Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography

2beta-(R)-Carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((R)-FIPCT, R-6) and 2beta-(S)-carbo-1-fluoro-2-propoxy-3beta-(4-chlorophenyl) tro pane ((S)-FIPCT, S-6) were prepared and evaluated in vitro and in vivo for dopamine transporter (DAT) selectivity and specificity. High specific activity [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were synthesized in 5% radiochemical yield (decay-corrected to end of bombardment (EOB)) by preparation of the precursors 2beta-carbo-R-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (R-12) and 2beta-carbo-S-1-mesyloxy-2-propoxy-3beta-(4-chlorop hen yl)tropane (S-12) followed by treatment with no carrier-added potassium[(18)F]fluoride and kyrptofix K222 in acetonitrile. Competition binding in cells stably expressing the transfected human DAT and serotonin transporter (SERT) labeled by [(3)H]WIN 35428 and [(3)H]citalopram, respectively, demonstrated the following order of DAT affinity (K(i) in nM): GBR 12909 (0.36) > CIT (0.48) > (S)-FIPCT (0.67) > (R)-FIPCT (3.2). The affinity of (S)-FIPCT and (R)-FIPCT for SERT was 127- and 20-fold lower, respectively, than for DAT. In vivo biodistribution studies were performed in male rats and demonstrated that the brain uptake of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT were selective and specific for DAT rich regions (caudate and putamen). PET brain imaging studies in monkeys demonstrated high [(18)F](R)-FIPCT and [(18)F](S)-FIPCT uptake in the caudate and putamen which resulted in caudate-to-cerebellum and putamen-to-cerebellum ratios of 2.5-3.5 at 115 min. [(18)F](R)-FIPCT uptake in the caudate/putamen achieved transient equilibrium at 75 min. In an imaging experiment with [(18)F](S)-FIPCT in a rhesus monkey with its left hemisphere lesioned with MPTP, radioactivity was reduced to background in the caudate and putamen of the lesioned hemisphere. The high specific activity one-step radiolabeling preparation and high specificity and selectivity of [(18)F](R)-FIPCT and [(18)F](S)-FIPCT for DAT indicate [(18)F](R)-FIPCT and [(18)F](S)-FIPCT are potential radioligands for mapping brain DAT in humans using PET.     

Synthesis, (18)F-labeling, and biological evaluation of piperidyl and pyrrolidyl benzilates as in vivo ligands for muscarinic acetylcholine receptors

A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, K(i) = 12.1 nM) and N-(2-fluoroethyl)-4-piperidyl benzilate (4-FEPB, 8, K(i) = 1. 83 nM) were selected for radiolabeling with fluorine-18. Using alkylation with 2-[(18)F]fluoroethyl triflate, 3-[(18)F]FEPB (42) and 4-[(18)F]FEPB (43) were produced in 7-9% radiochemical yield and >97% radiochemical purity. For in vivo studies, retention was moderate in mouse brain for 42; however, blocking with scopolamine showed that uptake was not muscarinic cholinergic receptor-mediated. Conversely, 43 exhibited high, receptor-mediated retention in mouse brain, with significant clearance after 1 h. These results suggest that 43 could have applications as an in vivo probe for measuring endogenous acetylcholine levels.     

Synthesis of 2-R1-2-(4-(2-fluoroethoxy)benzamido)acetate as potential PET imaging agents

Radiolabeled acetates have potential use in tumor imaging. Moreover, aryl fatty acid displays antitumor effect with phenylacetate currently in clinical trial. A series of 2-R¹-2-(4-(2-fluoroethoxy)benzamido)acetate were synthesized in the present investigation. 2-(4-(2-[¹⁸F]fluoroethoxy)benzamido)acetate ([¹⁸F]FEBA) was evaluated in tumor-bearing mice. It was compared with 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG), showing satisfied stability. Excitingly, the radiochemical purity of [¹⁸F]FEBA was more than 99% and the radiochemical yield was up to 25%. Although 2-R¹-2-(4-(2-fluoroethoxy)benzamido)acetate deserved further evaluations, the results might provide many experimental foundations and principles for the future study of the novel fluorine-18-labeled pharmaceuticals.     

