Synthesis and in vitro evaluation of 18F labeled tyrosine derivatives as potential positron emission tomography (PET) imaging agents

Three new ¹⁸F labeled fluoroalkyl tyrosine derivatives, O-(2-[¹⁸F]fluoroethyl)-α-methyltyrosine (FEMT, [¹⁸F]2), O-(2-[¹⁸F]fluoroethyl)-2-l-azatyrosine (FEAT, [¹⁸F]3), O-(2-[¹⁸F]fluoroethyl)-l-tyrosineamide (FETA, [¹⁸F]4) have been synthesized and radiofluorinated with 5–34% decay-corrected yield. In vitro studies were carried out in U-138 MG human glioblastoma. Cellular uptake of new tracers was compared to clinically utilized imaging agent O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (FET, [¹⁸F]1). The uptake of tracers followed the order of FET ([¹⁸F]1) > FEAT([¹⁸F]3) > FEMT ([¹⁸F]2) ≈ FETA ([¹⁸F]4).     

Syntheses of F-18 labeled fluoroalkyltyrosine derivatives and their biological evaluation in rat bearing 9L tumor

We hereby report the synthesis of four fluorine-18 labeled tyrosine derivatives, 3-(2-[(18)F]fluoroethyl)tyrosine ([(18)F]1, [(18)F]ortho-FET), 3-(3-[(18)F]fluoropropyl)tyrosine ([(18)F]2, [(18)F]ortho-FPT) O-methyl-[3-(2-[(18)F]fluoroethyl)]tyrosine ([(18)F]3, [(18)F]MFET), and O-methyl-[3-(3-[(18)F]fluoropropyl)]tyrosine ([(18)F]4, [(18)F]MFPT). The fluorine-18 labeled tyrosine derivatives were prepared by the displacement reaction of the ethyl and propyl tosylates with K[(18)F]/K2.2.2 in acetonitrile under no-carrier-added (NCA) conditions, followed by hydrolysis with 4N HCl. The biological properties of labeled compounds were evaluated in rats bearing 9L tumor after an intravenous injection and PET image was obtained. The tumor/blood and tumor/brain ratios were 2.06, 2.92 for [(18)F]1, 2.25, 4.05 for [(18)F]2, 2.88, 1.90 for [(18)F]3, and 2.00, 2.60 for [(18)F]4 at 60 min post injection, respectively. The PET image showed localized accumulation of PET tracers in 9L glioma of the rat.     

The utility of 1-[18F]fluoro-3-iodopropane for the synthesis of certain dopamine D-1 and benzodiazepine receptor radioligands

No-carrier-added (NCA) R(+)-7-chloro-8-hydroxy-3-(3′-[¹⁸F]fluoropropyl)-1-phenyl-2,3,4,5-tetrahydro-3-benzazepine (2b) (an analog of dopamine D-1 receptor ligand SCH 23390), ethyl 8-fluoro-5,6-dihydro-5-(3′-fluoropropyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (4b) and 3′-[¹⁸F]fluoropropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (6b) (analogs of the benzodiazepine RO 15-1788) were synthesized by alkylation of the corresponding nor-compound with NCA 1-[¹⁸F]fluoro-3-iodopropane in 10–15% yield (EOB) in ~110min and with a mass of 2–3nmol. Compound 2 is less potent (~ 12–14 times) than SCH 23390 in binding to rat striatal membranes in vitro. Compounds 2b, 4b and 6b exhibit no specific anatomical distribution to mouse brain. These results suggest that the substituent at position 3 of SCH 23390, and position 5 and carboxylate group of RO 15-1788 are critical determinants both of affinity and selectivity for receptor binding, and underscores the evaluation necessary when even minor changes (C1 to C3) are made in bioactive compounds.     

