PET quantification of 5-HT2A receptors in the human brain: a constant infusion paradigm with [18F]altanserin.

[18F]altanserin has been used to label serotonin 5-HT2A receptors, which are believed to be important in the pathophysiology of schizophrenia and depression. The purpose of this study was to test the feasibility of a constant infusion paradigm for equilibrium modeling of [18F]altanserin with PET. Kinetic modeling with [18F]altanserin may be hampered by the presence of lipophilic radiometabolites observed in plasma after intravenous administration. METHODS: Eight healthy volunteers were injected with [18F]altanserin as a bolus (208+/-9 MBq [5.62+/-0.25 mCi]) plus constant infusion (65+/-3 MBq/h [1.76+/-0.08 mCi/h]) ranging from 555 to 626 min (615+/-24 min) after injection. PET acquisitions (10-20 min) and venous blood sampling were performed every 30-60 min throughout the infusion period. RESULTS: Linear regression analysis revealed that time-activity curves for both brain activity and plasma [18F]altanserin and metabolite concentrations stabilized after about 6 h. This permitted equilibrium modeling and estimation of V3' (ratio of specific uptake [cortical-cerebellar] to total plasma parent concentration after 6 h). Values of V3' ranged from 1.57+/-0.38 for anterior cingulate cortex to 1.02+/-0.39 for frontal cortex. The binding potential V3 (ratio of specific uptake to free plasma parent concentration after 6 h, using group mean f1) was also calculated and ranged from 169+/-41 for anterior cingulate cortex to 110+/-42 for frontal cortex. From 6 h onward, the rate of change for V3' and V3 was only 1.11+/-1.69 %/h. CONCLUSION: These results demonstrate the feasibility of equilibrium imaging with [18F]altanserin over more than 5 radioactive half-lives and suggest a method to overcome difficulties associated with lipophilic radiolabeled metabolites. The stability in V3 and V3' once equilibrium is achieved suggests that a single PET acquisition obtained at 6 h may provide a reasonable measure of 5-HT2A receptor density.     

GMP-compliant radiosynthesis of [18F]altanserin and human plasma metabolite studies

[¹⁸F]altanserin is the preferred radiotracer for in-vivo labeling of serotonin 2A receptors by positron emission tomography (PET). We report a modified synthesis procedure suited for reliable production of multi-GBq amounts of [¹⁸F]altanserin useful for application in humans. We introduced thermal heating for drying of [¹⁸F]fluoride as well as for the reaction instead of microwave heating. We furthermore describe solid phase extraction and HPLC procedures for quantitative determination of [¹⁸F]altanserin and metabolites in plasma. The time course of arterial plasma activity with and without metabolite correction was determined. 90 min after bolus injection, 38.4% of total plasma activity derived from unchanged [¹⁸F]altanserin. Statistical comparison of kinetic profiles of [¹⁸F]altanserin metabolism in plasma samples collected in the course of two ongoing studies employing placebo, the serotonin releaser dexfenfluramine and the hallucinogen psilocybin, revealed the same tracer metabolism. We conclude that metabolite analysis for correction of individual plasma input functions used in tracer modeling is not necessary for [¹⁸F]altanserin studies involving psilocybin or dexfenfluramine treatment.     

Comparison of [(18)F]altanserin and [(18)F]deuteroaltanserin for PET imaging of serotonin(2A) receptors in baboon brain: pharmacological studies

The regional distribution in brain, distribution volumes, and pharmacological specificity of the PET 5-HT(2A) receptor radiotracer [(18)F]deuteroaltanserin were evaluated and compared to those of its non-deuterated derivative [(18)F]altanserin. Both radiotracers were administered to baboons by bolus plus constant infusion and PET images were acquired up to 8 h. The time-activity curves for both tracers stabilized between 4 and 6 h. The ratio of total and free parent to metabolites was not significantly different between radiotracers; nevertheless, total cortical R(T) (equilibrium ratio of specific to nondisplaceable brain uptake) was significantly higher (34-78%) for [(18)F]deuteroaltanserin than for [(18)F]altanserin. In contrast, the binding potential (Bmax/K(D)) was similar between radiotracers. [(18)F]Deuteroaltanserin cortical activity was displaced by the 5-HT(2A) receptor antagonist SR 46349B but was not altered by changes in endogenous 5-HT induced by fenfluramine. These findings suggest that [(18)F]deuteroaltanserin is essentially equivalent to [(18)F]altanserin for 5-HT(2A) receptor imaging in the baboon.     

