Biomedical subjects

Victor W Pike

Publications and source records attributed to Victor W Pike.

At least 37 records · Page 2Linked to original sources

PubMed2005

PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease.

PURPOSE: The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify beta-amyloid (Abeta) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). METHODS: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0+/-1.8 months; 23.6+/-2.6 g) overexpressing a mutated form of human beta-amyloid precursor protein (APP) known to result in the production of Abeta plaques, and in six elderly wild-type litter mates (age 21.8+/-1.6 months; 29.5+/-4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. RESULTS: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06+/-0.04 vs 0.98+/-0.07, p=0.04; 1.06+/-0.09 vs 0.93+/-0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Abeta plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. CONCLUSION: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

Alzheimer Disease↗

PubMed2005

N-oxide analogs of WAY-100635: new high affinity 5-HT(1A) receptor antagonists.

WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-desmethyl derivative DWAY 2 are well-known high affinity 5-HT(1A) receptor antagonists, which when labeled with carbon-11 (beta+; t(1/2) = 20.4 min) in the carbonyl group are effective radioligands for imaging brain 5-HT(1A) receptors with positron emission tomography (PET). In a search for new 5-HT(1A) antagonists with different pharmacokinetic and metabolic properties, the pyridinyl N-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of 1 was oxidized to the pyridinyl N-oxide, was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine-N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4, a more lipophilic (pyridinyl-6)-chloro derivative of 3, was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2-(6-bromo)aminopyridinyl-N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5, in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2, was prepared in five steps from 2-(chloroacetylamino)pyridine. N-Oxides 3-5 were found to be high affinity antagonists at 5-HT(1A) receptors, with 3 having the highest affinity and a Ki value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (LogP = 1.87) is lower than that of 1 by 1.25 LogP units while TLC and reverse phase HPLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-11 in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-11C]3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT(1A) receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation of 3 was not apparent in vivo; in cynomolgus monkey plasma radioactive metabolites of [carbonyl-11C]3 appeared less rapidly than from the radioligands [carbonyl-11C]1 and [carbonyl-11C]2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging.

Animals↗

PubMed2005

Amyloid imaging: from benchtop to bedside.

Tremendous efforts have been made in the search for a cure or effective treatment of Alzheimer's disease (AD) to develop therapies aimed at halting or reversing amyloid plaque deposition in the brain. This necessitates in vivo detection and quantification of amyloid plaques in the brain for efficacy evaluation of anti-amyloid therapies. For this purpose, a wide array of amyloid-imaging probes has been developed, mainly for in vivo studies based on positron emission tomography and single photon emission computed tomography. This review provides a full account of the development of amyloid-imaging agents. The in vitro binding properties and in vivo pharmacokinetic profiles of all amyloid-imaging agents so far reported are comprehensively and uniquely surveyed. Emphasis is placed on the development of small-molecule probes based on amyloid dyes, such as Congo red and thioflavin T. Compared to large biomolecules, these small-molecule probes have been systematically investigated through extensive structure activity relationship studies. Many of the probes show favorable properties for in vivo studies. As a result, three lead compounds, termed PIB (Pittsburgh-Compound B, [(11)C]6-OH-BTA-1), FDDNP (2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile), and SB-13 (4-N-methylamino-4'-hydroxystilbene), have been identified and evaluated in human subjects. Preliminary studies have indicated that these lead compounds exhibit a characteristic retention in AD subjects that is consistent with the AD pathology, thus proving the concept that amyloid deposits in the brain can be readily detected and quantified in vivo. The progress to date paves the way for further investigation in various aspects of AD research. Once developed, these amyloid-imaging agents could be used as biomarkers to aid in early and definitive diagnosis of AD, facilitate drug discovery and development, and allow pathophysiological studies of the disease mechanism. Furthermore, the success in the development of amyloid-imaging agents helps with the development of imaging agents for in vivo studies of other AD pathologies in particular and of neurodegenerative disorders in general.

Alzheimer Disease↗

PubMed2005

Development of novel amyloid imaging agents based upon thioflavin S.

