RESUMEN

We designed and synthesized a novel platinum complex conjugated with 2-fluorinated 2-deoxyglucoside, named FGC-Pt, to capitalize on the Warburg effect and metabolic trapping properties of [18F]2-deoxy-2-fluoro-d-glucose ([18F]FDG). Then, we conducted comprehensive in vitro and in vivo studies to evaluate the effects of FGC-Pt. In vitro cytotoxicity assays using HeLa cells revealed that FGC-Pt exhibited concentration-dependent cytotoxicity, even though its cytotoxic effect was less pronounced than that of cisplatin. In the evaluation of in vivo biodistribution in mice, platinum concentration in tumors and major organs (muscle, bone, blood, liver, and kidney) and the ratio of platinum concentration in tumors to major organs following the tail vein injection of FGC-Pt and cisplatin suggest that FGC-Pt is more retained in tumors than in other organs and tends to accumulate in tumors more than cisplatin. Furthermore, an in vivo assessment of the antitumor effect conducted in A549 cell-bearing mice demonstrated that FGC-Pt possesses substantial potential as an antitumor agent. It exhibited a tumor growth-inhibitory effect comparable to that of cisplatin while inducing lower toxicity, as evidenced by lower weight loss after administration. Herein, we successfully produced a novel compound with a tumor-growth-inhibitory effect comparable to that of cisplatin and low toxicity.

RESUMEN

Acyclic asymmetric quaternary stereocenters, which are composed of four carbon-carbon bonds, were finely constructed by utilizing a face-selective alkylation of enolate intermediates derived from an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,ß-unsaturated esters. The present face-selective alkylation was able to employ diverse alkyl halides as an electrophile to afford various Michael adducts having an all-carbon quaternary stereocenter. With regard to the deprotection of the chiral auxiliary, N-iodosuccinimide used in our previous study did not work in the present cases; however, we found that pyridine iodine monochloride in the presence of H2O was effective to remove the bornyl group and the benzyl group on the amino group to provide the ß-amino ester derivative.

Asunto(s)

Aminas/química , Carbono/química , Ésteres/química , Estructura Molecular , Estereoisomerismo

RESUMEN

Erythropoietin-producing hepatocellular (Eph) receptors are receptor tyrosine kinases involved in cell-cell contact. The EphA2 receptor is associated with cancer proliferation and migration. Therefore, EphA2 receptor imaging has the potential for cancer diagnosis. Here, we synthesized N-(5-((4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)-2-methylphenyl)-5-[123I]iodonicotinamide ([123I]ETB) and evaluated it as an imaging tracer for single-photon emission computed tomography (SPECT) imaging of the EphA2 receptor. [123I]ETB was designed on the basis of ALW-II-41-27, an inhibitor of EphA2 receptor kinase. Nonradioactive ETB was also synthesized and has been shown to efficiently inhibit EphA2 receptor kinase activity in vitro (IC50: ETB, 90.2 ± 18.9 nM). A cell-binding assay demonstrated that [125I]ETB binds specifically to the EphA2 receptor. The ex vivo biodistribution study of [125I]ETB in U87MG tumor-bearing mice also revealed tumor uptake (2.2% ID/g at 240 min). In addition, [123I]ETB uptake in tumors was visualized via SPECT/CT imaging. On the basis of the above, [123I]ETB can be considered a potential SPECT imaging tracer for the EphA2 receptor.

