Synthesis and preclinical evaluation of [11C]D617, a metabolite of (R)-[11C]verapamil

Objectives(R)-[¹¹C]verapamil is widely used as a positron emission tomography (PET) tracer to evaluate P-glycoprotein (P-gp) functionality at the blood–brain barrier in man. A disadvantage of (R)-[¹¹C]verapamil is the fact that its main metabolite, [¹¹C]D617, also enters the brain. For quantitative analysis of (R)-[¹¹C]verapamil data, it has been assumed that the cerebral kinetics of (R)-[¹¹C]verapamil and [¹¹C]D617 are the same. The aim of the present study was to investigate whether the cerebral kinetics of (R)-[¹¹C]verapamil and [¹¹C]D617 are indeed similar and, if so, whether [¹¹C]D617 itself could serve as an alternative PET tracer for P-gp.Methods[¹¹C]D617 was synthesized and its ex vivo biodistribution was investigated in male rats at four time points following intravenous administration of [¹¹C]D617 (50 MBq) without (n=4) or with (n=4) pretreatment with the P-gp inhibitor tariquidar (15 mg·kg^?1, intraperitoneally). Brain distribution was further assessed using consecutive PET scans (n=8) before and after pretreatment with tariquidar (15 mg·kg^?1, intravenously), as well as metabolite analysis (n=4).ResultsThe precursor for the radiosynthesis of [¹¹C]D617, 5-amino-2-(3,4-dimethoxy-phenyl)-2-isopropyl-pentanitrile (desmethyl D617), was synthesized in 41% overall yield. [¹¹C]D617 was synthesized in 58%–77% decay-corrected yield with a radiochemical purity of ≥99%. The homogeneously distributed cerebral volume of distribution (V_T) of [¹¹C]D617 was 1.1, and this increased 2.4-fold after tariquidar pretreatment.ConclusionV_T of [¹¹C]D617 was comparable to that of (R)-[¹¹C]verapamil, but its increase after tariquidar pretreatment was substantially lower. Hence, (R)-[¹¹C]verapamil and [¹¹C]D617 do not show similar brain kinetics after inhibition of P-gp with tariquidar.     

Radiosynthesis and in vivo evaluation of [(11)C]MP-10 as a positron emission tomography radioligand for phosphodiesterase 10A

Introduction

The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [¹¹C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET.

Methods

A procedure was developed for labeling MP-10 with carbon-11. [¹¹C]MP-10 was evaluated in vivo both in the pig and baboon brain.

Results

Alkylation of the corresponding desmethyl compound with [¹¹C]methyl iodide produced [¹¹C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [¹¹C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1–2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [¹¹C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [¹¹C]MP-10 were slower, reaching peak tissue concentrations at 30–60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [¹¹C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V_T) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP_ND) as the outcome measure of specific binding. Quantification of [¹¹C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP_ND estimates consistent with those obtained by the two-tissue compartment model.

Conclusion

We demonstrated that [¹¹C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.     

In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography

3-Amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, labeled with carbon-11 ([11C]-DASB), is a recently introduced radiotracer for imaging the serotonin transporter (SERT) by positron emission tomography (PET). A series of in vitro and in vivo experiments were performed to further characterise the properties of [11C]-DASB as an in vivo imaging agent for SERT. In vitro binding assays confirmed that DASB binds specifically to SERT with nanomolar affinity and high selectivity over a large number of other receptors, ion-channels and enzymes in the central nervous system. Ex vivo, [11C]-DASB binding in rat brain was shown to be saturable (ED(50) of 56 nmoles/kg), and sensitive to both the number of available SERT binding sites and the number of viable serotonin neurons. Estimates of the radiation dose in man were extrapolated from rat biodistribution data (effective dose 5.5 E-03 mSv/MBq; critical organ --urinary bladder wall). Together with previous studies, the present findings indicate that [11C]-DASB is a very useful radiopharmaceutical for probing changes in SERT densities using PET imaging in the living human brain.     

Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA, [11C]glucose, and [11C]methionine

A patient with an anaplastic (malignant) astrocytoma was examined with computed tomography (CT) and with positron emission tomography (PET), in the latter case using [68Ga]EDTA, [11C]glucose, and [11C]methionine. The CT examination as well as the [68Ga]EDTA study showed a small tumor located in the region of the head of the left caudate nucleus. The [11C]glucose examination showed increased uptake on the same region, as did the [11C]methionine examination, but the latter also showed a considerable uptake in the entire left thalamic region. The patient died 15 days after the [11C]methionine study and a histologic evaluation of thin sections obtained at autopsy showed excellent agreement between tumor extent and activity distribution after [11C]methionine administration. The tumor tissue seen only with [11C]methionine was histologically different from that part of the tumor observed with the other tracers. Although cytologically similar, the latter showed large necrotic areas and an ability to induce marked endothelial proliferation, whereas in the former neither necroses nor notable endothelial proliferation was seen. In this case more than 50% of the tumor would have remained radiologically imperceptible without the [11C]methionine PET examination.     

Synthesis and in vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand

The potential of a ¹¹C-labeled selective sigma₁ receptor ligand, 1-(3,4-dimethoxyphenethyl)-4-[3-(3,4-dichlorophenyl)propyl]piperazine ([¹¹C]SA6298), was evaluated as a positron emission tomography (PET) ligand for mapping sigma₁ receptors in the central nervous system and peripheral organs. [¹¹C]SA6298 was synthesized by methylation of the desmethyl SA6298 with [¹¹C]CH₃I, with the decay-corrected radiochemical yield of 39 ± 5% based on [¹¹C]CH₃I and with the specific activity of 53 ± 17 TBq/mmol within 20 min from end of bombardment (EOB). In mice, the uptake of [¹¹C]SA6298 was significantly decreased by carrier loading in the brain, liver, spleen, heart, lung, small intestine, and kidney in which sigma receptors are present as well as in the skeletal muscle. Pretreatment with SA6298 also blocked the uptake of [¹¹C]SA6298 by these organs except for the small intestine, but significant displacement of [¹¹C]SA6298 by posttreatment with SA6298 was observed only in the heart, lung, and muscle. In the blocking study with one of the eight sigma receptor ligands, including haloperidol, SA6298, NE-100, (+)-pentazocine, SA4503, (−)-pentazocine, (+)-3-PPP, and (+)-SKF 10,047 (in the order of the affinity for sigma₁ receptor subtype), only SA6298 and an analog SA4503 significantly reduced the brain uptake of [¹¹C]SA6298 to approximately 80% of the control, but the other six ligands did not. Peripherally, the uptake of [¹¹C]SA6298 by the organs described above was decreased predominantly by SA6298 or SA4503, but the blocking effects of the other five ligands except for NE-100 depended on their affinity for sigma₁ receptors. The saturable brain uptake of [¹¹C]SA6298, approximately 20%, was also observed by tissue dissection method in rats and by PET in a cat. Ex vivo autoradiography of the rat brain showed a high uptake in the cortex and thalamus. In the cat brain a relatively high uptake was found in the cortex, thalamus, striatum, and cerebellum. These results have indicated a receptor-mediated uptake of the tracer to some extent in the brain and peripheral organs. However, the tracer has a limited potential for the PET study of the brain receptors because of a relatively high nonspecific binding.     

Synthesis of [isopropyl-11C]nimodipine for in vivo studies of dihydropyridine binding in man using positron emission tomography

Nimodipine, an antagonist of the L-type calcium ion channel, was labelled with ¹¹C for in vivo positron emission tomography studies of dihydropyridine binding in the human brain. The synthesis was based on esterification of the corresponding acid (W2100) using [2-¹¹C]isopropyl iodide as the labelling precursor. The effects of different bases, solvent mixtures and reaction temperatures on radiochemical yields were investigated. The synthesis, including purification by semi-preparative reversed-phase HPLC, required 60–65 min. Conversion of [2-¹¹C]isopropyl iodide to [isopropyl-¹¹C]nimodipine was of the order of 60–80%. The radiochemical yield (isolated) was 20–25%, based on [¹¹C]carbon dioxide. The specific activity of the isolated product varied from 4–40 GBq/μmol (end-of-synthesis).     