Equilibrium modeling of 5-ht2a receptors with [f]deuteroaltanserin and pet: feasibility of a constant infusion paradigm

ABSTRACT. [¹⁸F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT_2A) receptors. The deuterium substitution of both of the 2′-hydrogens of altanserin ([¹⁸F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [¹⁸F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an ¹⁸F-labeled tracer (T_1/2 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [¹⁸F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [¹⁸F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [¹⁸F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V^′₃ (ratio of specific uptake to total plasma parent concentration) and the binding potential V₃ (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [¹⁸F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [¹⁸F]deuteroaltanserin and suggest that it may be superior to [¹⁸F]altanserin as a PET radioligand.     

Equilibrium modeling of 5-HT(2A) receptors with [18F]deuteroaltanserin and PET: feasibility of a constant infusion paradigm

ABSTRACT. [¹⁸F]Altanserin has emerged as a promising positron emission tomography (PET) ligand for serotonin-2A (5-HT_2A) receptors. The deuterium substitution of both of the 2′-hydrogens of altanserin ([¹⁸F]deuteroaltanserin) yields a metabolically more stable radiotracer with higher ratios of parent tracer to radiometabolites and increased specific brain uptake than [¹⁸F]altanserin. The slower metabolism of the deuterated analog might preclude the possibility of achieving stable plasma and brain activities with a bolus plus constant infusion within a reasonable time frame for an ¹⁸F-labeled tracer (T_1/2 110 min). Thus, the purpose of this study was to test the feasibility in human subjects of a constant infusion paradigm for equilibrium modeling of [¹⁸F]deuteroaltanserin with PET. Seven healthy male subjects were injected with [¹⁸F]deuteroaltanserin as a bolus plus constant infusion lasting 10 h postinjection. PET acquisitions and venous blood sampling were performed throughout the infusion period. Linear regression analysis revealed that time-activity curves for both specific brain uptake and plasma [¹⁸F]deuteroaltanserin concentration stabilized after about 5 h. This permitted equilibrium modeling and estimation of V^′₃ (ratio of specific uptake to total plasma parent concentration) and the binding potential V₃ (ratio of specific uptake to free plasma parent concentration). Cortical/cerebellar ratios were increased by 26% relative to those we previously observed with [¹⁸F]altanserin using similar methodology in a somewhat older subject sample. These results demonstrate feasibility of equilibrium imaging with [¹⁸F]deuteroaltanserin and suggest that it may be superior to [¹⁸F]altanserin as a PET radioligand.     

In vivo delineation of 5-HT1A receptors in human brain with [18F]MPPF.

Serotonin-1A (5-hydroxytryptamine-1A [5-HT1A]) receptors have been reported to play an important role in the pathophysiology of a variety of psychiatric and neurodegenerative disorders. Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2'-pyridinyl)-p-[18F]fluorobenzamido ]ethylpiperazine ([18F]MPPF) may be suitable for 5-HT1A receptor imaging in humans. The aim of this study was to determine if [18F]MPPF can be used for the quantitative analysis of 5-HT1A receptor densities in brain regions of healthy human volunteers. METHODS: [15O]H2O perfusion scanning was performed before intravenous injection of [18F]MPPF to obtain anatomic information. Cerebral radioactivity was monitored using a PET camera. Plasma metabolites of [18F]MPPF were determined by high-performance liquid chromatography. Binding potentials were calculated using the metabolite-corrected arterial input function and a linear graphic method (Logan-Patlak analysis). RESULTS: The highest levels of radioactivity were observed in the medial temporal cortex, especially in the hippocampal area. In contrast, the cerebellum and basal ganglia showed low uptake of 18F, in accordance with known 5-HT1A receptor distribution. The calculated binding potentials correlated well with literature values for 5-HT1A receptor densities. The binding potentials for [18F]MPPF were 4-6 times lower than those that have been reported for [carbonyl-1C]-(N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyrid yl) cyclohexane-carboxamide (WAY 100635), indicating that [18F]MPPF has a lower in vivo affinity for 5-HT1A receptors. CONCLUSION: These results confirm that [18F]MPPF can be used for the quantitative analysis of 5-HT1A receptor distribution in the living human brain. The rapid dissociation from the receptor makes this ligand a possible candidate to monitor changes in endogenous serotonin levels.     

