Preliminary PET Study Research Articles

Synthesis of (R,S)-isoproterenol, an inhibitor of tau aggregation, as an 11C-labeled PET tracer via reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone.

(R,S)-Isoproterenol inhibits the formation of toxic granular tau oligomers associated with neuronal loss and development of cognitive disorders, and is an attractive drug candidate for Alzheimer's disease. To elucidate its behavior in the brain by positron emission tomography, we synthesize (R,S)-[11C]isoproterenol by reductive alkylation of (R,S)-norepinephrine with [2-11C]acetone, which was in turn synthesized in situ under improved conditions afforded a decay-corrected radiochemical yield of 54%. The reductive alkylation using NaBH(OAc)3 as reducing agent in the presence of benzoic acid in DMSO/DMF (60:40 v/v) at 100 °C for 10 min gave (R,S)-[11C]isoproterenol in an 87% radio-high performance liquid chromatography (HPLC) analytical yield. HPLC separation using a strong cation exchange column, followed by pharmaceutical formulation in the presence of d/l-tartaric acid, afforded (R,S)-[11C]isoproterenol with a total radioactivity of 2.0 ± 0.2 GBq, a decay-corrected radiochemical yield of 19 ± 2%, chemical and radiochemical purities of 71% and >99%, respectively, and a molar activity of 100 ± 13 GBq/μmol (n = 3). The overall synthesis time from the end of the bombardment to pharmaceutical formulation was 48 min. A preliminary preclinical PET study in a rat demonstrated the potential of the radioligand for the evaluation of the penetration of (R,S)-isoproterenol in human brain.

Synthesis and biological evaluation of [18F]fluorovinpocetine, a potential PET radioligand for TSPO imaging.

Despite of various PET radioligands targeting the translocator protein TSPO 18-KDa are used for the investigations of neuroinflammatory conditions associated with neurological disorders, development of new TSPO radiotracers is still an active area of the researches with a major focus on the 18F-labelled radiotracers. Here, we report the radiochemical synthesis of [18F]vinpocetine, fluorinated analogue of previously reported TSPO radioligand, [11C]vinpocetine. Radiolabeling was achieved by [18F]fluoroethylation of apovincaminic acid with [18F]fluoroethyl bromide. [18F]vinpocetine was obtained in quantities >2.7 GBq in RCY of 13% (non-decay corrected), and molar activity >60 GBq/µmol within 95 min synthesis time. Preliminary PET studies in a cynomolgus monkey and metabolite studies by HPLC demonstrated similar results by [18F]vinpocetine as for [11C]vinpocetine, including high blood-brain barrier permeability, regional uptake pattern and fast washout from the NHP brain. These results demonstrate that [18F]fluorovinpocetine warrants further evaluation as an easier accessible alternative to [11C]vinpocetine.

Molecular Imaging and Updated Diagnostic Criteria in Lewy Body Dementias.

The aims of the study were to review recent advances in molecular imaging in the Lewy body dementias (LBD) and determine if these may support the clinical but contested temporal profile distinction between Parkinson disease (PD) with dementia (PDD) versus dementia with Lewy bodies (DLB). There do not appear to be major regional cerebral metabolic or neurotransmitter distinctions between PDD and DLB. However, recent studies highlight the relative discriminating roles of Alzheimer proteinopathies. PDD patients have lower cortical β-amyloid deposition than DLB. Preliminary tau PET studies suggest a gradient of increasing tau binding from cognitively normal PD (absent to lowest) to cognitively impaired PD (low) to DLB (intermediate) to Alzheimer disease (AD; highest). However, tau binding in DLB, including the medial temporal lobe, is substantially lower than in AD. Alzheimer-type proteinopathies appear to be more common in DLB compared to PDD with relative but no absolute differences. Given the spectrum of overlapping pathologies, future α-synuclein ligands are expected to have the best potential to distinguish the LBD from pure AD.