In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in rhesus monkeys

The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2-pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and 11% in the cerebellum, whereas an increase was found for the uptake of (S)(-)[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of [11C]MPA to nicotinic receptors in the brain in a simple classical displacement study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain.     

Preclinical and clinical evaluation of O-[11C]methyl-L-tyrosine for tumor imaging by positron emission tomography

We performed preclinical and clinical studies of O-[11C]methyl-L-tyrosine, a potential tracer for imaging amino acid transport of tumors by positron emission tomography (PET). Examinations of the radiation-absorbed dose by O-[11C]methyl-L-tyrosine and the acute toxicity and mutagenicity of O-methyl-L-tyrosine showed suitability of the tracer for clinical use. The whole-body imaging of monkeys and healthy humans by PET showed low uptake of O-[11C]methyl-L-tyrosine in all normal organs except for the urinary track and bladder, suggesting that the O-[11C]methyl-L-tyrosine PET has the potential for tumor imaging in the whole-body. Finally, the brain tumor imaging was preliminarily demonstrated.     

11C]-MeJDTic: a novel radioligand for kappa-opioid receptor positron emission tomography imaging

INTRODUCTION: Radiopharmaceuticals that can bind selectively the kappa-opioid receptor may present opportunities for staging clinical brain disorders and evaluating the efficiency of new therapies related to stroke, neurodegenerative diseases or opiate addiction. The N-methylated derivative of JDTic (named MeJDTic), which has been recently described as a potent and selective antagonist of kappa-opioid receptor in vitro, was labeled with carbon-11 and evaluated for in vivo imaging the kappa-opioid receptor in mice. METHODS: [(11)C]-MeJDTic was prepared by methylation of JDTic with [(11)C]-methyl triflate. The binding of [(11)C]-MeJDTic to kappa-opioid receptor was investigated ex vivo by biodistribution and competition studies using nonfasted male CD1 mice. RESULTS: [(11)C]-MeJDTic exhibited a high and rapid distribution in peripheral organs. The uptake was maximal in lung where the kappa receptor is largely expressed. [(11)C]-MeJDTic rapidly crossed the blood-brain barrier and accumulated in the brain regions of interest (hypothalamus). The parent ligand remained the major radioactive compound in brain during the experiment. Chase studies with U50,488 (a kappa referring agonist), morphine (a mu agonist) and naltrindole (a delta antagonist) demonstrated that this uptake was the result of specific binding to the kappa-opioid receptor. CONCLUSION: These findings suggested that [(11)C]-MeJDTic appeared to be a promising selective "lead" radioligand for kappa-opioid receptor PET imaging.     

Synthesis of d-[11C]oxyphenonium iodide,a potential radioligand for in vivo visualization of human cholinergic muscarinic receptor-sites by positron emission tomography

Carbon-11 labeled d-oxyphenonium iodide, a cholinergic antagonist is synthesized for in vivo visualization of muscarinic receptor-sites on airway tissue by positron emission tomography (PET). Methylation with [¹¹C]CH₃I of d-demethyloxyphenonium, followed by HPLC purification affords the desired radiopharmaceutical with a radiochemical yield of 66% (based on [¹¹C]CH₃I, and corrected for decay) and with a specific activity of 110–300 Ci/mmol. The biologically active labeled d-enantiomer is prepared within 40 min after EOB. Optical and chemical purity proved to be better than 99.9%. Radiochemical purity was determined to be higher than 99%.     

Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with positron emission tomography

[methyl-11C]choline (11C-choline) is a radioligand potentially useful for oncological positron emission tomography (PET). As a first step towards the development of a kinetic model for quantification of 11C-choline uptake, blood metabolism of 11C-choline during PET imaging was studied in humans. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used for the analysis of 11C-choline and its radioactive metabolites. Prior to human PET imaging we studied ex vivo the biodistribution and metabolism of intravenously administered 11C-choline in rats. Our results revealed that the radioactivity accumulated particularly in kidney, lung, adrenal gland and liver. Chromatographic analysis showed that the level of unmetabolized 11C-choline in rat plasma decreased from 42% +/- 20% (mean +/- SD) at 5 min to 21% +/- 10% at 15 min after injection. In accordance with these findings, in humans the unmetabolized 11C-choline represents 62% +/- 19% of the total radioactivity in arterial plasma at 5 min after injection and 27% +/- 12% at 15 min. In human venous plasma the corresponding values were 85% +/- 12% and 48% +/- 12% at 5 and 10 min, respectively. The major metabolite observed in both human and rat plasma was identified as 11C-betaine. In human arterial plasma this maximally represented 82% +/- 9% of the total radioactivity at 25 min after radiotracer injection. By 20 min after injection, the 11C-choline and 11C-betaine in human arterial plasma reached a plateau, and their fractional activities remained nearly constant thereafter. Although most of the circulating 11C-choline in blood is transported to tissues, it does not disappear totally from blood within the first 40 min after tracer injection.     

Blood metabolism of [methyl- 11C]choline; implications for in vivo imaging with positron emission tomography

[methyl-¹¹C]Choline (¹¹C-choline) is a radioligand potentially useful for oncological positron emission tomography (PET). As a first step towards the development of a kinetic model for quantification of ¹¹C-choline uptake, blood metabolism of ¹¹C-choline during PET imaging was studied in humans. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used for the analysis of ¹¹C-choline and its radioactive metabolites. Prior to human PET imaging we studied ex vivo the biodistribution and metabolism of intravenously administered ¹¹C-choline in rats. Our results revealed that the radioactivity accumulated particularly in kidney, lung, adrenal gland and liver. Chromatographic analysis showed that the level of unmetabolized ¹¹C-choline in rat plasma decreased from 42%±20% (mean±SD) at 5 min to 21%±10% at 15 min after injection. In accordance with these findings, in humans the unmetabolized ¹¹C-choline represents 62%±19% of the total radioactivity in arterial plasma at 5 min after injection and 27%±12% at 15 min. In human venous plasma the corresponding values were 85%±12% and 48%±12% at 5 and 10 min, respectively. The major metabolite observed in both human and rat plasma was identified as ¹¹C-betaine. In human arterial plasma this maximally represented 82%±9% of the total radioactivity at 25 min after radiotracer injection. By 20 min after injection, the ¹¹C-choline and ¹¹C-betaine in human arterial plasma reached a plateau, and their fractional activities remained nearly constant thereafter. Although most of the circulating ¹¹C-choline in blood is transported to tissues, it does not disappear totally from blood within the first 40 min after tracer injection. Received 7 July and in revised form 16 September 1999     

Evaluation of [11C]GB67, a novel radioligand for imaging myocardial alpha 1-adrenoceptors with positron emission tomography

