Evaluation of [O-methyl-11C]RS-15385-197 as a positron emission tomography radioligand for central alpha2-adrenoceptors

Carbon-11 labelled RS-15385-197 and its ethylsulphonyl analogue, RS-79948-197, were evaluated in rats as potential radioligands to image central alpha2-adrenoceptors in vivo. The biodistributions of both compounds were comparable with that obtained in an earlier study using tritiated RS-79948-197 and were consistent with the known localisation of alpha2-adrenoceptors. The maximal signals (total to non-specific binding) were, however, reduced, in the order [11C]RS-79948-197 < [11C]RS-15385-197 < [3H]RS-79948-197, primarily due to the difference in radiolabel position (O-methyl for carbon- 11 compared with S-ethyl for tritium). This resulted in the in-growth of radiolabelled metabolites in plasma, which, in turn, contributed to the non-specific component of brain radioactivity. Nonetheless, the signal ratio of approximately 5 for a receptor-dense tissue compared with the receptor-sparse cerebellum, at 90-120 min after radioligand injection, encouraged the development of [O-methyl-11C]RS-15385-197 for human positron emission tomography (PET). Unfortunately, in two human PET scans (each of 90 min), brain extraction of the radioligand was minimal, with volumes of distribution more than an order of magnitude lower than that measured in rats. Following intravenous injection, radioactivity was retained in plasma and metabolism of the radiolabelled compound was very low. Retrospective measurements of in vitro plasma protein binding and in vivo brain uptake index (BUI) in rats demonstrated a higher protein binding of the radioligand in human compared with rat plasma and a lower BUI in the presence of human plasma. It is feasible that a higher affinity of RS-15385-197 for human plasma protein compared with receptor limited the transport of the radioligand. Although one of the PET scans showed a slight heterogeneity in biodistribution of radioactivity which was consistent with the known localisation of alpha2-adrenoceptors in human brain, it was concluded that [O-methyl-11C]RS-15385-197 showed little promise for routine quantification of alpha2-adrenoceptors in man.     

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.     

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     

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.     

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.     

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%.     

Correction of head movement by frame-to-frame image realignment for receptor imaging in positron emission tomography studies with [11C]raclopride and [11C]FLB 457

Annals of Nuclear Medicine - Positron emission tomography (PET) scans of imaging receptors require 60–90-min dynamic acquisition for quantitative analysis. Head movement is often observed...     

Evaluation of O-[18F]fluoromethyl-d-tyrosine as a radiotracer for tumor imaging with positron emission tomography

O-[¹⁸F]Fluoromethyl-d-tyrosine (d-[¹⁸F]FMT) has been reported as a potential tumor-detecting agent for positron emission tomography (PET). However, the reason why d-[¹⁸F]FMT is better than l-[¹⁸F]FMT is unclear. To clarify this point, we examined the mechanism of their transport and their suitability for tumor detection. The stereo-selective uptake and release of enantiomerically pure d- and l-[¹⁸F]FMT by rat C6 glioma cells and human cervix adenocarcinoma HeLa cells were examined. The results of a competitive inhibition study using various amino acids and a selective inhibitor for transport system L suggested that d-[¹⁸F]FMT, as well as l-[¹⁸F]FMT, was transported via system L, the large neutral amino acid transporter, possibly via LAT1. The in vivo distribution of both [¹⁸F]FMT and [¹⁸F]FDG in tumor-bearing mice and rats was imaged with a high-resolution small-animal PET system. In vivo PET imaging of d-[¹⁸F]FMT in mouse xenograft and rat allograft tumor models showed high contrast with a low background, especially in the abdominal and brain region. The results of our in vitro and in vivo studies indicate that l-[¹⁸F]FMT and d-[¹⁸F]FMT are specifically taken up by tumor cells via system L. d-[¹⁸F]FMT, however, provides a better tumor-to-background contrast with a tumor/background (contralateral region) ratio of 2.741 vs. 1.878 with the l-isomer, whose difference appears to be caused by a difference in the influence of extracellular amino acids on the uptake and excretion of these two isomers in various organs. Therefore, d-[¹⁸F]FMT would be a more powerful tool as a tumor-detecting agent for PET, especially for the imaging of a brain cancer and an abdominal cancer.     

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.     

11C-coenzyme Q10: a new myocardial imaging tracer for positron emission tomography

Coenzyme Q10 (CoQ10) is a co-factor of the mitochondrial electron-transfer system. 11C-Labeled CoQ10 was synthesized and its biodistribution in rats was examined comparing two kinds of preparation methods using different emulsifiers as a basic study for application of positron emission tomography. 11C-CoQ10 emulsified in saline with polyoxyethylene hydrogenated castor oil was present in the highest concentration in the blood at 30 min. On the other hand, the 11C-CoQ10 emulsified with phospholipids was rapidly cleared from the blood. The liver and spleen uptakes were high probably due to endocytosis, reflecting the characteristics of liposomes. The myocardial uptake was also high just after administration, and the heart-to-blood concentration ratio was over 10 after 5 min. These results suggest that 11C-CoQ10 prepared with liposomes may be a myocardial imaging tracer.     