Brain Metabolism in Substance-Induced Psychosis and Schizophrenia: A Preliminary PET Study

Introduction: The relation between schizophrenia and cannabis abuse has been widely discussed from etiopathogenetic, psychopathological and neurometabolic points of view. Relatively little has been written about the differences between schizophrenia with co-occurrent cannabis abuse and substance-induced psychotic disorder (SIPD). Given these premises, our study aims to investigate the psychopathological and neurometabolic features of these clinical entities. Methods: We enrolled patients experiencing an acute psychotic episode, affected either by schizophrenia with or without cannabis abuse (SCZ +/- CA; n = 5 and n = 5, respectively) with recent onset (<5 years of illness) or by SIPD (n = 6), as diagnosed by the Structured Clinical Interview for DSM-IV Axis I. Patients affected by SIPD were all cannabis abusers. All patients were assessed with the PANSS (Positive and Negative Scale for Schizophrenia), urinary toxicological tests and brain 18-FDG-PET scanning in resting condition. Statistical analysis (ANOVA) was performed with Statistical Parametric Mapping SPM8 and Scenium software. Results: Bilateral hypermetabolism in the posterior cingulum and the precuneus (p < 0.001) was observed in SIPD patients compared to patients with schizophrenia, with or without cannabis abuse. Conclusions: Our preliminary PET findings suggest that substance abuse may cause increased brain metabolism in patients with induced psychosis but not in those with schizophrenia. These differences in brain metabolism were found in the posterior cingulum and precuneus, which are two core regions of the default mode network in humans. © 2014 S. Karger AG, Basel

White matter metabolism differentiates schizophrenia and bipolar disorder: a preliminary PET study

Fluorodeoxyglucose-F18 positron emission tomography studies (FDG-PET) have shown similar corticolimbic metabolic dysregulation in bipolar disorder and schizophrenia, with hypoactive prefrontal cortex coupled with hyperactive anterior limbic areas. However, it is not clear whether white matter metabolism connecting these regions is differently affected in the two disorders. Twenty-six patients with schizophrenia (mean age±S.D.=30.23±9.7 year-old; 19 males; mean weight±S.D.=71±3kg) and 26 patients with bipolar disorder (mean age±S.D.=48.73±13 year-old; 18 males; mean weight±S.D.=75±15kg) underwent an FDG-PET scan. Normalized datasets the two groups of patients were compared on a voxel-by-voxel basis using a two-sample t statistic test as implemented in SPM8, and adding age as covariate. Group differences were assessed applying a threshold of p<0.0005. White matter metabolic rates significantly differed between schizophrenia and bipolar disorder, whereas no differences were shown for cortical activity. This is the first FDG-PET, to our best knowledge, directly comparing subjects with schizophrenia to those with bipolar disorder. It reports decreased activity in the center of large fronto-temporal and cerebellar white matter tracts in patients with schizophrenia in respect to those with bipolar disorder. This feature may characterize and differentiate the regional brain metabolism of the two illnesses.

Twins in spirit: DOTATATE and high-affinity DOTATATE

Since the introduction of somatostatin receptor (sst) imaging using I-Tyr-octreotide [1], peptide receptor imaging and radiotherapy (PRRT) has become an established modality in the management of neuroendocrine tumours (NET) [2]. Based on the findings of a previous study [3] investigating metal-labelled DOTA-octreotides substituted at Tyr, we hypothesized that derivatives of DOTA-iodo-Tyr-octreotide might be excellent candidates for sstr imaging and therapy. Consequently, we evaluated Ga-DOTA-iodoTyr-octreo tate (Ga-HA-DOTATATE; HA, high affinity) in vitro and in a preliminary PET study. As hypothesized, Ga-HADOTATATE showed high affinity for human sst2,5 as well as diagnostic and logistical advantages, i.e. unlimited precursor availability. The (Leu,D-Trp, [I]Tyr)-SST28 IC50 values (in nanomoles) for Ga-HA-DOTATATE were >10.000 (sst1), 0.64±0.23 (sst2), >1,000 (sst3 and sst4) and 59.7±15.1 (sst5), and for Ga-DOTATATE were >10,000 (sst1), 0.67±0.25 (sst2), >1.000 (sst3), 822±327 (sst4) and >1,000 (sst5). In a first PET study a 73-year-old patient suffering from a NETwith unknown primary and liver metastases was investigated with Ga-HA-DOTATATE and Ga-DOTATATE. Both agents showed a possible small primary tumour in the midgut and five liver metastases that showed somewhat higher Ga-HA-DOTATATE uptake (mean SUVmax 23.8 vs. 21.6). The visual detectability of three small liver metastases with low uptake was superior with Ga-HADOTATATE. In summary, Ga-HA-DOTATATE provides high-quality images comparable to or better than those with GaDOTATATE. Further clinical studies are needed to confirm these first results and explore the use of HA-DOTATATE agents for PRRT.