Dysfunction of the sympathetic nervous system underlies a number of myocardial disorders. Positron emission tomography (PET) offers a way of assessing receptor function non-invasively in humans, but there are no PET radioligands for assessing myocardial alpha-adrenoceptors. GB67, a structural and pharmacological analogue of the alpha 1-adrenoceptor antagonist prazosin, was labelled with positron-emitting carbon-11 (t1/2 = 20.4 min) by 11C-methylation of N-desmethylamido-GB67 (GB99). [11C]GB67 was injected intravenously into conscious rats. Serial arterial blood samples were taken. Rats were killed and tissues removed to determine radioactivity. The percentages of unchanged [11C]GB67 and its radioactive metabolites in plasma and tissues were assessed by HPLC. Plasma clearance of radioactivity was rapid. Myocardial uptake was maximal at 1-2 min and decreased slowly during 60 min. Predosing with adrenoceptor antagonists demonstrated selectivity for myocardial alpha 1-adrenoceptors. GB67 and prazosin blocked uptake of radioactivity; the non-selective antagonist, phentolamine, partially blocked uptake; the alpha 2-adrenoceptor antagonist, RX 821002, only blocked uptake at high dose and the beta-adrenoceptor antagonist, CGP 12177, had no effect. Additionally, injection of prazosin at 20 min after radioligand displaced radioactivity. In vivo competition curves obtained by injecting [11C]GB67 with varying amounts of either unlabelled GB67 or its precursor GB99 were fitted to a competitive binding model to provide estimates of the maximum number of binding sites (Bmax) and half saturation doses (K) for myocardium. Assuming a tissue protein content of 10%, the values of Bmax [approximately 13 pmol.(g tissue)-1[ were similar to those ]50-170 fmol.(mg protein)-1] reported for myocardial alpha 1-adrenoceptors assessed in vitro. Both GB67 and its precursor GB99 had high affinity for alpha 1-adrenoceptors [KGB67 = 1.5 nmol.(kg body weight)-1, KGB99 = 4.8 nmol.(kg body weight)-1]. HPLC demonstrated four radioactive metabolites in plasma. [11C]GB67 was 80% of the radioactivity at 5 min and 50% at 45 min. No radioactive metabolites were detected in myocardium up to 60 min after injection. [11C]GB67 was assessed in two male human volunteers. PET demonstrated high myocardial uptake. The profile of radioactive metabolites in plasma was comparable to that in the rat, although metabolism was slower in humans. Thus, [11C]GB67 is a promising radioligand for assessing alpha 1-adrenoceptors in human myocardium with PET.     

Synthesis of radiotracers for studying muscarinic cholinergic receptors in the living human brain using positron emission tomography: [11C]dexetimide and [11C]levetimide

Dexetimide (Fig. 1a), a potent muscarinic cholinergic receptor antagonist, and levetimide (Fig. 1b), its pharmacologically inactive enantiomer, were labeled with ¹¹C for non-invasive in vivo studies of muscarinic cholinergic receptors in the human brain using positron emission tomography. The syntheses were completed in approximately 32 min using [α-¹¹C]benzyl iodide as the precursor. The synthesis, purification, characterization and determination of specific activity are presented and discussed.     

N-[11C-Methyl]chlorphentermine and N,N-[11C-dimethyl]chlorphentermine as brain blood-flow agents for positron emission tomography

N-[11C-methyl]chlorphentermine ([11C]NMCP) and N,N-[11C-dimethyl]chlorphentermine ([11C]NDMCP) were prepared from chlorphentermine and 11CH3I in DMF and evaluated in rats as brain blood-flow agents for positron emission tomography (PET). Tissue distribution of [11C]NMCP showed that brain uptake was 2.70 +/- 0.40% of injected dose per organ at 5 min with no change in radioactivity concentration up to 30 min after i.v. injection. Approximately 80% of the initial brain uptake remained at 60 min. On the other hand, initial brain uptake of [11C] NDMCP (3.66 +/- 0.31 and 3.63 +/- 0.88% injected dose per organ at 5 and 15 min, respectively) was greater than that of [11C]NMCP. The brain activity however, rapidly decreased to 2.38 +/- 0.17 and 1.82 +/- 0.32% at 30 and 60 min, respectively. Because of its longer retention in the brain compared with [11C]NDMCP, [11C]NMCP would be a potential brain blood-flow agent for quantitative PET studies.     

Quantitative evaluation of L-[methyl-C-11] methionine uptake in tumor using positron emission tomography

Tumor uptake of L-[methyl-11C]methionine ([11C]Met) was assessed in six patients with brain tumors and three patients with lung cancer using positron emission tomography (PET). In arterial plasma samples taken at 5, 15, 30, and 60 min after injection, a fraction of [11C]Met was measured using high performance liquid chromatography in individual patients. Employing curve fitting, a history of [11C]Met activity was obtained as an input function. By means of sequential PET scannings and graphic analysis, uptake rate and distribution volume of [11C]Met in tumor tissue were calculated. In two studies irreversible uptake into the tumors was not seen when total plasma 11C activity was used as the input; however when [11C]Met plasma activity was used, definite irreversible uptake was seen, indicating tumor viability. In other studies, up to 24% underestimation of uptake rate was found. The present results demonstrated the importance of measuring [11C]Met in plasma for quantitative assessment of in vivo amino acid metabolism in tumors.     

Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB

Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenylthio) b enzylamine (DAPP) and (N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine (D ASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [11C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [11C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans.     

Imaging the serotonin transporter with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB

Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenylthio)benzylamine (DAPP) and (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DASB), were radiolabeled with carbon-11 and evaluated as in vivo probes of the serotonin transporter (SERT) using positron emission tomography (PET). Both compounds are highly selective, with nanomolar affinity for the serotonin transporter and micromolar affinity for the dopamine and norepinephrine transporters. Six volunteers were imaged twice, once with each of the two radioligands. Both ligands displayed very good brain penetration and selective retention in regions rich in serotonin reuptake sites. Both had similar brain uptake and kinetics, but the cyano analogue, [¹¹C]DASB, had a slightly higher brain penetration in all subjects. Plasma analysis revealed that both radiotracers were rapidly metabolized to give mainly hydrophilic species as determined by reverse-phase high-performance liquid chromatography. Inhibition of specific binding to the SERT was demonstrated in three additional subjects imaged with [¹¹C]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate that both these substituted phenylthiobenzylamines have highly suitable characteristics for probing the serotonin reuptake system with PET in humans.     

Cortical dysplasia localized by [11C]methionine positron emission tomography: case report

Numerous functional neuroimaging techniques have progressively been added to the presurgical evaluation of refractory partial epilepsies. These investigations can help confirm the origin of seizure onset previously suggested by MR imaging and electro-clinical data, provide independent prognostic information, and provide critical diagnostic value when MR imaging results are strictly normal or show multifocal abnormalities. Of the various functional neuroimaging modalities, [11C]methionine positron emission tomography for methionine uptake into seizure foci is still in the preliminary stages of investigation. A single case of medically intractable epilepsy with focal cortical dysplasia documented by [11C]methionine positron emission tomography and possible hypotheses to explain the methionine uptake into the seizure focus are described below.     

Changes in myocardial oxidative metabolism after biventricular pacing as evaluated by [11C]acetate positron emission tomography

A 70-year-old woman with dilated cardiomyopathy and recurrent severe heart failure was admitted for biventricular pacing (BVP), which was recently reported to have clinical efficacy for severe heart failure with intraventricular conduction delay. An electrocardiogram showed complete left bundle branch block, and the QRS interval was markedly prolonged at 195 msec. Echocardiogram showed marked dilatation, diffuse hypokinesis and dyssynchrony of the left ventricle, and grade III mitral valve regurgitation. The patient underwent implantation of an atriobiventricular pacemaker and three pacing leads transvenously. The QRS interval shortened to 165 msec immediately after the BVP therapy, and improvements in echocardiographic parameters were seen at 5 months after BVP therapy. Myocardial oxidative metabolism was assessed by the monoexponential clearance rate of [¹¹C]acetate (Kmono) as measured by positron emission tomography (PET), and myocardial efficiency was assessed by the work metabolic index (WMI) at 1 and 5 months after the BVP therapy. The PET images obtained 5 months after BVP therapy showed a decrease in the clearance of [¹¹C]acetate compared with that obtained 1 month after BVP therapy. The Kmono of the whole left ventricle decreased from 0.051 at 1 month to 0.038 min⁻¹ at 5 months after BVP therapy, and that of the septum, anterior wall, lateral wall and posterior wall also decreased. The WMI increased from 4.2×10⁶ to 6.8×10⁶ mmHg·ml/m². These results suggest that BVP improved left ventricular function without increasing myocardial oxidative metabolism, resulting in improved myocardial efficiency, and that BVP may improve the long-term prognosis of heart failure patients with ventricular dyssynchrony. [¹¹C]acetate PET is a useful method of evaluating global and regional myocardial oxidative metabolism in patients who have undergone BVP therapy.