To date, small-molecule amyloid-imaging agents for in vivo detection and quantitation of amyloid deposits in Alzheimer's disease (AD) have been developed and successfully applied to human subjects. Preliminary studies have indicated that these amyloid-imaging agents were accumulated in the AD brains in a pattern that is relatively consistent with AD pathology, at least in the regions of amyloid-rich grey matter. These studies have also proven the concept that amyloid dyes, normally too hydrophilic to enter the brain, can be chemically modified to enhance brain permeability, binding affinity, as well as improve binding specificity for amyloid deposits. Related studies have suggested that structurally different agents can be developed that bind to different sites on amyloid deposits. In fact, in vivo cross-referencing studies based upon different amyloid-imaging agents may permit better characterization of AD pathology. But more importantly, novel amyloid imaging agents are required that will allow direct correlation between the results of animal models and human subjects based upon identical imaging modalities. Thus far, amyloid stains such as Congo red and thioflavin T have been extensively studied. However, another widely used amyloid dye, thioflavin S, has not been previously explored. This is in part due to the fact that thioflavin S exists as a mixture, not a pure chemical entity, albeit that the major component has been characterized. We hypothesized that neutral analogs, based upon the major component, could be developed as novel amyloid imaging agents, that exhibit complementary binding properties and pharmacokinetic profiles compatible with potential human studies.

Amyloid↗

PubMed2004

Syntheses of 11C- and 18F-labeled carboxylic esters within a hydrodynamically-driven micro-reactor.

Carboxylic esters were successfully labeled with one of two short-lived positron-emitters, carbon-11 or fluorine-18, within a hydrodynamically-driven micro-reactor. The non-radioactive methyl ester was obtained at room temperature; its yield increased with higher substrate concentration and with reduced infusion rate. Radioactive methyl ester was obtained from the reaction of (10 mM) with in 56% decay-corrected radiochemical yield (RCY) at an infusion rate of 10 microL min(-1), and when the infusion rate was reduced to 1 microL min(-1), the RCY increased to 88%. The synthesis of the non-radioactive fluoroethyl ester from and required heating of the micro-reactor on a heating block at 80 degrees C (14-17% RCY), whilst the corresponding radioactive from and was obtained in 10% RCY. The radioactive 'peripheral' benzodiazepine receptor ligand was obtained from the reaction of acid with labeling agent in 45% RCY at an infusion rate of 10 microL min(-1). When the infusion rate was reduced to 1 microL min(-1), the RCY increased to 65%. The results exemplify a new methodology for producing radiotracers for imaging with positron emission tomography that has many potential advantages, including a requirement for small quantities of substrates, enhanced reaction, rapid reaction optimisation and easy product purification.

Carbon Dioxide↗

PubMed2004

Synthesis and first in vivo evaluation of new selective high affinity beta1-adrenoceptor radioligands for SPECT based on ICI 89,406.

The results of cardiac biopsies suggest that myocardial beta1-adrenoceptor (AR) density is reduced in patients with chronic heart failure, while changes in cardiac beta2-ARs vary. A technique for visualization and quantification of beta1-AR populations rather than total beta-AR densities in the human heart would be of great clinical interest. Molecular imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET), with appropriate radiopharmaceuticals offer the possibility to assess beta-AR density noninvasively in humans, but to date, neither a SPECT nor a PET-radioligand is clinically established for the selective imaging of cardiac beta1-ARs. The aim of this study was to design a high affinity selective beta1-AR radioligand for the noninvasive in vivo imaging of cardiac beta1-AR density in man using SPECT. Based on the well-known selective beta1-AR antagonist, ICI 89,406, both the racemic iodinated target compound 11a and the (S)-enantiomer 15a were synthesized. Competition studies using the nonselective AR ligand, [(125)I]iodocyanopindolol ([(125)I]ICYP), and ventricular membrane preparations from mice showed that 11a and 15a possess higher beta1-AR affinities (up to 265-fold) and beta1-AR selectivities (up to 245-fold) than ICI 89,406. Encouraged by these results, the radioiodinated counterparts of racemic 11a (11b: (125)I, 11c: (123)I) and (S)-configurated 15a (15b: (125)I, 15c: (123)I) were synthesized. The target compounds were evaluated in rats. Biodistribution and metabolism studies in rats indicated that there is a specific heart uptake of 11b-c and especially 15b-c accompanied by rapid metabolism of the radioligands. Therefore, radioiodinated 11c and 15c appeared to be unpromising SPECT-radioligands for assessing beta1-ARs in vivo in the rat. However, the rat may metabolize beta-AR ligands more rapidly than other species as demonstrated for (S)-[(11)C]CGP 12177, a radioligand structurally related to 11a-c and 15a-c. Therefore further studies in a different animal model will be carried out.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2004

Synthesis and evaluation of two 18F-labeled 6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine derivatives as prospective radioligands for beta-amyloid in Alzheimer's disease.