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.     

Preclinical studies on [11C]MPDX for mapping adenosine A1 receptors by positron emission tomography

In previous in vivo studies with mice, rats and cats, we have demonstrated that [11C]MPDX ([1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A1 receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [11C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [11C]MPDX. We have concluded that [11C]MPDX is suitable for mapping adenosine A1 receptors in the human brain by PET.     

Differential diagnosis of solitary pulmonary nodules with positron emission tomography using [11C]L-methionine

Two patients with solitary pulmonary nodules, 1.5-2.0 cm in diameter, were studied by positron emission tomography using [11C-Methyl]L-methionine (11C-Met). Case 1 showed high accumulation of 11C-Met in the tumor, and a tumor/muscle ratio of 6.0 suggesting malignancy. Tissue obtained by biopsy revealed a squamous cell carcinoma. Case 2 showed nonspecific isotope accumulation in the tumor, and a tumor/muscle ratio of 1.2 suggesting a benign lesion. Lung biopsy demonstrated granuloma. Positron emission tomography with 11C-Met seems to be useful for the differential diagnosis of solitary lung nodules.     

11C]methionine pancreatic scanning with positron emission computed tomography.

By the use of [11C]methionine and positron computed tomography (PCT), images of the pancreas were obtained in 32 patients. The injection of between 10 and 20 mCi of this product enables four to six transverse sections to be obtained. Seventeen of the patients studied had no exocrine pancreatic disease, and in all these cases the pancreas was clearly visible. In four cases of pancreatic carcinoma and one of retroperitoneal tumor, there were abnormalities visible. In five cases of chronic pancreatitis, no pancreatic uptake was observed. In a sixth case, concentration was visible, but only in the head of the pancreas. One case of acute pancreatitis, which showed no concentration during the acute phase, returned to normal after recovery. When visible, the pancreas was easily located and distinguishable from the intestinal image, except in two cases that were uninterpretable for technical reasons. No false positive or negative was observed, but a differential diagnosis between cancer and pancreatitis was impossible.     

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.     

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.     

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.     

Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury

Objective

[¹¹C]Flumazenil ([¹¹C]FMZ) positron emission tomography (PET) can be used as a measure of neuronal loss. The purpose of this study was to validate reference tissue kinetic modelling of [¹¹C]FMZ PET within a group of patients with head injury.

Methods

Following earlier studies, the pons was used as the reference region. PET scans were performed on 16 controls and 11 patients at least 6 months following injury, each of whom also had arterial blood sampling to provide whole blood and metabolite-corrected plasma input functions. Regional non-displaceable binding potentials (BP_ND) were calculated from five reference tissue models and compared to BP_ND from arterial input models. For the patients, the regions included a peri-lesional region of interest (ROI).

Results

Total distribution volume of the pons was not significantly different between control and patient groups (P = 0.24). BP_ND from all the reference tissue approaches correlated well with BP_ND from the plasma input models for both controls (r ² = 0.98–1.00; P < 0.001) and patients (r ² = 0.99–1.00; P < 0.001). For the peri-lesional regions (n = 11 ROI values), the correlation was also high (r ² = 0.91).

Conclusions

These results indicate that reference tissue modelling with the pons as the reference region is valid for [¹¹C]FMZ PET in head-injured patients at 6 months following injury within both normal appearing and peri-lesional brain regions.     

Synthesis and autoradiographic localization of muscarinic cholinergic antagonist (+)N-[11C]methyl-3-piperidyl benzilate as a potent radioligand for positron emission tomography.

(+)N-[11C]methyl-3-piperidyl benzilate, a relatively low affinity muscarinic cholinergic receptor antagonist was synthesized by N-[11C]methylation of (+)3-piperidyl benzilate using [11C]methyl iodide. The product was isolated by HPLC, and obtained with radiochemical yield of 60-70% from [11C]methyl iodide, and a specific activity of 500-1000 Ci mmol-1 (18.5-37 GBq mumol-1) at EOS and radiochemical purity of > 98%. In vitro autoradiographic studies showed selective binding for this radiotracer in the different regions of the rat brain: high in corpus striatum, hippocampus and cerebral cortex, and low in cerebellum, consistent with muscarinic cholinergic receptor distributions. This radiotracer thus had potential as radioligand for positron emission tomography.