Synthesis, in vitro characterization, and radiolabeling of reboxetine analogs as potential PET radioligands for imaging the norepinephrine transporter

Six new (S,S)-enantiomers of reboxetine derivatives were synthesized and their binding affinities were determined via competition binding assays in cells expressing the human norepinephrine transporter (NET), serotonin transporter (SERT) or dopamine transporter (DAT). All six compounds prepared exhibit high affinity for the NET (K(i)相似文献   

Radiosynthesis and evaluation of N-(3-[18F]fluoropropyl)paroxetine as a radiotracer for in vivo labeling of serotonin uptake sites by PET

To visualize serotonin uptake sites by positron emission tomography (PET), N-(3-[¹⁸F]fluoropropyl)-paroxetine ([¹⁸F]FPP) (Fig. 1), a derivative of the selective serotonin uptake blocker paroxetine, was synthesized from 3-[¹⁸F]fluoropropyltosylate and paroxetine via a one-pot procedure. The rate of formation of [¹⁸F]FPP was a function of the ratio of the initial amount of paroxetine to that of 1,3-propanediol bistosylate with which [¹⁸F]fluoropropyltosylate was synthesized. When the reaction mixture contained an excess amount of paroxetine over that of the propyl-bistosylate, the radiosynthesis followed by HPLC purification, which took approx. 90 min, gave [¹⁸F]FPP in a radiochemical yield of approx. 8%, and in high radiochemical and chemical purity. The specific activity was 2640 ± 360 mCi/μmol.The brain biodistribution of [¹⁸F]FPP showed no distinguishable localization in regions with high density of serotonin uptake sites such as hypothalamus or olfactory tubercles. In vitro binding assays revealed that N-fluoropropylation of paroxetine reduced the affinity for the serotonin uptake site by three orders of magnitude.     

Synthesis and preliminary biological evaluation of a novel P2X7R radioligand [18F]IUR-1601

The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [¹⁸F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[¹⁸F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl-GSK1482160 with 2-[¹⁸F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol-bis-tosylate and K[¹⁸F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1–3% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74–370?GBq/μmol. The potency of IUR-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [¹¹C]GSK1482160, and the binding affinity K_i values for IUR-1601 and GSK1482160 are 4.31 and 5.14?nM, respectively.     

Mechanistic Positron Emission Tomography Studies of 6-[18F]Fluorodopamine in Living Baboon Heart: Selective Imaging and Control of Radiotracer Metabolism Using the Deuterium Isotope Effect

Abstract: Mechanistic positron emission tomography (PET) studies using the deuterium isotope effect and specific pharmacological intervention were undertaken to examine the behavior of 6-[¹⁸F]fluorodopamine (6-[¹⁸F]FDA; 1 ) and (?)-6-[¹⁸F]fluoronorepinephrine {(?)-6-[¹⁸F]FNE; 2 } in the baboon heart. Two regiospecifically deuterated derivatives of 6-[¹⁸F]FDA [α,α-D₂(3 ) and β,β-D₂ (4 )] were used to assess the contributions of monoamine oxidase (MAO) and dopamine β-hydroxylase, respectively, to the clearance kinetics of 6-[¹⁸F]FDA. Compound 3 showed a reduced rate of clearance, consistent with MAO-catalyzed cleavage of the α C-D bond, whereas compound 4 showed no change, indicating that cleavage of the β C-D bond is not a rate-limiting step. Pretreatment with pargyline, an MAO inhibitor, also decreased the rate of clearance. Desipramine and tomoxetine [norepinephrine (NE) uptake inhibitors], but not GBR-12909 (a dopamine uptake inhibitor), blocked the uptake of both (?)-6-[¹⁸F]FNE and 6-[¹⁸F]FDA, with (?)-6-[¹⁸F]FNE showing a higher degree of blockade. Chiral HPLC demonstrated that 6-[¹⁸F]FDA is stereoselectively converted to (?)-6-[¹⁸F]FNE in vivo in the rat heart. These studies demonstrate that (a) the more rapid clearance of 6-[¹⁸F]FDA relative to (?)-6-[¹⁸F]FNE can be largely accounted for by metabolism by MAO; (b) selective deuterium substitution can be used to protect a radiotracer from metabolism in vivo and to favor a particular pathway; (c) 6-[¹⁸F]FDA and (?)-6-[¹⁸F]FNE share the NE transporter; (d) 6-[¹⁸F]FDA is stereoselectively converted to (?)-6-[¹⁸F]FNE in vivo; and (e) the profile of radioactivity in the heart for 6-[¹⁸F]FDA is complex, probably including labeled metabolites as well as neuronal and nonneuronal uptake.     