This study evaluated (18)F-labeled IMPY [6-iodo-2-(4'-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging beta-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Abeta-aggregates with K(i) = 27 +/- 8 and 40 +/- 5 nM, respectively. A "one-pot" method for (18)F-2-fluoroethylation and (18)F-3-fluoropropylation of the precursor was developed. The overall decay-corrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for [(18)F]FEM-IMPY at 1.2 min, and 5.7% ID/g for [(18)F]FPM-IMPY at 0.8 min. These values were similar to those of [(123)I/(125)I]IMPY (7.2% ID/g at 2 min). Polar and nonpolar radioactive metabolites were observed in both plasma and brain homogenates after injection of [(18)F]FEM or [(18)F]FPM-IMPY. In contrast to the single-exponential washout of [(123)I/(125)I]IMPY, the washouts of brain activity for the two fluorinated analogues were biphasic, with an initial rapid phase over 20 min and a subsequent much slower phase. Residual brain activity at 2 h, which may represent polar metabolites trapped in the brain, was 4.5% ID/g for [(18)F]FEM-IMPY and 2.1% ID/g for [(18)F]FPM-IMPY. Substantial skull uptake of [(18)F]fluoride was also clearly observed. With a view to slow the metabolism of [(18)F]FEM-IMPY, an analogue was prepared with deuteriums substituted for the four ethyl hydrogens. However, D(4)-[(18)F]FEM-IMPY showed the same brain uptake and clearance as the protio analogue. Metabolism of the [(18)F]FEM-IMPY was appreciably slower in rhesus monkey than in mouse. Autoradiography of postmortem brain sections of human Alzheimer's disease patients with [(18)F]FEM-IMPY showed high displaceable uptake in gray matter and low nonspecific binding in the white matter. This study demonstrates that the IMPY derivatives have favorable in vivo brain pharmacokinetics and a moderate affinity for imaging beta-amyloid plaques; however, further improvements are needed to reduce radioactive metabolites, increase binding affinity, and reduce lipophilicity.

Alzheimer Disease↗

PubMed2004

PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain.

(S,S)-2-(alpha-(2-Fluoromethoxyphenoxy)benzyl)morpholine ((S,S)-FMeNER) was found to be a selective high-affinity ligand for the norepinephrine transporter (NET). (S,S)-FMeNER) was labeled with fluorine-18 (t1/2 = 109.8 min) by O-fluoromethylation of desfluoromethoxy-(S,S)-FMeNER with [18F]bromofluoromethane. An analog, di-deuterated in the fluoromethoxy group ((S,S)-FMeNER-D2), was similarly labeled with di-deutero-[18F]bromofluoromethane. These two new radioligands were obtained in radiochemical purities greater than 98% and with specific radioactivities ranging from 111-185 GBq/micromol at the end of synthesis (75 min). After intravenous injection of (S,S)-[18F]FMeNER into cynomolgus monkey, PET examination with the head in the field of view revealed skull-bound radioactivity, contaminating images of the brain, and indicated fast defluorination of the radioligand. Defluorination was much reduced in similar PET experiments with (S,S)-[18F]FMeNER-D2. Ratios of radioactivity in the lower brainstem, mesencephalon, thalamus, and temporal cortex to striatum obtained with (S,S)-[18F]FMeNER-D2 at 160 min after i.v. injection were 1.5, 1.6, 1.3, and 1.5, respectively. In another PET experiment, pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the radioactivity ratios in all examined regions to near unity (e.g., to a ratio of 1.03 in mesencephalon). Labeled metabolites of (S,S)-[18F]FMeNER-D2 or (S,S)-[18F]FMeNER found in plasma were all more polar than the parent radioligand. In vitro autoradiography of (S,S)-[18F]FMeNER-D2 on post-mortem human brain cryosections furthermore showed specific binding to NET in the locus coeruleus and thalamus. (S,S)-[18F]FMeNER-D2 is the first useful radiofluorinated ligand for imaging brain NET in monkey in vivo and is superior to (S,S)-[11C]MeNER because a specific binding peak equilibrium is obtained during the PET experiment at a lower noise level.

Animals↗

PubMed2004

Whole-body biodistribution and radiation dosimetry estimates for the PET dopamine transporter probe 18F-FECNT in non-human primates.

