEM (58% ± 2.7%) than [125I]α-bungarotoxin (23% ± 0.2%), potentially indicating different binding properties to heteromeric α7ß2 nAChR. [18F]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for α7 nAChR. Blocking with SSR-180,711 resulted in a significant decrease in [18F]ASEM binding. Our findings indicate that [125I]Iodo-ASEM allows sensitive and selective imaging of α7 nAChR in vitro, with better signal-to-noise ratio than previous tracers. Preliminary data of [18F]ASEM in the pig brain demonstrated principal suitable kinetic properties for in vivo quantification of α7 nAChR, comparable to previously published data.


Assuntos
Fluordesoxiglucose F18 , Radioisótopos do Iodo , Traçadores Radioativos , Compostos Radiofarmacêuticos , Tiofenos/química , Receptor Nicotínico de Acetilcolina alfa7/química , Animais , Autorradiografia , Fluordesoxiglucose F18/química , Radioisótopos do Iodo/química , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Ligação Proteica , Multimerização Proteica , Compostos Radiofarmacêuticos/química , Suínos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
14.
Molecules ; 25(7)2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32283680

RESUMO

The need for increasingly personalized medicine solutions (precision medicine) and quality medical treatments, has led to a growing demand and research for image-guided therapeutic solutions. Positron emission tomography (PET) is a powerful imaging technique that can be established using complementary imaging systems and selective imaging agents-chemical probes or radiotracers-which are drugs labeled with a radionuclide, also called radiopharmaceuticals. PET has two complementary purposes: selective imaging for diagnosis and monitoring of disease progression and response to treatment. The development of selective imaging agents is a growing research area, with a high number of diverse drugs, labeled with different radionuclides, being reported nowadays. This review article is focused on the use of pyrazoles as suitable scaffolds for the development of 18F-labeled radiotracers for PET imaging. A brief introduction to PET and pyrazoles, as key scaffolds in medicinal chemistry, is presented, followed by a description of the most important [18F]pyrazole-derived radiotracers (PET tracers) that have been developed in the last 20 years for selective PET imaging, grouped according to their specific targets.


Assuntos
Radioisótopos de Flúor/química , Tomografia por Emissão de Pósitrons , Pirazóis/química , Traçadores Radioativos , Compostos Radiofarmacêuticos/química , Animais , Desenvolvimento de Medicamentos , Humanos , Ligantes , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica , Relação Estrutura-Atividade
15.
Molecules ; 25(7)2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32290196

RESUMO

Prostate cancer is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related deaths in Western civilization. Although localized prostate cancer can be treated effectively in different ways, almost all patients progress to the incurable metastatic castration-resistant prostate cancer. Due to the significant mortality and morbidity rate associated with the progression of this disease, there is an urgent need for new and targeted treatments. In this review, we summarize the recent advances in research on identification of prostate tissue-specific antigens for targeted therapy, generation of highly specific and selective molecules targeting these antigens, availability of therapeutic radionuclides for widespread medical applications, and recent achievements in the development of new-generation small-molecule inhibitors and antibody-based strategies for targeted prostate cancer therapy with alpha-, beta-, and Auger electron-emitting radionuclides.


Assuntos
Terapia de Alvo Molecular , Neoplasias da Próstata/terapia , Radioisótopos , Compostos Radiofarmacêuticos , Animais , Biomarcadores Tumorais , Desenvolvimento de Medicamentos , Humanos , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Ligantes , Masculino , Terapia de Alvo Molecular/métodos , Nanopartículas/química , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Radioisótopos/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/química , Nanomedicina Teranóstica
16.
Int J Mol Sci ; 21(7)2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32225110