RESUMEN

Glucose transporter 2 (GLUT2) is involved in glucose uptake by hepatocytes, pancreatic beta cells, and absorptive cells in the intestine and proximal tubules in the kidney. Pancreatic GLUT2 also plays an important role in the mechanism of glucose-stimulated insulin secretion. In this study, novel Fluorine-18-labeled streptozotocin (STZ) derivatives were synthesized to serve as glycoside analogs for in-vivo GLUT2 imaging. Fluorine was introduced to hexyl groups at the 3'-positions of the compounds, and we aimed to synthesize compounds that were more stable than STZ. The nitroso derivatives exhibited relatively good stability during purification and purity analysis after radiosynthesis. We then evaluated the compounds in PET imaging and ex-vivo biodistribution studies. We observed high levels of radioactivity in the liver and kidney, which indicated accumulation in these organs within 5 min of administration. In contrast, the denitroso derivatives accumulated only in the kidney and bladder shortly after administration. Compounds with nitroso groups are thus expected to accumulate in GLUT2-expressing organs, and the presence of a nitroso group is essential for in-vivo GLUT2 imaging.

Asunto(s)

Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Estreptozocina/química , Animales , Radioisótopos de Flúor/química , Transportador de Glucosa de Tipo 2/metabolismo , Cinética , Ratones , Radiofármacos/química , Radiofármacos/metabolismo , Estreptozocina/síntesis química , Estreptozocina/metabolismo , Distribución Tisular

RESUMEN

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels that have been implicated in higher brain functions. To elucidate the functional mechanisms underlying nAChRs and contribute significantly to development of drugs targeting neurological and neuropsychiatric diseases, non-invasive nuclear medical imaging can be used for evaluation. In addition, technetium-99m (99mTc) is a versatile radionuclide used clinically as a tracer in single-photon emission computed tomography. Because A85380 is known as a potent α4ß2-nAChR agonist, we prepared A85380 derivatives labeled with 99mTc using a bifunctional chelate system. A computational scientific approach was used to design the probe efficiently. We used non-radioactive rhenium (Re) for a 99mTc analog and found that one of the derivatives, Re-A-YN-IDA-C4, exhibited high binding affinity at α4ß2-nAChR in both the docking simulation (-19.3 kcal/mol) and binding assay (Ki = 0.4 ±â€¯0.04 nM). Further, 99mTc-A-YN-IDA-C4 was synthesized using microwaves, and its properties were examined. Consequently, we found that 99mTc-A-YN-IDA-C4, with a structure optimized by using computational chemistry techniques, maintained affinity and selectivity for nAChR in vitro and possessed efficient characteristics as a nuclear medicine molecular imaging probe, demonstrated usefulness of computational scientific approach for molecular improvement strategy.

Asunto(s)

Radioisótopos/química , Receptores Nicotínicos/metabolismo , Tecnecio/química , Tomografía Computarizada de Emisión de Fotón Único/métodos , Humanos

RESUMEN

Quantitative evaluations of the functions of uptake and efflux transporters directly in vivo is desired to understand an efficient hepatobiliary transport of substrate drugs. Pitavastatin is a substrate of organic anion transporting polypeptides (OATPs) and canalicular efflux transporters; thus, it can be a suitable probe for positron-emission tomography (PET) imaging of hepatic transporter functions. To characterize the performance of [18F]PTV-F1, an analogue of pitavastatin, we investigated the impact of rifampicin (a typical OATP inhibitor) coadministration or Bcrp (breast cancer resistance protein) knockout on [18F]PTV-F1 hepatic uptake and efflux in rats by PET imaging. After intravenous administration, [18F]PTV-F1 selectively accumulated in the liver, and the radioactivity detected in plasma, liver, and bile mainly derived from the parent PTV-F1 during the PET study (∼40 min). Coadministration of rifampicin largely decreased the hepatic uptake of [18F]PTV-F1 by 73%. Because of its lower clearance in rats, [18F]PTV-F1 is more sensitive for monitoring changes in hepatic OATP1B function that other previously reported OATP1B PET probes. Rifampicin coadministration also significantly decreased the biliary excretion of radioactivity by 65%. Bcrp knockout did not show a significant impact on its biliary excretion.[18F]PTV-F1 enables quantitative analysis of the hepatobiliary transport system for organic anions.