Synthesis and simple 18F-labeling of 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a high affinity radioligand for imaging monkey brain metabotropic glutamate subtype-5 receptors with positron emission tomography

2-fluoromethyl analogs of (3-[(2-methyl-1,3-thiazol-4yl)ethynyl]pyridine) were synthesized as potential ligands for metabotropic glutamate subtype-5 receptors (mGluR5s). One of these, namely, 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile (3), was found to have exceptionally high affinity (IC50 = 36 pM) and potency in a phosphoinositol hydrolysis assay (IC50 = 0.714 pM) for mGluR5. Compound 3 was labeled with fluorine-18 (t1/2 = 109.7 min) in high radiochemical yield (87%) by treatment of its synthesized bromomethyl analog (17) with [18F]fluoride ion and its radioligand behavior was assessed with positron emission tomography (PET). Following intravenous injection of [18F]3 into rhesus monkey, radioactivity was avidly taken up into brain with high uptake in mGluR5 receptor-rich regions such as striata. [18F]3 was stable in monkey plasma and human whole blood in vitro and in monkey and human brain homogenates. In monkey in vivo, a single polar radiometabolite of [18F]3 appeared rapidly in plasma. [18F]3 merits further evaluation as a PET radioligand for mGluR5 in human subjects.     

Synthesis and evaluation of no-carrier-added 8-cyclopentyl-3-(3-[(18)F]fluoropropyl)-1-propylxanthine ([(18)F]CPFPX): a potent and selective A(1)-adenosine receptor antagonist for in vivo imaging

This report describes the precursor synthesis and the no-carrier-added (nca) radiosynthesis of the new A(1) adenosine receptor (A(1)AR) antagonist [(18)F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX), 3, with fluorine-18 (half-life = 109.6 min). Nucleophilic radiofluorination of the precursor tosylate 8-cyclopentyl-3-(3-tosyloxypropyl)-7-pivaloyloxymethyl-1-propylxanthine, 2, with nca [(18)F]KF under aminopolyether-mediated conditions (Kryptofix 2.2.2/K(2)CO(3)) followed by deprotection was straightforward and, after formulation, gave the radioligand ready for injection with a radiochemical yield of 45 +/- 7%, a radiochemical purity of >98% and a specific radioactivity of >270 GBq/micromol (>7.2 Ci/micromol). Preparation time averaged 55 min. The synthesis proved reliable for high batch yields ( approximately 7.5 GBq) in routine production (n = 120 runs). The radiotracer was pharmacologically evaluated in vitro and in vivo and its pharmacokinetics in rodents determined in detail. After iv injection a high accumulation of radioactivity occurred in several regions of mouse brain including thalamus, striatum, cortex, and cerebellum. Antagonism by the specific A(1)AR antagonists 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and N(6)-cyclopentyl-9-methyladenine (N-0840), but not with the A(2)AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), indicated specific and reversible binding of the radioligand to A(1)AR in cortical and subcortical regions of interest. In mouse blood at least two polar metabolites formed rapidly (50% at 5 min after tracer application). However, chromatographic analyses of brain homogenate extracts taken 60 min pi showed that >98% of radioactivity was unchanged radioligand. Chromatographic isolation and reinjection of peripherally formed radioactive metabolites revealed no accumulation of radioactivity in mouse brain, probably due to the polarity of the metabolites. These preliminary results suggest that nca [(18)F]CPFPX is a useful radioligand for the noninvasive imaging of the brain A(1)AR.     