Synthesis and Preliminary Evaluation of 18-18F-Fluoro-4-Thia-Oleate as a PET Probe of Fatty Acid Oxidation

Fatty acid oxidation (FAO) is a major energy-providing process with important implications in cardiovascular, oncologic, neurologic, and metabolic diseases. A novel 4-thia oleate analog, 18-(18)F-fluoro-4-thia-oleate ((18)F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-(18)F-fluoro-4-thia-palmitate ((18)F-FTP) as an FAO probe. (18)F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with (18)F-FTO and (18)F-FTP in rats. A practical synthesis of (18)F-FTO was developed, providing a radiotracer of high radiochemical purity (>99%). In fasted rats, myocardial uptake of (18)F-FTO (0.70 +/- 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of (18)F-FTP at 30 min after injection. At 2 h, myocardial uptake of (18)F-FTO was maintained, whereas (18)F-FTP uptake in the heart was 82% reduced. Similar to (18)F-FTP, (18)F-FTO uptake by the heart was approximately 80% reduced at 30 min by pretreatment of rats with the CPT-I inhibitor etomoxir. Folch-type extraction analyses showed 70-90% protein-bound fractions in the heart, liver, and skeletal muscle, consistent with efficient trafficking of (18)F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of (18)F-FTO and of (18)F-FTP into the heart and liver. Images of (18)F-FTO accumulation in the rat myocardium were clearly superior to those of (18)F-FTP. (18)F-FTO is shown to be a promising metabolically trapped FAO probe that warrants further evaluation.

Age-related diurnal effect on D2 receptor binding: a preliminary PET study

Animal research has shown a diurnal variation in dopamine neurotransmission, with a reduced release at night. Variations in biomarkers for the dopamine system over the day have, however, not been investigated in human subjects. In this preliminary PET study, we used the radioligands [11C]raclopride and [11C]FLB 457 to determine dopamine D2-receptor binding in 16 human subjects in the morning and evening on the same day. The average difference between morning and evening examinations did not indicate a diurnal effect on D2 receptor availability. However, when age was taken into account in the analysis, a pattern emerged where individuals in the lower age range showed reduced evening binding while in older subjects binding potential increased. The product-moment correlation between morning-evening change and age was statistically significant in insula, medial frontal cortex and rostral anterior cingulate. The findings, if replicated, have direct relevance for applied PET studies and could also prove relevant with regard to age effects on dopamine-related behaviour such as arousal and cognitive performance.

Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients –A preliminary PET study

Objectives To explore neurobiological risk factors for major depressive disorder (MDD) and adjustment disorder in cancer patients by examining regional brain metabolism before psychiatric manifestation using positron emission tomography and by prospectively observing depressive and anxiety symptoms. Method Cancer patients who showed no psychiatric symptoms when they underwent 18F-fluorodeoxyglucose positron emission tomography ( 18F-FDG PET) were followed up for one year using the Hospital Anxiety and Depression Scale (HADS). Fourteen patients who showed high HADS scores and 14 patients who showed low HADS scores were assessed by a psychiatrist 2 years after the PET scan and grouped into the deterioration group ( n = 10) and the no-change group ( n = 9). 18F-FDG PET images were analyzed to examine the difference in local brain glucose metabolism between the two groups. Results The deterioration group showed a decreased glucose metabolism in the right medial frontal gyrus (BA6) and an increased glucose metabolism in the right posterior cingulate (BA29), right anterior cingulate (BA25), left subcallosal gyrus (BA25), and left caudate compared with the no-change group. Conclusion Cancer patients who later developed MDD or adjustment disorder showed regional brain metabolic changes. These regions may be associated with vulnerability to the onset of MDD or adjustment disorder in cancer patients.