Asunto(s)

Bilis/metabolismo , Hígado/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Tomografía de Emisión de Positrones , Quinolinas/química , Administración Intravenosa , Animales , Transporte Biológico , Radioisótopos de Flúor , Hígado/química , Masculino , Proteínas de Transporte de Membrana/química , Quinolinas/administración & dosificación , Quinolinas/metabolismo , Ratas , Ratas Sprague-Dawley

Asunto(s)

Oclusión Coronaria/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Imagen de Perfusión Miocárdica/métodos , Tomografía de Emisión de Positrones , Piridazinas/administración & dosificación , Radiofármacos/administración & dosificación , Animales , Oclusión Coronaria/metabolismo , Oclusión Coronaria/fisiopatología , Modelos Animales de Enfermedad , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Inyecciones Intravenosas , Miocardio/metabolismo , Piridazinas/farmacocinética , Radiofármacos/farmacocinética , Sus scrofa , Distribución Tisular

RESUMEN

We have designed (S)-(5-(azetidin-2-ylmethoxy)pyridine-3-yl)methyl cyclopentadienyltricarbonyl technetium carboxylate ([99mTc]CPTT-A-E) with high affinity for nicotinic acetylcholine receptors (nAChRs) using (2(S)-azetidinylmethoxy)-pyridine (A-85380) as the lead compound to develop a Tc-99m-cyclopentadienyltricarbonyl-technetium (99mTc)-labeled nAChR imaging probe. Because technetium does not contain a stable isotope, cyclopentadienyltricarbonyl rhenium (CPTR) was synthesized by coordinating rhenium, which is a homologous element having the same coordination structure as technetium. Further, the binding affinity to nAChR was evaluated. CPTR-A-E exhibited a high binding affinity to nAChR (Ki = 0.55 nM). Through the radiosynthesis of [99mTc]CPTT-A-E, an objective compound could be obtained with a radiochemical yield of 33% and a radiochemical purity of greater than 97%. In vitro autoradiographic study of the brain exhibited that the local nAChR density strongly correlated with the amount of [99mTc]CPTT-A-E that was accumulated in each region of interest. Further, the in vivo evaluation of biodistribution revealed a higher accumulation of [99mTc]CPTT-A-E in the thalamus (characterized by the high nAChR density) when compared with that in the cerebellum (characterized by the low nAChR density). Although additional studies will be necessary to improve the uptake of [99mTc]CPTT-A-E to the brain, [99mTc]CPTT-A-E met the basic requirements for nAChR imaging.

Asunto(s)

Azetidinas/farmacología , Encéfalo/metabolismo , Compuestos de Organotecnecio/farmacología , Radiofármacos/farmacología , Receptores Nicotínicos/metabolismo , Animales , Azetidinas/síntesis química , Azetidinas/farmacocinética , Masculino , Ratones , Compuestos de Organotecnecio/síntesis química , Compuestos de Organotecnecio/farmacocinética , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Ratas Sprague-Dawley , Tomografía Computarizada de Emisión de Fotón Único/métodos

RESUMEN

Gallium-68 (68 Ga, t1/2  = 68 min) can be easily obtained from a 68 Ge/68 Ga generator, and several such systems are commercially available. The use of positron emission tomography (PET) imaging using 68 Ga-labeled radiopharmaceuticals is expected to increase in both preclinical and clinical settings. However, the chelation between a 68 Ga cation and the bifunctional macrocyclic chelates that are used for labeling bioactive substances, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), requires a relatively long reaction time and high temperature to achieve a high radiochemical yield. Previously, we reported on a novel resonant-type microwave reactor that can be used for radiosynthesis and the usefulness of this reactor in the PET radiosynthesis of 18 F. In the present study, the usefulness of this resonant-type microwave reactor was evaluated for the radiolabeling of model macrocyclic chelates with 68 Ga. As a result, microwave heating of resonant-type microwave reactor notably improved the rate of the 68 Ga labeling chelate reaction in a short time period of 2 minutes, compared with the use of a conventional heating method. Additionally, it was found that the use of this reactor made it possible to decrease the amount of precursors required in the reaction and to improve the molar activity of the labeled compounds.