Radiosynthesis and biological evaluation of L- and D-S-(3-[18F]fluoropropyl)homocysteine for tumor imaging using positron emission tomography

Interest in radiolabeled amino acids for metabolic imaging of cancer and limitations with [(11)C]methionine has prompted the development of a new (18)F-labeled methionine derivative S-(3-[(18)F]fluoropropyl)homocysteine ([(18)F]FPHCys). The L and D enantiomers of [(18)F]FPHCys were prepared from their respective protected S-(3-tosyloxypropyl)homocysteine precursors 1 by [(18)F]fluoride substitution using K(2.2.2) and potassium oxalate, followed by acid hydrolysis on a Tracerlab FX(FN) synthesis module. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys were isolated in 20 ± 5% radiochemical yield and >98% radiochemical and enantiomeric purity in 65 min. Competitive uptake studies in A375 and HT29 tumor cells suggest that L- and D-[(18)F]FPHCys are taken up by the L-transporter system. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys displayed good stability In Vivo without incorporation into protein at least 2 h postinjection. Biodistribution studies demonstrate good uptake in A375 tumor-bearing rodents with tumor to blood ratios of 3.5 and 5.0 for [(18)F]-L-FPHCys and [(18)F]-D-FPHCys, respectively, at 2 h postinjection.     

New 3-[4-(2,3-dihydro-14-benzodioxin-5-yl)piperazin-1-yl]-1-(5-substituted benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT(1A) serotonin receptors and serotonin transporter as a new class of antidepressants

Compounds derived from 2,3-dihydro-(1,4-benzodioxin-5-yl)piperazine and benzo[b]thiophene with different substituents in 5 position (H, F, NO2, NH2, CH3 and OH) have been synthesized in order to obtain new dual antidepressant drugs. The final compounds were evaluated for in vitro 5-HT(1A) receptor affinity and serotonin reuptake inhibition by radioligand assays. Compounds 1-(5-nitrobenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propan-1-ol (4c) (Ki = 6.8 for 5-HT(1A) receptor and Ki = 14 for 5-HT transporter) and 1-(5-hydroxybenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl] propan-1-ol (4f) (Ki = 6.2 for 5-HT(1A) receptor and Ki = 18.2 for 5-HT transporter) showed the best results for both activities.     

Radiolabeled amino acids for tumor imaging with PET: radiosynthesis and biological evaluation of 2-amino-3-[18F]fluoro-2-methylpropanoic acid and 3-[18F]fluoro-2-methyl-2-(methylamino)propanoic acid

Novel radiopharmaceuticals, including amino acids, that target neoplasms through their altered metabolic states have shown promising results in preclinical and clinical studies. Two fluorinated analogues of alpha-aminoisobutyric acid, 2-amino-3-fluoro-2-methylpropanoic acid (FAMP) and 3-fluoro-2-methyl-2-(methylamino)propanoic acid (N-MeFAMP), have been radiolabeled with fluorine-18, characterized in amino acid uptake assays, and evaluated in vivo in normal rats and a rodent tumor model. The key steps in the syntheses of both radiotracers involved the preparation of cyclic sulfamidate precursors. Radiosyntheses of both [18F]FAMP and [18F]N-MeFAMP via no-carrier-added nucleophilic substitution provided high yields (>78% decay-corrected) in high radiochemical purity (>99%). Amino acid transport assays using 9L gliosarcoma cells demonstrated that both compounds are substrates for the A type amino acid transport system, with [18F]N-MeFAMP showing higher specificity than [18F]FAMP for A type transport. Tissue distribution studies in normal Fischer rats and Fischer rats implanted intracranially with 9L gliosarcoma tumor cells were also performed. At 60 min postinjection, the tumor vs normal brain ratio of radioactivity was 36:1 in animals receiving [18F]FAMP and 104:1 in animals receiving [18F]N-MeFAMP. On the basis of these studies, both [18F]FAMP and [18F]N-MeFAMP are promising imaging agents for the detection of intracranial neoplasms via positron emission tomography.     

Synthesis and structure-activity relationships of 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic acid antibacterials having fluorinated 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] substituents

A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.     