Synthesis of 4-([18F]fluoromethyl)-2-chlorophenylisothiocyanate: A novel bifunctional 18F-labelling agent

Abstract The one-step radiosynthesis of 4-([18F]fluoromethyl)-2-chlorophenylisothiocyanate 18F-7 as a novel bifunctional 18F-labelling agent is described. Optimised reaction conditions in a remotely controlled synthesis module gave isothiocyanate 18F-7 in radiochemical yields of 45% (decay-corrected) within 40 min and high radiochemical purity of &gt;95% after solid-phase-extraction. Coupling of compound 18F-7 with the primary amine benzylamine as a model reaction afforded the corresponding ((4-[18F]fluoromethyl)-2-chloro-phenyl)-benzyl thiourea 18F-8 in a high radiochemical yield of &gt;90%. Stability studies of thiourea 18F-8 in terms of radiodefluorination showed appreciable buffer stability at pH 7.4, whereas significant radiodefluorination was observed when 18F-8 was incubated in buffers at pH 3.6 and pH 9.4. Preliminary dynamic PET studies with thiourea 18F-8 in male Wistar rats showed high bone accumulation, indicative of high in vivo radiodefluorination.

Relationship between trait anxiety, brain activity and natural killer cell activity in cancer patients: a preliminary PET study.

The purpose of this study is to examine the relationship between psychological factors, regional brain activity and natural killer cell activity (NKA). Eight patients with malignant diseases were studied by FDG-PET under a resting condition. NKA and degree of anxiety and depression were measured using Taylor's manifest anxiety scale (MAS) and Zung's self-rating depression scale (SDS). Linear correlation of NKA and psychological measures to the regional brain metabolism in cancer patients was examined using statistical parametric mapping (SPM). Positive linear correlation between NKA and regional metabolic rate ratios was identified in the visual association cortex, anterior cingulate gyrus (CG) and sensorimotor area, and negative correlation was identified in the inferolateral prefrontal cortex (ILPFC), prefrontal cortex (PFC), orbitofrontal cortex (OFC) and anterior temporal cortex. Positive linear correlation to the MAS score was identified in the visual association cortex, anterior CG, primary sensorimotor area and the posterior parietal cortex, and negative correlation was detected in the ILPFC, PFC, OFC and anterior temporal cortex. The NKA and MAS scores positively correlated with each other (p<0.001). The result might serve as supporting data for a hypothesis that psycho-immune interaction is also mediated by the cerebral cortex and limbic system.

Mapping of CNS sigma(1) receptors in the conscious monkey: preliminary PET study with [(11)C]SA4503.

Mapping of CNS sigma(1) receptors in the conscious monkey: preliminary PET study with [(11)C]SA4503.

Synthesis of [ 11C]dapoxetine · HCl, a serotonin re-uptake inhibitor: Biodistribution in rat and preliminary PET imaging in the monkey

[ 11C]Dapoxetine · HCl, S-( + )- N,N-dimethyl-a-[2-(naphthalenyloxy)ethyl] benzenemethanamine hydrochloride, a potent serotonin re-uptake inhibitor was prepared from its mono-methyl precursor, S-( + )- N-methyl-a-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride. Biodistribution was determined in rats at 5, 30 and 60 min after injection and preliminary PET studies were performed in a Rhesus monkey. 11CH 3I was bubbled into a solution of S-( + )- N-methyl-α-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride (3.0 mg in DMSO) and the mixture was heated at 110 °C for 8 min. [ 11C]Dapoxetine · HCl was purified by HPLC on a C 18 cartridge eluted with MeOH:phosphate buffer, pH 7.2 (75:25) with a 10% yield (end of synthesis). The time required for the synthesis was 40 min, from the end of bombardment. Radiochemical purity of the final product was >99% and specific activity was routinely >400 mCi/μmol [EOS]. In the biodistribution studies the highest concentration (%ID/g ± SEM) of dapoxetine · HCl was detected in lung: 4.56 ± 0.27 (5 min), 1.28 ± 0.18 (30 min) and 0.67 ± 0.04 (60 min). Brain accumulation was 0.76 ± 0.02 (5 min), 0.46 ± 0.04 (30 min) and 0.27 ± 0.01 (60 min). Preliminary PET studies demonstrated significant displaceable binding in the cerebral cortex and subcortical grey matter. These results demonstrate that [ 11C]dapoxetine · HCl can be prepared in high purity and may be useful for the in vivo evaluation of serotonin re-uptake mechanisms.