Asunto(s)

Radioisótopos de Galio/química , Compuestos Heterocíclicos con 1 Anillo/química , Radiofármacos/síntesis química , Quelantes/química , Técnicas de Química Sintética/instrumentación , Técnicas de Química Sintética/métodos , Microondas

RESUMEN

A facile and convenient synthesis of trisubstituted (E)-α,ß-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in ß-hydroxy esters, furnishing α,ß-unsaturated esters in shorter steps than the previous method: an acetylation of ß-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,ß-unsaturated esters.

Asunto(s)

Ésteres/síntesis química , Acetilación , Ésteres/química , Estructura Molecular , Estereoisomerismo

RESUMEN

The renin angiotensin aldosterone system (RAAS) is a hormonal cascade involved in the regulation of blood pressure and electrolyte balance, and represents a common target for the treatment of various diseases including hypertension, heart failure, and diabetes. Herein we present a novel 18 F-labeled derivative of the drug irbesartan, one of the most prescribed angiotensin II type 1 receptor (AT1 R) antagonists, for in vivo positron emission tomography (PET). This allows the in vivo measurement of AT1 R expression, and thus the evaluation of functional changes in its expression under pathophysiological conditions. We followed various synthetic approaches optimized for the introduction of fluorine into different positions of the aliphatic side chain of irbesartan. Radioligand binding studies revealed that fluorine atoms at specified positions (α-position (IC50 =6.6 nm) and δ-position (IC50 =8.5 nm) of the aliphatic side chain) do not alter the binding properties of irbesartan (IC50 =1.6 nm). After successful radiolabeling with fluorine-18 in a radiochemical yield of 11 %, we observed high renal uptake in healthy rats and pigs, which could be decreased by pretreatment with the parent compound irbesartan.

Asunto(s)

Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Radioisótopos de Flúor/química , Irbesartán/análogos & derivados , Tomografía de Emisión de Positrones/métodos , Radiofármacos/química , Receptores de Angiotensina/análisis , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Animales , Femenino , Radioisótopos de Flúor/farmacocinética , Irbesartán/farmacocinética , Riñón/química , Riñón/diagnóstico por imagen , Riñón/metabolismo , Radiofármacos/farmacocinética , Porcinos

RESUMEN

The tripeptide formyl-Met-Leu-Phe (fMLF) is a prototype of N-formylated chemotactic peptides for neutrophils owing to its ability to bind and activate the G protein-coupled formyl peptide receptor (FPR). Here, we developed an 18F-labeled fMLF derivative targeting FPR as a positron emission tomography (PET) imaging probe for bacterial infections. The study demonstrates that the fMLF derivative fMLFXYk(FB)k (X = Nle) has a high affinity for FPR (Ki = 0.62 ±â€¯0.13 nM). The radiochemical yield and purity of [18F]fMLFXYk(FB)k were 16% and >96%, respectively. The in vivo biodistribution study showed that [18F]fMLFXYk(FB)k uptake was higher in the bacterial infected region than in the non-infected region. We observed considerably higher infection-to-muscle ratio of 4.6 at 60 min after [18F]fMLFXYk(FB)k injection. Furthermore, small-animal PET imaging studies suggested that [18F]fMLFXYk(FB)k uptake in the bacterial infected region was clearly visualized 60 min after injection.