Synthesis and in vitro evaluation of three novel radiotracers for imaging of metabotropic glutamate receptor subtype 2 in rat brain

The purpose of this study was to develop three new radiotracers, 1-(cyclopropylmethyl)-4-([¹¹C/¹⁸F]substituted-phenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([¹¹C]1, [¹¹C]2, and [¹⁸F]4), and to examine their specific bindings with metabotropic glutamate receptor subtype 2 (mGluR2) in rat brain sections by using in vitro autoradiography. These compounds were found to possess potent in vitro binding affinities (K_i: 8.0–34.1 nM) for mGluR2 in rat brain homogenate. [¹¹C]1, [¹¹C]2, and [¹⁸F]4 were synthesized by [¹¹C/¹⁸F]alkylation of the corresponding phenol precursors with [¹¹C]methyl iodide or [¹⁸F]fluoroethyl bromide with >98% radiochemical purity and 80–130 GBq/μmol specific activity at the end of synthesis. In vitro autoradiography indicated that these radiotracers showed heterogeneous specific bindings in mGluR2-rich brain regions, such as the cerebral cortex, striatum, hippocampus, and granular layer of the cerebellum.     

Preparation and biological evaluation of 18F-labeled benzamide analogs as potential dopamine D2 receptor ligands

Three ¹⁸F-labeled benzamide derivatives were prepared and evaluated as potential ligands to study the dopamine D₂ receptor phenomenon. The compounds are analogs of iodobenzamide, eticlopride and raclopride and are labeled with an N-2-[¹⁸F]fluoroethyl functionality on the pyrrolidine ring. The compounds were tested in vitro for binding affinity and found to exhibit somewhat lower affinity than the non-fluorinated analog. In vivo distribution studies revealed that all compounds were more highly bound to plasma proteins than was raclopride. In addition, compartmentation of radioactivity demonstrated nonspecific binding to be the predominate retention in the brain as reflected by the low caudate to cerebellum ratios for these compounds. These three ¹⁸F-labeled benzamide derivatives are inferior to raclopride and iodobenzamide for studies of the D₂ receptor system using positron emission tomography.     

In vivo binding of the dopamine uptake inhibitor [18F]GBR 13119 in MPTP-treated C57BL/6 mice

The in vivo regional distribution of [¹⁸F]GBR 13119 (1-[(4-[¹⁸F]fluorophenyl(phenyl)methoxy)ethyl]-4-(3-phenylpropyl) piperazine), a specific dopamine reuptake inhibitor, was examined in brains of C57BL/6 mice after MPTP treatment. At 2 weeks post MPTP the in vivo specific binding of [¹⁸F]GBR 13119 in striatum was decreased 63% relative to age and sex-matched controls. Animals studied at 6 and 8 weeks after MPTP treatment showed a gradual recovery of specific [¹⁸F]GBR 13119 binding in the striatum. No significant changes were observed in binding of radiotracer to cerebellum or cortex after MPTP treatment, nor were age-related changes observed in control mice. In vivo radiotracer studies thus appear useful for following gradual changes in the dopamine uptake system of mouse brain after neurotoxin treatment.     

Synthesis and preliminary biological evaluation of O-2((2-[18F]fluoroethyl)methylamino)ethyltyrosine ([18F]FEMAET) as a potential cationic amino acid PET tracer for tumor imaging