Synthesis and in vitro evaluation of 5-[(18)f]fluoroalkyl pyrimidine nucleosides for molecular imaging of herpes simplex virus type 1 thymidine kinase reporter gene expression

Two novel series of 5-fluoroalkyl-2'-deoxyuridines (FPrDU, FBuDU, FPeDU) and 2'-fluoro-2'-deoxy-5-fluoroalkylarabinouridines (FFPrAU, FFBuAU, FFPeAU) that have three, four, or five methylene units (propyl, butyl, or pentyl) at C-5 were prepared and tested as reporter probes for imaging herpes simplex virus type 1 thymidine kinase (HSV1- tk) gene expression. The Negishi coupling methodology was employed in efficiently synthesizing the radiolabeling precursors. All six 5-[(18)F]fluoroalkyl pyrimidines were readily prepared from 3-N-benzoyl-3',5'-di-O-benzoyl-protected 5-O-mesylate precursors in 17-35% radiochemical yield (decay-corrected). In vitro studies highlighted that all six [(18)F]-labeled nucleosides selectively accumulated in cells expressing the HSV1-TK protein and there was negligible uptake in control cells. [(18)F]FPrDU, [(18)F]FBuDU, [(18)F]FPeDU, and [(18)F]FFBuAU had the best uptake profiles. Despite their selective accumulation in HSV1- tk-expressing cells, all 5-fluoroalkyl pyrimidine nucleosides had low-to-negligible cytotoxic activity (CC50 > 1000-1209 microM). Ultimately, the results demonstrated that 5-[(18)F]fluoropropyl, [(18)F]fluorobutyl, and [(18)F]fluoropentyl pyrimidine nucleosides have the potential to be in vivo HSV1-TK PET reporter probes over a dynamic range of reporter gene expression levels.     

Selective synthesis of L-2-[18F]fluoro-alpha-methylphenylalanine via copper-mediated 18F-fluorination of (mesityl)(aryl)iodonium salt

L-2-[¹⁸F]fluoro-alpha-methylphenylalanine (2-[¹⁸F]FAMP) is a promising amino acid tracer for positron emission tomography (PET) imaging, yet the low production yield of direct electrophilic radiofluorination with [¹⁸F]F₂ necessitates further optimization of the radiolabeling process. This paper describes a two-step preparation method for L-2-[¹⁸F]fluoro-alpha-methylphenylalanine (2-[¹⁸F]FAMP) starting from [¹⁸F]fluoride. The (Mesityl)(L-alpha-methylphenylalanine)-2-iodonium tetrafluoroborate precursors with various protecting groups were prepared. The copper-mediated ¹⁸F-fluorination of the iodonium salt precursors successfully produced 2-[¹⁸F]FAMP. The highest radio chemical conversion of 57.6% was noted with N-Piv-protected (mesityl)(aryl)iodonium salt in the presence of 5 equivalent of Cu (OTf)₂. Subsequent deprotection with 57% hydrogen iodide produced 2-[¹⁸F]FAMP within 120 min in 21.4 ± 11.7% overall radiochemical yield with >95% radiochemical purity and an enantiomeric excess >99%. The obtained 2-[¹⁸F]FAMP showed comparable biodistribution profiles in normal mice with that of the carrier-added 2-[¹⁸F]FAMP. These results indicate that usefulness of copper mediated ¹⁸F-fluorination for the production of 2-[¹⁸F]FAMP, which would facilitate clinical translation of the promising tumor specific amino acid tracer. Individual facilities could adopt either production method based on radioactivity demand and equipment availability.     

Radiosynthesis and evaluation of an (18)F-labeled positron emission tomography (PET) radioligand for brain histamine subtype-3 receptors based on a nonimidazole 2-aminoethylbenzofuran chemotype

A known chemotype of H(3) receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H(3)) receptors in vivo with positron emission tomography (PET), namely nonimidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)methanone (9). Compound 9 was labeled with fluorine-18 (t(1/2) = 109.7 min) in high specific activity by treating the prepared nitro analogue (12) with cyclotron-produced [(18)F]fluoride ion. [(18)F]9 was studied with PET in mouse and in monkey after intravenous injection. [(18)F]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H(3) receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H(3) receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands.     