RESUMO

BACKGROUND: CD73 is an ectonucleotidase regulating extracellular adenosine concentration and plays an important role in adenosine-mediated immunosuppressive pathways. The efficacy of CD73-targeted therapy depends on the expression levels of CD73; therefore, monitoring CD73 status in cancer patients would provide helpful information for selection of patients who would benefit from CD73-targeted therapy. Here, we evaluated the ability of 111In-labeled antibody 067-213, which has high affinity for human CD73, to act as a noninvasive imaging probe. METHODS: Cell binding and competitive inhibition assays for 111In-labeled 067-213 were conducted using MIAPaCa-2 (high CD73 expression) and A431 (low CD73 expression) cells. For in vivo assessments, biodistribution and SPECT/CT studies were conducted in MIAPaCa-2 and A431 tumor-bearing mice. To estimate the absorbed dose in humans, biodistribution and SPECT/CT studies were conducted in healthy rats. RESULTS: 111In-labeled 067-213 bound to MIAPaCa-2 and A431 cells in a CD73-dependent manner and the affinity loss after 111In-labeling was limited. Biodistribution and SPECT/CT studies with 111In-labeled 067-213 in mice showed high uptake in MIAPaCa-2 tumors and lower uptake in A431 tumors. In rats, the probe did not show high uptake in normal organs, including endogenously CD73-expressing organs. The estimated absorbed doses in humans were reasonably low. CONCLUSIONS: 111In-labeled 067-213 showed CD73-expression-dependent tumor uptake and low uptake in normal organs and tissues. Radiolabeled 067-213 holds promise as an imaging probe for noninvasive evaluation of CD73 expression levels in patients. Our data encourage further clinical studies to clarify a role for CD73 monitoring in patients receiving CD73-targeted immune therapy.


Assuntos
5'-Nucleotidase/imunologia , Anticorpos Monoclonais/imunologia , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Anticorpos Monoclonais/química , Linhagem Celular Tumoral , Feminino , Humanos , Radioisótopos de Índio/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Radiofarmacêuticos/química , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
17.
Int J Mol Sci ; 21(6)2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32183096

RESUMO

HER3-binding affibody molecules are a promising format for visualization of HER3 expression. Cobalt-55, a positron-emitting isotope, with a half-life of 17.5 h, allows for next-day imaging. We investigated the influence of the charge of the radiocobalt-chelator complex on the biodistribution of anti-HER3 affibody molecule (HE)3-ZHER3 and compared the best radiocobalt-labeled variant with a recently optimized gallium-labeled variant. Affibody conjugates (HE)3-ZHER3-X (X = NOTA, NODAGA, DOTA, DOTAGA) were labeled with [57Co]Co (surrogate for 55Co). Affinity measurements, binding specificity and cellular processing were studied in two HER3-expressing cancer cell lines. Biodistribution was studied 3 and 24 h post-injection (pi) in mice with HER3-expressing BxPC-3 xenografts and compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA. Micro-single-photon emission tomography/computed tomography (microSPECT/CT) and micro-positron emission tomography/computed tomography (microPET/CT) imaging was performed 3 and 24 h pi. Stably labeled conjugates bound to HER3 with subnanomolar affinity. [57Co]Co-(HE)3-ZHER3-DOTA had the best tumor retention and a significantly lower concentration in blood than other conjugates, leading to superior tumor-to-blood and tumor-to-liver ratios 24 h pi. Compared to [68Ga]Ga-(HE)3-ZHER3-NODAGA 3 h pi, [57Co]Co-(HE)3-ZHER3-DOTA provided superior imaging contrast in liver 24 h pi. Concluding, the composition and charge of the [57Co]Co-chelator complex influenced the uptake in tumors and normal tissue. [57Co]Co-(HE)3-ZHER3-DOTA provided the best imaging properties among the cobalt-labeled conjugates. Delayed imaging of HER3 expression with [57Co]Co-(HE)3-ZHER3-DOTA improved imaging contrast compared to early-time-point imaging with [68Ga]Ga-(HE)3-ZHER3-NODAGA.