Asunto(s)

Infecciones por Escherichia coli/diagnóstico por imagen , Sondas Moleculares/química , N-Formilmetionina Leucil-Fenilalanina/química , Tomografía de Emisión de Positrones , Relación Dosis-Respuesta a Droga , Radioisótopos de Flúor , Sondas Moleculares/síntesis química , Estructura Molecular , N-Formilmetionina Leucil-Fenilalanina/síntesis química , Relación Estructura-Actividad

RESUMEN

Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR-TKIs) are used as molecular targeted therapy for non-small cell lung cancer (NSCLC) patients. The therapy is applied to the patients having EGFR-primary L858R mutation, but drug tolerance caused by EGFR-secondary mutation is occurred within one and half years. For the non-invasive detection of the EGFR-TKIs treatment positive patients by positron emission tomograpy (PET) imagaing, fluorine-18 labeled thienopyrimidine derivative, [18F]FTP2 was newly synthesized. EGFR inhibition assay, cell uptake study, and blocking study indicated [18F]FTP2 binds with high and selective affinity for EGFR with L858R mutation, and not with L858R/T790M dual mutations. On animal PET study using tumor bearing mice, H3255 cells expressing L858R mutated EGFR was more clearly visualized than H1975 cells expressing L858R/T790M dual mutated EGFR. [18F]FTP2 has potential for detecting NSCLC which is susceptible to EGFR-TKI treatment.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/diagnóstico por imagen , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/química , Radiofármacos/química , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Relación Dosis-Respuesta a Droga , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Radiofármacos/síntesis química , Radiofármacos/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

ß-cell mass (BCM) is known to be decreased in subjects with type-2 diabetes (T2D). Quantitative analysis for BCM would be useful for understanding how T2D progresses and how BCM affects treatment efficacy and for earlier diagnosis of T2D and development of new therapeutic strategies. However, a noninvasive method to measure BCM has not yet been developed. We developed four 18F-labeled exendin(9-39) derivatives for ß-cell imaging by PET: [18F]FB9-Ex(9-39), [18F]FB12-Ex(9-39), [18F]FB27-Ex(9-39), and [18F]FB40-Ex(9-39). Affinity to the glucagon-like peptide-1 receptor (GLP-1R) was evaluated with dispersed islet cells of ddY mice. Uptake of exendin(9-39) derivatives in the pancreas as well as in other organs was evaluated by a biodistribution study. Small-animal PET study was performed after injecting [18F]FB40-Ex(9-39). FB40-Ex(9-39) showed moderate affinity to the GLP-1R. Among all of the derivatives, [18F]FB40-Ex(9-39) resulted in the highest uptake of radioactivity in the pancreas 30 min after injection. Moreover, it showed significantly less radioactivity accumulated in the liver and kidney, resulting in an overall increase in the pancreas-to-organ ratio. In the PET imaging study, pancreas was visualized at 30 min after injection of [18F]FB40-Ex(9-39). [18F]FB40-Ex(9-39) met the basic requirements for an imaging probe for GLP-1R in pancreatic ß-cells. Further enhancement of pancreatic uptake and specific binding to GLP-1R will lead to a clear visualization of pancreatic ß-cells.

Asunto(s)

Receptor del Péptido 1 Similar al Glucagón/metabolismo , Islotes Pancreáticos/metabolismo , Imagen Molecular , Fragmentos de Péptidos/farmacocinética , Radiofármacos/farmacocinética , Animales , Relación Dosis-Respuesta a Droga , Radioisótopos de Flúor , Islotes Pancreáticos/citología , Masculino , Ratones , Ratones Endogámicos , Estructura Molecular , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/química , Tomografía de Emisión de Positrones , Radiofármacos/administración & dosificación , Radiofármacos/química , Relación Estructura-Actividad , Distribución Tisular