S-(2-18F-氟代乙基)-L-蛋氨酸的合成及其放射药理活性

目的研制肿瘤氨基酸代谢显像剂S-(2-18F-氟代乙基)-L-蛋氨酸(18FEMET),评价其区分炎症和肿瘤的价值。方法采用亲核取代反应,由两步法合成18FEMET。测定正常小鼠、肿瘤及炎症小鼠体内FEMET生物分布,对模型小鼠进行18FEMET PET显像,并与2-18F-2-脱氧-D-葡萄糖(FDG)和O-(2-18F-氟代乙基)-L-酪氨酸(FET)比较。结果18FEMET手工合成时间约为70 min,未校正总放化产率为15%～25%,放化纯度大于95%。正常小鼠中胰腺、肾脏、结肠、肝和心脏等脏器摄取18FEMET较高,且放射性滞留时间较长,血液和脑摄取18FEMET较低。肿瘤细胞可高度摄取18FEMET,FDG和FET,炎症组织也可高度摄取FDG,但几乎不摄取18FEMET和FET。结论18FEMET制备简便,能够区分肿瘤和炎症,可望成为一种有前景的特异性肿瘤氨基酸代谢PET显像剂。     

Automated synthesis of (R)-[18F]MH.MZ on the iPhase Flexlab reaction platform

(R)-[¹⁸F]MH.MZ ([¹⁸F]MH.MZ) is a promising positron emission tomography (PET) radiotracer for in vivo study of the 5-HT_2A receptor. To facilitate clinical trials, a fully automated radiosynthesis procedure for [¹⁸F]MH.MZ was developed using commercially available materials on the iPhase Flexlab module. The overall synthesis time was 100 min with a radiochemical yield of 7 ± 0.9% (n = 3). The radiochemical purity was greater than 99% for [¹⁸F]MH.MZ with a molar activity of 361 ± 57 GBq/μmol (n = 3). The protocol described herein reliably provides [¹⁸F]MH.MZ that meets all relevant release criteria for a GMP radiopharmaceutical.     

Synthesis of syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC), potential PET ligands for tumor detection

syn- and anti-1-amino-3-[18F]fluoromethyl-cyclobutane-1-carboxylic acid (FMACBC, 16 and 17), analogues of anti-1-amino-3-[18F]fluorocyclobutyl-1-carboxylic acid (FACBC), were prepared to evaluate the contributions of C-3 substitution and configuration on the uptake of these radiolabeled amino acids in a rodent model of brain tumors. Radiofluorinated targets [18F]16 and [18F]17 were prepared by no-carrier-added radiofluorination from their corresponding methanesulfonyl esters 12 and 13, respectively, with decay-corrected radiochemical yields of 30% for [18F]16 and 20% for [18F]17. In amino acid transport assays performed in vitro using 9L gliosarcoma cells, both [18F]16 and [18F]17 were substrates for L type amino acid transport, while [18F]17 but not [18F]16 was a substrate for A type transport. Biodistribution studies in normal Fischer rats with [18F]16 and [18F]17 showed high uptake of radioactivity (>2.0% dose/g) in the pancreas while other tissues studied, including liver, heart, lung, kidney, blood, muscle, and testis, showed relatively low uptake of radioactivity (<1.0% dose/g). In rats implanted intracranially with 9L gliosarcoma cells, the retention of radioactivity in tumor tissue was high at 5, 60, and 120 min after intravenous injection of [18F]16 and [18F]17 while the uptake of radioactivity in brain tissue contralateral to the tumor remained low (<0.3% dose/g). Ratios of tumor uptake to normal brain uptake for [18F]16 were 7.5:1, 7:1, and 5:1 at 5, 60, and 120 min, respectively, while for [18F]17 the ratios were 7.5:1, 9:1, and 9:1 at the same time points. This work demonstrates that like anti-[18F]FACBC, [18F]16 and [18F]17 are excellent candidates for imaging brain tumors.     