[18F]Fallypride: Metabolism studies and quantification of the radiotracer and its radiometabolites in plasma using a simple and rapid solid-phase extraction method

Introduction[¹⁸F]Fallypride, a fluorinated and substituted benzamide with high affinity for D₂/D₃ receptors, is a useful PET radioligand for the study of striatal/extrastriatal areas. Since [¹⁸F]fallypride is extensively metabolized in vivo and since PET examinations are long lasting in humans, the rapid measurement of the unchanged radiotracer in plasma is essential for the quantification of images. The present study aims: i) to evaluate if the radiometabolites of [¹⁸F]fallypride cross the blood–brain barrier in rodents, ii) to identify these radiometabolites in baboon plasma and iii) to develop a rapid solid phase extraction method (SPE) suitable for human applications to quantify both [¹⁸F]fallypride and its radiometabolites in plasma.MethodsThe metabolites P450-dependant in rat and human liver microsomes were characterized by LC–MS–MS and compared to those detected in vivo. Sequential solvent elution on Oasis®-MCX-SPE cartridges was used to quantify [¹⁸F]fallypride and its radiometabolites.ResultIn rat microsomal incubations, five metabolites generated upon N/O-dealkylation or hydroxylation at the pyrrolidine and/or at the benzamide moiety were identified. No radiometabolite was detected in the rat brain. N-dealkylated and hydroxylated derivatives were detected in human microsomal incubations as well as in baboon plasma. The use of SPE (total recovery 100.2% ± 2.8%, extraction yield 95.5% ± 0.3%) allowed a complete separation of [¹⁸F]fallypride from its radiometabolites in plasma and evaluate [¹⁸F]fallypride at 150 min pi to be 22% ± 5% of plasma radioactivity.ConclusionsThe major in vivo radiometabolites of [¹⁸F]fallypride were produced by N-dealkylation and hydroxylation. Allowing the rapid analysis of multiple plasma samples, SPE is a method of choice for the determination of [¹⁸F]fallypride until late images required for quantitative PET imaging in humans.     

Dopamine D(4) receptor antagonist 3-(4-[(18)F]fluorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one([(18)F]FMTP): radiosynthesis and in vivo characterization in rats.

We synthesized a novel (18)F-labeled dopamine D(4) receptor antagonist (Ki=4.3 nM), 3-(4-[(18)F]fluorobenzyl)-8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one ([(18)F]FMTP), which has exhibited high affinity and selectivity. Radiosyntheses were accomplished by the reaction of fluorine-18-labeled intermediate with 8-methoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one (1) followed by HPLC purification. The overall radiochemical yield of the radiosynthesis was 19.5% (decay corrected), the specific radioactivity was about 110 GBq/micromol and the radiochemical purity was greater than 99%, the time of synthesis and purification was approximately 110 min. Tissue distribution studies of the [(18)F]FMTP in rats showed that the radioactivity in the brain was concentrated in frontal cortex and medulla, the region that has a high density of D(4) receptors. Pre-treatment with nonradioactive FMTP (1.0mg/kg) produced a significant reduction of radioactivity in all the regions. About 40% of total radioactivity in plasma and 100% in rat brain extract represented unchanged radioligand at 60 min after injection as determined by HPLC. These results indicate that [(18)F]FMTP have some specific binding to the D(4) receptor.     

A complete remote-control system for reliable preparation of [18F]altanserin.