RESUMEN

A non-invasive method of pancreatic ß-cell mass measurement is needed to enhance our understanding of the pathogenesis of diabetes, facilitate the early diagnosis of this disease, and promote the development of novel therapeutics. Here, we described the synthesis of a novel indium-111 (111In) exendin-4 derivative, [Lys12(In-BnDTPA-Ahx)]exendin-4, through a process involving isothiocyanate-benzyl-DTPA (BnDTPA) and 6-aminohexanoic acid (Ahx) attached to an ɛ-amino group at the lysine-12 residue. We further evaluated the potential use of this derivative as a SPECT probe for pancreatic ß-cell imaging. An in vitro binding assay revealed that [Lys12(natIn-BnDTPA-Ahx)]exendin-4 has a high affinity for GLP-1 receptors (IC50=0.43nM). In biodistribution experiments involving normal mice, high [Lys12(111In-BnDTPA-Ahx)]exendin-4 uptake was observed in the pancreas (21.8 ± 4.0%ID/g) and was maintained for 2h after injection. Pre-injection of excess exendin(9-39) markedly reduced the pancreatic uptake of [Lys12(111In-BnDTPA-Ahx)]exendin-4 (95.2%), indicating that the uptake of this tracer is specific and mediated by GLP-1 receptors. Ex vivo autoradiography experiments involving pancreatic sections from MIP-GFP mice confirmed the accumulation of [Lys12(111In-BnDTPA-Ahx)]exendin-4 in pancreatic ß-cells. Finally, in mice, [Lys12(111In-BnDTPA-Ahx)]exendin-4 SPECT/CT yielded clear images of the pancreas at 30min post-injection. In conclusion, SPECT with [Lys12(111In-BnDTPA-Ahx)]exendin-4 enables to visualize ß-cells in vivo non-invasively.

Asunto(s)

Radioisótopos de Indio , Células Secretoras de Insulina/metabolismo , Imagen Molecular , Péptidos/síntesis química , Péptidos/farmacología , Tomografía Computarizada de Emisión de Fotón Único/métodos , Ponzoñas/síntesis química , Ponzoñas/farmacología , Animales , Bioensayo , Exenatida , Células Secretoras de Insulina/citología , Masculino , Ratones , Péptidos/química , Ponzoñas/química

RESUMEN

In nonsmall-cell lung carcinoma patients, L858R mutation of epidermal growth factor receptor (EGFR) is often found, and molecular target therapy using EGFR tyrosine kinase inhibitors is effective for the patients. However, the treatment frequently develops drug resistance by secondary mutation, of which approximately 50% is T790M mutation. Therefore, the ability to predict whether EGFR will undergo secondary mutation is extremely important. We synthesized a novel radiofluorinated 4-(anilino)pyrido[3,4-d]pyrimidine derivative ([18F]APP-1) and evaluated its potential as a positron emission tomography (PET) imaging probe to discriminate the difference in mutations of tumors. EGFR inhibition assay, cell uptake, and biodistribution study showed that [18F]APP-1 binds specifically to the L858R mutant EGFR but not to the L858R/T790M mutant. Finally, on PET imaging study using [18F]APP-1 with tumor-bearing mice, the H3255 tumor (L858R mutant) was more clearly visualized than the H1975 tumor (L858R/T790M mutant).

RESUMEN

We synthesize optically active (R)-terbutaline 2, which is an anti-asthmatic drug, through recyclable catalytic asymmetric transfer hydrogenation (RCATH). Various chloroketones 4 were prepared and RCATH was performed on them. The products exhibit moderate to high enantioselectivity. In particular, the hydrogenation of acyl substituted substrates 4c yields chiral secondary alcohols 5c in good yield and enantioselectivity. Furthermore, (R)-terbutaline 2 can be synthesized in one step from the resulting secondary alcohol 5 without racemization.

Asunto(s)

Antiasmáticos/síntesis química , Tecnología Química Verde , Líquidos Iónicos/química , Terbutalina/síntesis química , Antiasmáticos/química , Catálisis , Hidrogenación , Estructura Molecular , Estereoisomerismo , Terbutalina/química

RESUMEN

Insulinoma is a tumor derived from pancreatic ß-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (111In)-benzyl-diethylenetriaminepentaacetic acid (111In-BnDTPA)-conjugated exendin(9-39), 111In-BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50=2.5nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of 111In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6%ID/g at 15min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B=2.55, T/M=22.7, T/P=2.7 at 1h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1h after 111In-BnDTPA-exendin(9-39) injection, indicating that the GLP-1R mediated a majority of 111In-BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally, 111In-BnDTPA-exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30min post-injection. These results suggest that 111In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas.