BACKGROUND AND AIM: 2 beta-Carbomethoxy-3-(4-chlorophenyl)-8-(2-[18F]fluoroethyl)nortropane (18F-FECNT) is a selective radioligand for the in vivo quantification of dopamine transporters by using positron emission tomography. The aim of the current study was to quantify the distribution of radioactivity in three rhesus monkeys after the injection of approximately 185 MBq (5 mCi) of 18F-FECNT. METHOD: Whole-body images were acquired at 23-30 time points for a total of 220 min following injection of the radioligand. Source organs were identified at each time point from planar images. RESULTS: The peak activities in planar images in the six identified source organs (expressed as per cent injected dose (%ID)) were lungs (16.5%ID at 2 min), kidneys (12.5%ID at 3 min), brain (9.5%ID at 6 min), liver (7.5%ID at 3 min), red bone marrow (3.5%ID at 12 min), and urinary bladder (2%ID at 98 min). Radiation absorbed doses were calculated using the gastrointestinal tract model in two ways: (1) assuming no urine voiding, and (2) using a dynamic bladder model with voiding intervals of 2.4 and 4.8 h. Using the gastrointestinal tract model and dynamic bladder model with a voiding interval 4.8 h, the three organs with highest exposure (in mu Gy.MBq(-1) (mrad.mCi(-1)) were kidneys 75.68 (280), lungs 44.86 (166) and urinary bladder 58.38 (216). Effective doses estimated with and without urine voiding were in the range 21.35-22.70 mu Gy.MBq(-1) (79-84 mrad.mCi(-1)). CONCLUSION: The estimated radiation burden of 18F-FECNT is relatively modest and would allow multiple scans per research subject per year.

Animals↗

PubMed2003

Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET.

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT(4)) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT(4) receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT(4) receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT(4) receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [(123)I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT(4) receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT(4) receptor antagonist, SB 204070, at 20 min before [(123)I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [(123)I]SB 207710 is an effective radioligand for imaging brain 5-HT(4) receptors in vivo.

Animals↗

PubMed2003

Design of new beta1-selective adrenoceptor ligands as potential radioligands for in vivo imaging.

In general, the failing human heart is characterized by a selective reduction in beta(1)-adrenoceptors (beta(1)-ARs) without change in beta(2)-AR density. Medical imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET) with appropriate radioligands, offer the possibility of assessing beta-adrenoceptor density non-invasively in humans. To date, neither a SPECT nor a PET radioligand is available for the selective imaging of cardiac beta(1)-ARs. The aim of this study was to develop potential high affinity beta(1)-selective AR radioligands for the non-invasive in vivo imaging of the beta(1)-AR density in the human heart using SPECT or PET. A variety of racemic N-aryl-N'-[2-[3-aryloxy-2-hydroxy-propylamino]-ethyl]-urea derivatives and chain-elongated analogues, related to the established beta(1)-AR antagonist, ICI 89,406 8i, were synthesized. Competition studies using the non-selective AR ligand, [(125)I]iodocyanopindolol ([(125)I]ICYP), and ventricular membrane preparations of wild-type mice revealed nine ligands with higher beta(1)-AR affinities (up to 76-fold) and beta(1)-AR selectivities (up to 139-fold) than 8i. Mostly, these ligands possess a 2-substituted phenoxy group and a 4-substituted phenyl residue in contrast to the lead compound 8i. The non-radioactive counterparts of the desired SPECT- and PET-radiotracers were synthesized as reference compounds [e.g., 8f, 8g, 8h and 8l as the non-radioactive analogues of the radioiodinated SPECT radioligands, 8e and 8h as the non-radioactive compounds of C-11 labelled PET-tracers (C-11 in the methoxy group)]. The established library of high affinity beta(1)-selective AR antagonists was screened for chemical precursors for the radiosynthesis of the mentioned radioligands. Furthermore, the library consists of some comparison compounds that are unsubstituted, allyl- and alkyl-substituted or chain-elongated (e.g., 8a, 8j, 8o and 8r-t). Future steps will include radiolabelling and pharmacokinetic evaluation of the beta(1)-selective target compounds, which could be applied as sympathetic innervation agents for in vivo investigations and diagnostics in patients suffering from cardiac diseases like heart failure and ventricular arrhythmias.

Adrenergic beta-1 Receptor Antagonists↗

PubMed2003

Synthesis of a [6-pyridinyl-18F]-labelled fluoro derivative of WAY-100635 as a candidate radioligand for brain 5-HT1A receptor imaging with PET.