Assuntos
Radioisótopos de Cobalto/química , Neoplasias Experimentais/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Receptor ErbB-3/genética , Acetatos/química , Animais , Anticorpos/química , Anticorpos/imunologia , Linhagem Celular Tumoral , Feminino , Compostos Heterocíclicos com 1 Anel/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ligação Proteica , Compostos Radiofarmacêuticos/química , Receptor ErbB-3/imunologia , Receptor ErbB-3/metabolismo , Distribuição Tecidual
18.
Int J Nanomedicine ; 15: 1253-1266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161456

RESUMO

Purpose: This study aimed to develop a chelate-free radiolabeled nanoparticle platform for simultaneous positron emission tomography (PET) and magnetic resonance (MR) imaging that provides contrast-enhanced diagnostic imaging and significant image quality gain by integrating the high spatial resolution of MR with the high sensitivity of PET. Methods: A commercially available super-paramagnetic iron oxide nanoparticle (SPION) (Feraheme®, FH) was labeled with the [89Zr]Zr using a novel chelate-free radiolabeling technique, heat-induced radiolabeling (HIR). Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and radio-thin layer chromatography (radio-TLC). Characterization of the non-radioactive isotope 90Zr-labeled FH was performed by transmission electron microscopy (TEM). Simultaneous PET-MR phantom imaging was performed with different 89Zr-FH concentrations. The MR quantitative image analysis determined the contrast-enhancing properties of FH. The signal-to-noise ratio (SNR) and full-width half-maximum (FWHM) of the line spread function (LSF) were calculated before and after co-registering the PET and MR image data. Results: High RCY (92%) and RCP (98%) of the [89Zr]Zr-FH product was achieved. TEM analysis confirmed the 90Zr atoms adsorption onto the SPION surface (≈ 10% average radial increase). Simultaneous PET-MR scans confirmed the capability of the [89Zr]Zr-FH nano-platform for this multi-modal imaging technique. Relative contrast image analysis showed that [89Zr]Zr-FH can act as a dual-mode T1/T2 contrast agent. For co-registered PET-MR images, higher spatial resolution (FWHM enhancement ≈ 3) and SNR (enhancement ≈ 8) was achieved at a clinical dose of radio-isotope and Fe. Conclusion: Our results demonstrate FH is a highly suitable SPION-based platform for chelate-free labeling of PET tracers for hybrid PET-MR. The high RCY and RCP confirmed the robustness of the chelate-free HIR technique. An overall image quality gain was achieved compared to PET- or MR-alone imaging with a relatively low dosage of [89Zr]Zr-FH. Additionally, FH is suitable as a dual-mode T1/T2 MR image contrast agent.


Assuntos
Imagem por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/química , Cromatografia em Gel , Cromatografia em Camada Delgada , Meios de Contraste/química , Óxido Ferroso-Férrico/química , Humanos , Nanopartículas de Magnetita/uso terapêutico , Imagens de Fantasmas , Radioisótopos/química , Razão Sinal-Ruído , Zircônio/química
19.
Jpn J Clin Oncol ; 50(4): 349-356, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32147685

RESUMO

From a clinical perspective, prostate-specific membrane antigen (PSMA) is a valuable target for both diagnosis and radioligand therapy (RLT) of prostate cancer. The term 'specific' has been used to characterize a histologic hallmark of overexpression in the membrane of most prostate cancer. Many PSMA ligands have been developed since the previous decade and have been used in several clinical trials and clinical studies. However, procedure, specification, protocol, interpretation criteria, radiation dose, and cost-effectiveness of PSMA ligands have not been fully explained. Regardless of worldwide use of promising PSMA-ligand PET and RLT, it has not been approved in Japan. Expedited introduction of PSMA-ligand PET and RLT to Japan and implementation of clinical study are eager for many patients with prostate cancer.


Assuntos
Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/terapia , Compostos Radiofarmacêuticos/uso terapêutico , Humanos , Ligantes , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos/química
20.
Cancer Biother Radiopharm ; 35(3): 163-166, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32196363

RESUMO

Gallium-68 (68Ga) is an important radionuclide due to its successful use in the clinic. Currently, 68Ga is produced and supplied by using germanium-68/Gallium-68 (68Ge/68Ga) generator systems in the preclinical and clinical environments. Until recently, the supply of 68Ge/68Ga generators, specifically the good manufacturing practices (GMP) grade, had a long lead time (up to 18 months). This led researchers to investigate the cyclotron production of 68Ga by using solid and liquid targets. This report summarizes an overview of the chemistry, coordination chemistry, and radiochemistry of Ga and the current status of manufacturing and supply of 68Ga radionuclide.


Assuntos
Radioisótopos de Gálio/química , Compostos Radiofarmacêuticos/química
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