Amino acid transport is an attractive target for oncologic imaging. Despite a high demand of cancer cells for cationic amino acids, their potential as PET probes remains unexplored. Arginine, in particular, is involved in a number of biosynthetic pathways that significantly influence carcinogenesis and tumor biology. Cationic amino acids are transported by several cationic transport systems including, ATB^0,+ (SLC6A14), which is upregulated in certain human cancers including cervical, colorectal and estrogen receptor-positive breast cancer. In this work, we report the synthesis and preliminary biological evaluation of a new cationic analog of the clinically used PET tumor imaging agent O-(2-[¹⁸F]fluroethyl)-l-tyrosine ([¹⁸F]FET), namely O-2((2-[¹⁸F]fluoroethyl)methylamino)ethyltyrosine ([¹⁸F]FEMAET). Reference compound and precursor were prepared by multi-step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [¹⁸F]fluorination in 16–20 % decay-corrected yields with radiochemical purity >99 %. The new tracer showed good stability in vitro and in vivo. Cell uptake assays demonstrated that FEMAET and [¹⁸F]FEMAET accumulate in prostate cancer (PC-3) and small cell lung cancer cells (NCI-H69), with an energy-dependent mechanism. Small animal PET imaging with NCI-H69 xenograft-bearing mice revealed good tumor visualization comparable to [¹⁸F]FET and low brain uptake, indicating negligible transport across the blood–brain barrier. In conclusion, the non-natural cationic amino acid PET probe [¹⁸F]FEMAET accumulates in cancer cells in vitro and in vivo with possible involvement of ATB^0,+.     

Evaluation of 18F-labeled exendin(9-39) derivatives targeting glucagon-like peptide-1 receptor for pancreatic β-cell imaging

β-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 β-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 β-cells. Further enhancement of pancreatic uptake and specific binding to GLP-1R will lead to a clear visualization of pancreatic β-cells.     

Tumor diagnosis by pet: potential of seven tracers examined in five experimental tumors including an artificial metastasis model

The potential of seven tracers for the metabolic imaging of tumors by positron emission tomography was studied using five experimental tumor models. The tracers examined were 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG), 2-deoxy-2-[¹⁸F]fluoro-d-galactose (2-[¹⁸F]FdGal) and 2-deoxy-2-[¹⁸F]fluoro-l-fucose (2-[¹⁸F]FdFuc) for investigating energy metabolism. l-[methyl-¹¹C]Methionine ([¹¹C]Met) and 6-[¹⁸F]fluoro-l-fucose (6-[¹⁸F]FFuc) were used for assessing protein and glycoprotein synthesis, while [³H]thymidine ([³ H]Thd) and 2-deoxy-5′-[¹⁸F]fluorouridine ([¹⁸F]FdUrd) were used to investigate nucleic acid metabolism. The highest mean uptake by the five different tumors was found for [³H]Thd, followed in order by [¹⁸F]FDG, [¹¹C]Met, 2-[¹⁸F]FdGal, [¹⁸F]FdUrd, 2-[¹⁸F]FdFuc and 6-[¹⁸F]FFuc. The tumor-to-tissue uptake ratios indicated that the nucleosides, [¹¹C]Met and 6-[¹⁸F]FFuc were better tracers in the brain region. All the tracers except for the fucose analogs were suitable for the thoracic region, while [¹¹C]Thd and [¹⁸ F]FDG were superior in the abdominal region. In comparison with the primary tumor model of Lewis lung carcinoma (3LL), [³H]Thd uptake in the artificial metastatic 3LL model showed the maximum enhancement, followed by [¹⁸F]FDG, [¹¹C]Met and the other tracers. The [¹⁸F]FDG uptake correlated with the [³H]Thd uptake. [¹⁸F]FdUrd, 6-[¹⁸F]FFuc and 2-[¹⁸F]FdGal could be used for distinguishing different types of tumors. The combined use of these radiotracers can possibly allow the assessment of tumor metabolism, and this indicates the viability of tumors.     