Asunto(s)

Radioisótopos de Indio/química , Insulinoma/diagnóstico por imagen , Imagen Molecular , Neoplasias Pancreáticas/diagnóstico por imagen , Fragmentos de Péptidos/química , Radiofármacos/química , Tomografía Computarizada de Emisión de Fotón Único , Animales , Relación Dosis-Respuesta a Droga , Radioisótopos de Indio/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/síntesis química , Radiofármacos/administración & dosificación , Radiofármacos/síntesis química , Ratas , Relación Estructura-Actividad , Células Tumorales Cultivadas

RESUMEN

Pitavastatin is an antihyperlipidemic agent, a potent inhibitor of 3-hydroxymethyl-glutaryl-CoA reductase, which is selectively taken up into the liver mainly via hepatic organic anion transporting polypeptide 1B1 (OATP1B1). OATP1B1 can accept a variety of organic anions, and previous reports indicated that it is responsible for the hepatic clearance of several clinically used anionic drugs. Therefore, the pharmacokinetics and the hepatic distribution of pitavastatin provide an insight into the function of OATP1B1 in humans. For the development of the in vivo evaluation of OATP1B1 function by positron emission tomography imaging, we designed a novel [18 F]pitavastatin derivative ([18 F]PTV-F1), in which a [18 F]fluoroethoxy group is substituted for the [18 F]fluoro group of [18 F]pitavastatin, with the aim of convenient radiolabeling protocol and high radiochemical yield. In vitro studies suggested that transport activities of PTV-F1 mediated by OATP1B1 and OATP1B3 were very similar to those of pitavastatin and PTV-F1 was metabolically stable in human liver microsomes. In the radiosynthesis of [18 F]PTV-F1 from the tosylate precursor, nucleophilic fluorination and subsequent deprotection were performed using a one-pot procedure. [18 F]PTV-F1 was obtained with a radiochemical yield of 45% ± 3% (n = 3), and the operating time for the radiosynthesis of [18 F]PTV-F1 is very short (30 minutes) compared with [18 F]pitavastatin.

Asunto(s)

Técnicas de Química Sintética/métodos , Radioisótopos de Flúor/química , Hígado/metabolismo , Transportadores de Anión Orgánico/metabolismo , Quinolinas/síntesis química , Quinolinas/metabolismo , Radioquímica/métodos , Transporte Biológico , Quinolinas/química

RESUMEN

In the field of positron emission tomography (PET) radiochemistry, compact microreactors provide reliable and reproducible synthesis methods that reduce the use of expensive precursors for radiolabeling and make effective use of the limited space in a hot cell. To develop more compact microreactors for radiosynthesis of 18F-labeled compounds required for the multistep procedure, we attempted radiosynthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) via a three-step procedure using a microreactor. We examined individual steps for [18F]SFB using a batch reactor and microreactor and developed a new continuous-flow synthetic method with a single microfluidic chip to achieve rapid and efficient radiosynthesis of [18F]SFB. In the synthesis of [18F]SFB using this continuous-flow method, the three-step reaction was successfully completed within 6.5 min and the radiochemical yield was 64 ± 2% (n = 5). In addition, it was shown that the quality of [18F]SFB synthesized on this method was equal to that synthesized by conventional methods using a batch reactor in the radiolabeling of bovine serum albumin with [18F]SFB.

Asunto(s)

Benzoatos/síntesis química , Radioisótopos de Flúor/química , Microfluídica/métodos , Tomografía de Emisión de Positrones/métodos , Succinimidas/síntesis química , Benzoatos/química , Marcaje Isotópico/métodos , Radioquímica/métodos , Radiofármacos/química , Succinimidas/química