Synthesis and preliminary evaluation of ( R,S)-1-[2-((Carbamoyl-4-hydroxy)phenoxy)-ethylamino]-3-[4-(1-[ 11C]-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol ([ 11C]CGP 20712A) as a selective β1-adrenoceptor ligand for PET

The most selective β 1-adrenoceptor ligand known at this moment is ( S)-1-[2-((carbamoyl-4-hydroxy) phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol (CGP 26505), the S-isomer of CGP 20712A. We prepared the racemic 11C analogue by methylation with [ 11C]CH 3I of the corresponding desmethyl compound using a microwave oven to accelerate the reaction. Several radioactive by-products (about 70% of the non-volatile radioactive products) were formed. After HPLC purification [ 11C]CGP 20712A with a specific activity of 35 TBq/mmol was dissolved in a propylene glycol-ethanol-saline mixture to prepare it for injection. The total preparation time was 35 min. The radiochemical yield was 5% (calculated from [ 11C]CH 3I, not corrected for decay). The identity of [ 11C]CGP 20712A was proved by liquid chromatography-mass spectrometry (LC-MS). Tissue distribution studies in male Wistar rats have been performed. At 20 min after injection of the radioligand (0.1 nmol) the DAR [differential absorption ratio = (counts per minute recovered/g tissue)/(counts per min injected/g body weight)] in heart tissue decreased significantly ( P < 0.005) from 1.84 ± 0.11 to 1.21 ± 0.12 after blocking of β-adrenoceptors with 500/μg ( R,S)-propranolol. A preliminary PET study in a Wistar rat showed maximal uptake in the time frame 10–20 min after injection. The ratio of specific/non-specific binding at this interval was 2.6.

Improved synthesis of 1-[ 11C] d-glucose

An improved synthesis of 1-[ 11C] d-glucose is described. The major improvement is achieved when a 0.033 M borate buffer at pH 8.1 is used to effect the condensation of d-arabinose with NH 4 11CN. Subsequent reduction of the 1-[ 11C] d-aldonitriles gives the epimeric sugars 1-[ 11C] d-glucose and 1-[ 11C] d-mannose in a ratio of 1.8 ± 0.57 as the major products. The decay corrected radiochemical yield is about 30% for the mixture of sugars. The overall synthesis, starting with the production of NH 4 11CN, is conducted in a dedicated remote system. The remote gantry was easy to build with commercially available valves and glassware, and has been practically trouble-free after more than 2 years of use. Improved purification and quality control of the final product uses ion chromatography and a more efficient resin, and is also described. A preliminary PET study on a macaque has been conducted using 1-[ 11C] d-glucose obtained with this new improved synthesis.

No-carrier-added synthesis of 3-[ 18F]fluoro-1-(2-nitro-1-imidazolyl)-2-propanol. A potential PET agent for detecting hypoxic but viable tissues

Four different approaches towards the synthesis of [ 18F]FMISO have been studied. The first approach was based on the reaction of epoxide 4 and [ 18F]fluoride. Both specific activity and radiochemical yield (<1%) for [ 18F]FMISO were low. Two new approaches, starting with compounds 8 and 9, have failed to give [ 18F]FMISO. The fourth approach, based on the reaction of [ 18F]epifluorohydrin 10, prepared from Tosylate 13 and [ 18F]KF/Kryptofix 222, has provided a reliable, no-carrier added synthesis of [ 18F]FMISO. The product was obtained in a radiochemical yield of 7–12% at end-of-synthesis (based on [ 18F]fluoride) with a specific activity of >400 Ci/mmol and a synthesis time of 1.5 h. Preliminary PET studies suggest that [ 18F]FMISO may be a promising tracer for delineation of ischemic but viable myocardium.