In recent years, considerable effort has been spent on the design, synthesis and pharmacological characterization of radiofluorinated derivatives of the 5-HT(1A) receptor antagonist, WAY-100635, for the in vivo study of these receptors in human brain with PET. (Pyridinyl-6)-fluoro- and (pyridinyl-5)-fluoro-analogues of WAY-100635 (6-fluoro and 5-fluoro-WAY-100635, 5a/6a) were synthesized as well as the corresponding chloro-, bromo- and nitro-derivatives as precursors for labelling (5b-d and 6b-d). Comparative radiolabelling of these precursors with fluorine-18 (positron-emitting isotope, 109.8 min half-life) clearly demonstrated that only ortho-fluorination in this pyridine series, and not meta-fluorination, is of interest for the preparation of a radioligand by nucleophilic heteroaromatic substitution. 6-[(18)F]Fluoro-WAY-100635 ([(18)F]5a) can be efficiently synthesized in one step, either from the corresponding 6-bromo precursor (using conventional heating at 145 degrees C for 10 min) or from the corresponding 6-nitro precursor (using microwave activation at 100 W for 1 min). Typically, 15-25 mCi (0.55-0.92 GBq) of 6-[(18)F]fluoro-WAY-100635 ([(18)F]5a, 1-2 Ci/micromol or 37-72 GBq/micromol) were obtained in 50-70 min starting from a 100 mCi (3.7 GBq) aliquot of a batch of cyclotron-produced [(18)F]fluoride. This (18)F-labelled radioligand is now being evaluated in PET studies.

Brain Chemistry↗

PubMed2003

Distribution of 5-HT4 receptors in the postmortem human brain--an autoradiographic study using [125I]SB 207710.

The autoradiographic distribution of the 5-HT4 receptor was described using human postmortem brain sections and the selective radioligand [125I]SB 207710 [(1-n-butyl-4-piperidinyl)methyl-8-amino-7-[125I]iodo-1,4-benzodioxane-5-carboxylate]. The specific binding was highest in regions of the basal ganglia (caudate nucleus, putamen, nucleus accumbens, globus pallidus and substantia nigra) and the hippocampal formation (CA1 and subiculum). In the neocortex, the binding showed a distinct lamination pattern with high levels in superficial layers and a band displaying lower levels in deep cortical layers. The results confirm previous studies on the distribution of 5-HT4 receptors in the human brain in vitro and provide high-resolution correlates for in vivo imaging studies using the radioligand recently developed for single photon emission tomography (SPET), [123I]SB 207710.

Autoradiography↗

PubMed2003

Specific in vivo binding to the norepinephrine transporter demonstrated with the PET radioligand, (S,S)-[11C]MeNER.

(S,S)-2-(alpha-(2-Methoxyphenoxy)benzyl)morpholine (MeNER), an O-methyl analog of the selective and potent norepinephrine transporter (NET) inhibitor, (S,S)-reboxetine, and its less active enantiomer, (R,R)-MeNER, have each been radiolabeled by O-methylation of their corresponding phenolic precursors in good yields from [(11)C]methyl iodide or [(11)C]methyl triflate. Radiochemical purities were >99% and specific radioactivity at time of injection was about 74 GBq/micromol. Autoradiographic examination of (S,S)-[(11)C]MeNER binding to human brain slices post mortem indicated specific binding in a brain region including the locus coeruleus. PET examination of both [(11)C]MeNER enantiomers in a cynomolgus monkey demonstrated a higher specific binding of the (S,S)-enantiomer with ratios of 1.4-1.6 in the lower brainstem, mesencephalon and thalamus to striatum. Pretreatment with the NET ligand, desipramine, decreased the specific binding of (S,S)-[(11)C]MeNER. Labeled metabolites of [(11)C]MeNER were all more polar. (S,S)-[(11)C]MeNER is a good lead compound in the search for a selective radioligand for quantitation of NET in the human brain in vivo.

Animals↗

PubMed2002

Synthesis of (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives as high affinity probes for sigma1 and sigma2 binding sites.

Selective ligands for either sigma1 (sigma1) or sigma2 binding sites are potentially useful for gaining a better understanding of the physiological functions of these proteins. Moreover, potent and selective homochiral sigma1 and sigma2 binding site ligands represent leads to potential radioligands for tumour imaging with positron emission tomography (PET). On the basis of their structural similarity to previous leads, new (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives were synthesised and their binding affinities for sigma1 and sigma2 binding sites were determined. Each enantiomer showed high affinity for both sigma1 and sigma2 binding sites, but only (-)-cis-methyl-2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropane-carboxylate, (-)-4, showed appreciable selectivity for binding to sigma1 versus sigma2 sites. The enantiomers of cis-(2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropyl)methanol, 6, expressed the highest affinity for sigma1 and sigma2 binding sites. Ligands (-)-4, (+)-6 and (-)-6 might be rapidly labelled in their N-methyl groups by methylation of the N-desmethyl analogues with [11C]iodomethane to provide prospective radioligands for PET. The N-desmethyl analogues, which are also high affinity ligands, were prepared and shown to undergo satisfactory methylation with iodomethane.