New PET imaging agent for the serotonin transporter: [(18)F]ACF (2-[(2-amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine)

A new F-18-labeled phenylthiophenyl derivative specific for imaging of serotonin transporters (SERT) in the brain by positron emission tomography (PET) is described. Fluorinated phenylthiophenyl derivative, ACF, 2-[(2-amino-4-chloro-5-fluorophenyl)thio]-N,N-dimethyl-benzenmethanamine, was prepared by first coupling 2,5-dichloro-4-nitroaniline with 2-mercapto-N,N-dimethylbenzamide. The amino group of the coupled adduct was converted to a fluoro group through a Schiemann reaction. Subsequently, a one pot reduction of both nitro and amide groups by BH(3)-tetrahydrofuran yielded the nonradioactive ACF (yield 25%). In vitro binding assays using cell membrane homogenates of LLC cells expressing SERT, dopamine transporters (DAT), or norepinephrine transporters (NET) showed excellent binding affinity and selectivity for SERT (K(i) = 0.05, 3020, and 650 nM for SERT, DAT, and NET, respectively). For preparation of the [(18)F]ACF, the NH(2) group of the initially coupled adduct was converted to the trimethylammonium salt, which was replaced by [(18)F]fluoride in the presence of Kryptofix 222 and potassium carbonate. The final product, [(18)F]ACF, was obtained after a borane and stannous chloride reduction reaction. The combined two step reaction gave a radiochemical yield of 10-15% (EOB) and a radiochemical purity of >99%. Synthesis of the novel PET tracer, [(18)F]ACF, as a probe for binding to SERT in the brain was successfully achieved. The new tracer [(18)F]ACF showed excellent brain penetration and selective localization after an iv injection in rats (brain uptake at 2, 30, 60, 120, and 240 min was 3.27, 1.28, 0.69, 0.21, and 0.06% dose/organ, respectively). The hypothalamus/cerebellum ratio at 60 min post iv injection was 3.55. This specific localization in the hypothalamus was blocked by pretreatment of (+)McN5652. This novel ligand is a potential PET tracer for in vivo evaluation of SERT in the brain.     

Efficient Radiosynthesis of 2-[18F]Fluoroadenosine: A New Route to 2-[18F]Fluoropurine Nucleosides

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Synthesis and characterization of nucleosides and oligonucleotides bearing adducts of butadiene epoxides on adenine n(6) and guanine n(2)

Butadiene is a major industrial chemical whose genotoxic effects are attributed to the reaction of its oxidized metabolites, butadiene monoepoxide (BDO) and butadiene diepoxide (BDO2), with DNA. Nucleosides and oligonucleotides containing regio- and stereochemically specific adducts of BDO and the BDO2-related compound, butene 3,4-diol 1,2-epoxide (BDE), on guanine [(2R)- and (2S)-N(2)-(1-hydroxy-3-buten-2-yl) and (2R,3R)- and (2S,3S)-N(2)-(2,3,4-trihydroxybut-1-yl), respectively] and on adenine [(2R)- and (2S)-N(6)-(1-hydroxy-3-buten-2-yl) and (2R,3R)- and (2S,3S)-N(6)-(2,3,4-trihydroxybut-1-yl), respectively] have been prepared by nonbiomimetic routes. For guanine adducts, 2-fluoro-O(6)-(trimethylsilylethyl)-2'-deoxyinosine was treated with (2R)- and (2S)-2-amino-3-buten-1-ol to give the BDO adducts and with (2R,3R)- and (2S,3S)-1-amino-2,3,4-butanetriol to produce the BDE adducts; the adducted oligonucleotides were prepared from 11-mer oligonucleotides containing the halopurine. Adenine adducts were prepared in a similar fashion using 6-chloropurine 2'-deoxyriboside as the reactive purine component.     

Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography

The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.