[68Ga]Ga-DO2A-(OBu-l-tyr)2: Synthesis, 68Ga-radiolabeling and in vitro studies of a novel 68Ga-DO2A-tyrosine conjugate as potential tumor tracer for PET

The synthesis, ⁶⁸Ga-labeling and in vitro study of the novel tyrosine chelate derivative [⁶⁸Ga]Ga-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid-4,10-di-(O-butyl)-l-tyrosine ([⁶⁸Ga]Ga-DO₂A-(OBu-l-tyr)₂) as a potential tracer for imaging tumor metabolism by positron emission tomography (PET) is presented. This approach combines the biological amino acid transporter targeting properties of l-tyrosine with the outstanding availability of ⁶⁸Ga^III via the ⁶⁸Ge/⁶⁸Ga generator. In vitro studies utilizing the F98-glioblastoma cell line revealed specific uptake of [⁶⁸Ga]Ga-DO2A-(OBu-l-tyr)₂ that was comparable to that of the reference O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (FET). These promising results indicate a high potential of [⁶⁸Ga]Ga-DO₂A-(OBu-l-tyr)₂ for molecular imaging of tumor-driven amino acid uptake by PET.     

Synthesis and biological evaluation of novel F-18 labeled pyrazolo[1,5-a]pyrimidine derivatives: potential PET imaging agents for tumor detection

Two novel pyrazolo[1,5-a]pyrimidine derivatives, 7-(2-[¹⁸F]fluoroethylamino)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile ([¹⁸F]FEMPPC, [¹⁸F]1) and N-(2-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)-2-[¹⁸F]fluoro-4-nitrobenzamide ([¹⁸F]FCMPPN, [¹⁸F]2), have been designed and successively labeled with ¹⁸F by the nucleophilic substitution employing tosylate and nitryl as leaving groups, respectively. The radiochemical synthesis of both compounds was completed within 60 min with final high-performance liquid chromatography purification included. The corresponding radiochemical yields (without decay correction) were approximately 35% and 30%, respectively. Meanwhile, we compared the uptake characteristics of [¹⁸F]1 and [¹⁸F]2 with those of [¹⁸F]FDG and L-[¹⁸F]FET in S180 tumor cells. Furthermore, the tumor uptake of [¹⁸F]1 and [¹⁸F]2 was assessed in mice bearing S180 tumor and compared with [¹⁸F]FDG and L-[¹⁸F]FET in the same animal model. In vitro cell uptake studies showed [¹⁸F]1 had higher uptake than [¹⁸F]FDG, [¹⁸F]2 and L-[¹⁸F]FET over the 2 h period. In ex vivo biodistribution showed tumor/brain uptake ratios of [¹⁸F]2 were 12.35, 10.44, 8.69 and 5.13 at 15 min, 30 min, 60 min and 120 min post-injection, much higher than those of L-[¹⁸F]FET (2.43, 2.54, 2.93 and 2.95) and [¹⁸F]FDG (0.59, 0.61, 1.02 and 1.33) at the same time point. What’s more, the uptake of [¹⁸F]1 in tumor was 1.88, 4.37, 5.51, 2.95 and 2.88 at 5 min, 15 min, 30 min, 60 min and 120 min post-injection, respectively. There was a remarkable increasing trend before 30 min. The same trend was present for L-[¹⁸F]FET before 30 min and [¹⁸F]FDG before 60 min. Additionally, the tumor/brain uptake ratios of [¹⁸F]1 were superior to those of [¹⁸F]FDG at all the selected time points, the tumor/muscle and tumor/blood uptake ratios of [¹⁸F]1 at 30 min were higher than those of L-[¹⁸F]FET at the same time point. MicroPET image of [¹⁸F]1 administered into S180 tumor-bearing mouse acquired at 30 min post-injection illustrated that the uptake in S180 tumor was obvious. These results suggest that compound [¹⁸F]1 could be a new probe for PET tumor imaging.     

18F Labeled benzimidazole derivatives as potential radiotracer for positron emission tomography (PET) tumor imaging