Binding Sites↗

PubMed2002

Imaging the GABA-benzodiazepine receptor subtype containing the alpha5-subunit in vivo with [11C]Ro15 4513 positron emission tomography.

There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The alpha5-containing subtype is highly expressed in the hippocampus, and selective alpha5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the alpha1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the alpha5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the alpha1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the alpha5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

Animals↗

PubMed2002

The PET radioligand [carbonyl-(11)C]desmethyl-WAY-100635 binds to 5-HT(1A) receptors and provides a higher radioactive signal than [carbonyl-(11)C]WAY-100635 in the human brain.

UNLABELLED: 5-Hydroxytryptamine (serotonin)-1A (5-HT(1A)) receptors are of key interest in research on the pathophysiology and treatment of psychiatric disorders. The PET radioligand [carbonyl-(11)C]WAY-100635 ((11)C-WAY), where WAY-100635 is (3)H-(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexane-carboxamide, is commonly used for quantitation of 5-HT(1A) receptors in the human brain. The aim of this PET study was to compare (11)C-WAY with the putative metabolite and selective radioligand [carbonyl-(11)C]desmethyl-WAY-100635 ((11)C-DWAY). METHODS: A PET examination was performed on each of 5 healthy male volunteers after intravenous injection of (11)C-WAY and (11)C-DWAY on separate occasions. Radioactive metabolites in plasma were determined with high-performance liquid chromatography. The plasma metabolite--corrected input function was used in a kinetic compartment analysis. The simplified reference tissue model and peak equilibrium method, using the cerebellum as reference region, was applied for comparison of data. RESULTS: For both radioligands, the highest radioactivity was observed in the neocortex and the raphe nuclei, whereas radioactivity was low in the cerebellum. The regional binding potentials were similar for the 2 radioligands. The brain uptake was more than 2-fold higher for (11)C-DWAY than for (11)C-WAY, in part because of higher delivery (first-order rate constant K(1), 0.38 vs. 0.16). The time--activity curves were well described by a 3-compartment model for all regions, whereas uptake in the cerebellum could not be described by a 2-compartment model, supporting the existence of kinetically distinguishable nonspecific binding in the cerebellum or radioactive metabolites in the brain for both radioligands. Both radioligands were rapidly metabolized, and <10% of the radioactivity in plasma represented unchanged (11)C-WAY or (11)C-DWAY at 10 min after injection. The metabolic pattern was similar for both radioligands, with the formation of radiolabeled cyclohexanecarboxylic acid and more polar components. For (11)C-WAY, small amounts of an additional labeled metabolite comigrated with reference desmethyl-WAY-100635. CONCLUSION: The advantages of (11)C-DWAY over (11)C-WAY for research on central 5-HT(1A) receptors is supported by a significantly higher radioactivity signal at equipotent doses, providing improved imaging statistics and advantages in biomathematic modeling and the preclusion of (11)C-DWAY as a metabolite interfering with PET measurements.

Adult↗

PubMedDate not supplied

Synthesis and positron emission tomography evaluation of three norepinephrine transporter radioligands: [C-11]desipramine, [C-11]talopram and [C-11]talsupram.

Desipramine (DMI), talopram and talsupram, three of the most potent norepinephrine transporter (NET) inhibitors reported to date, were radiolabeled in high yields and at high specific radioactivity (58-75 GBq/micromol) by the methylation of nor-precursors with [C-11]methyl triflate. The regional brain distribution of each radioligand following intravenous injection into cynomolgus monkey was examined in vivo with positron emission tomography (PET). For all three radioligands, the regional brain distribution of radioactivity was slightly heterogeneous, with higher uptake of radioactivity in the mesencephalon, thalamus and lower brainstem than in striatum. The rank order of maximal brain radioactivity (as percentage of injected dose) was [C-11]DMI (2.7%) > [C-11]talsupram (1.3%) > [C-11]talopram (0.7%). The appearance of radioactive metabolites in plasma was similar for each radioligand (75-85% of radioactivity in plasma at 45 min). These metabolites were all more polar than their parent radioligand. The data show that these radioligands are inferior to existing radioligands for the study of brain NET with PET in vivo.

Animals↗