This article reported the synthesis and bioevaluation of two [¹⁸F] labeled benzimidazole derivatives, 4-(5-(2-[¹⁸F] fluoro-4-nitrobenzamido)-1-methyl-1H-benzimidazol-2-yl) butanoic acid ([¹⁸F] FNBMBBA, [¹⁸F]a1) and 3-(2-fluoroethyl)-7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid ([¹⁸F] FEMPBBA, [¹⁸F]b1) for PET tumor imaging. The preparation [¹⁸F] FEMPBBA was completed in 1 h with overall radiochemical yield of 50–60% (without decay corrected). Biodistribution assay in S180 tumor bearing mice of both compounds were carried out, and the results are both meaningful. [¹⁸F] FEMPBBA which can be taken as a revision of [¹⁸F] FNBMBBA got an excellent result, and has significant advantages in some aspects compared with L-[¹⁸F] FET and [¹⁸F]-FDG in the same animal model, especially in tumor/brain uptake ratio. The tumor/brain uptake ratio of [¹⁸F] FEMPBBA gets to 4.81, 7.15, and 9.8 at 30 min, 60 min and 120 min, and is much higher than that of L-[¹⁸F] FET (2.54, 2.92 and 2.95) and [¹⁸F]-FDG (0.61, 1.02, 1.33) at the same time point. The tumor/muscle and tumor/blood uptake ratio of [¹⁸F] FEMPBBA is also higher than that of L-[¹⁸F] FET at 30 min and 60 min. This result indicates compound [¹⁸F] FEMPBBA is a promising radiotracer for PET tumor imaging.     

<Superscript>18</Superscript>F-labeled tyrosine derivatives: Synthesis and experimental studies on accumulation in tumors and abscesses

Tyrosine derivatives labeled with a short-lived fluorine-18 isotope (T _1/2 110 min), namely 2-[¹⁸F]fluoro-L-tyrosine (FTYR) and O-(2′-[¹⁸F]fluoroethyl)-L-tyrosine (FET), promising radiopharmaceuticals (RPs) for positron emission tomography (PET), were obtained by asymmetric syntheses. Accumulation of FTYR and FET in the rat tumor “Glioma 35 rats tumor” and in abscesses induced in Wistar rats muscles was studied and compared with that of a well-known glycolysis radiotracer 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG). It was shown that the relative accumulation indices of amino acid RPs were considerably lower than those of FDG. At the same time, tumor/muscle ratios were high enough (2.9 for FET and 3.9 for FTYR 120 min after injection) for reliable tumor visualization. The data obtained indicated a possibility in principle to use FTYR and FET for differentiated PET diagnostics of brain tumors and inflammation lesions. Of the tyrosine derivatives studied, FET seems to be the most promising agent due to a simple and easily automated method of preparation based on direct nucleophilic substitution of the leaving tosyloxy group of an enantiomerically pure Ni-(S)-BPS-(S)-Tyr(CH₂CH₂OTs) precursor by an activated [¹⁸F]fluoride.     

[18F]FEAC and [18F]FEDAC: Two novel positron emission tomography ligands for peripheral-type benzodiazepine receptor in the brain

[¹⁸F]FEAC ([¹⁸F]4a) and [¹⁸F]FEDAC ([¹⁸F]4b) were developed as two novel positron emission tomography (PET) ligands for peripheral-type benzodiazepine receptor (PBR). [¹⁸F]4a and [¹⁸F]4b were synthesized by fluoroethylation of precursors 8a and 8b with [¹⁸F]FCH₂CH₂Br ([¹⁸F]9), respectively. Small-animal PET scan for a neuroinflammatory rat model showed that the two radioligands had high uptakes of radioactivity in the kainic acid-infused striatum, a brain region where PBR density was increased.     

Fluorinated isatin derivatives. Part 1: Synthesis of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins as potent caspase-3 and -7 inhibitors

A series of new N-substituted (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives has been synthesized and tested as inhibitors of caspases-3 and -7, which are known to be downstream enzymes critical in the execution of apoptosis. N-Propyl- and N-butyl isatins, as well as the corresponding terminal alcohols and regioisomeric fluorobutyl derivatives were shown to be excellent inhibitors having different binding potencies for caspases-3 and -7. In contrast, the corresponding fluoroethyl and fluoropropyl compounds were about 100–1000 times less active. Fluorinated N-benzyl isatins as well as trifluoroalkyl and difluoroalkyl derivatives were moderate inhibitors. However, isatins bearing different alkylether groups at N-1 are very weak or not active as inhibitors of caspases-3 and -7.