A complete remote control system was constructed for production of the PET 5-HT2A ligand [18F]altanserin by nitro-for-fluoro exchange. Comparing with published methods, the key features include (1) conducting azeotropic distillation and nucleophilic displacement in an open vessel heated by a commercial microwave oven; (2) purifying the product by a single HPLC procedure and (3) removing HPLC solvent by solid phase extraction. The preparation took 114 min with 23% yield and high quality.     

No-carrier-added nucleophilic 18F-labelling in an electrochemical cell exemplified by the routine production of [18F]altanserin.

A new type of electrochemical cell with anodic deposition of no-carrier-added [(18)F]fluoride and variable reaction volume has been developed. The reactor is designed for small reaction volumes and non-thermal drying of [(18)F]fluoride. The implementation of this reactor into a complete remotely controlled synthesis device is described for the routine production of [(18)F]altanserin. A radiochemical yield of 23+/-5% was obtained via cryptate-mediated nucleophilic (18)F-fluorination. Batches of up to 6 GBq [(18)F]altanserin, suitable for human application, with a molar activity of >500 GBq/micromol were obtained within 75 min.     

Characterization of the serotonin 2A receptor selective PET tracer (R)-[18F]MH.MZ in the human brain

European Journal of Nuclear Medicine and Molecular Imaging - The serotonin receptor subtype 2A antagonist (5-HT2AR) (R)-[18F]MH.MZ has in preclinical studies been identified as a promising PET...     

A new procedure for labeling alkylbenzenes with [18F]fluoride

A new procedure for labeling alkylbenzenes with no-carrier-added (nca) [¹⁸F]fluoride is reported. This will allow the use of [¹⁸F]-for-nitro aromatic nucleophilic displacement reaction for labeling aromatic compounds with no activating groups on the benzene ring. The new procedure involves (A) the [¹⁸F]-for-nitro displacement reaction on nitrophenones, and (B) the reduction of [¹⁸F]fluorophenones with triethylsilane and trifluoroacetic acid to alkylfluorobenzenes. The desired ¹⁸F-labeled alkylbenzenes were prepared in a synthesis time of 1 h with a radiochemical yield of 20% at end-of-synthesis. The procedure has been successfully applied to the synthesis of ¹⁸F-labeled alkylating agents, such as 4-[¹⁸F]fluorophenethyl bromide, 4, and 4-[¹⁸F]fluorophenbutyl chloride, 5. Using the reaction of piperidine and 4 as a model, the potential use of phenethylbromide 4 for labeling biologically important amines was examined. Initial results indicated that the desired alkylated piperidine was formed in low yields (<5%) due to the conversion of halide 4 to [¹⁸F]fluorostyrene (>85%) under basic conditions. The new procedure provides an easy method of labeling alkylbenzenes with fluorine-18.     

Synthesis and initial evaluation of [11C](R)-RWAY in monkey—a new, simply labeled antagonist radioligand for imaging brain 5-HT1A receptors with PET

PURPOSE: We aimed to fulfill a need for a radioligand that may be simply labeled with carbon-11 for effective positron emission tomography (PET) imaging of brain 5-HT(1A) receptors. METHODS: Racemic RWAY (2,3,4,5,6,7-hexahydro-1-[4-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylbutyryl]-1H-azepine) has high affinity for 5-HT(1A) receptors. The enantiomers of RWAY and O-desmethyl-RWAY, synthesized from commercially available materials, were each labeled with carbon-11 by treating the respective O-desmethyl precursor with [(11)C]iodomethane, and injected into rhesus monkey for measurement of regional brain uptake. The 5-HT(1A) selectivity of (R)-[(11)C]RWAY was checked by administering WAY-100635, before and after radioligand administration. Radiometabolites of (R)-[(11)C]RWAY in blood and urine were analyzed by HPLC with partial elucidation of their structures by LC-MS-MS. RESULTS: (R)-[(11)C]RWAY was a 5-HT(1A) receptor antagonist exhibiting high brain uptake with regional distribution consistent with specific binding to 5-HT(1A) receptors. The similar affinity, (S)-[(11)C]RWAY was a weak partial agonist at 5-HT(1A) receptors exhibiting similar brain peak uptake with much less 5-HT(1A) receptor-specific binding. The maximal ratio in receptor-rich cingulate gyrus to receptor-devoid cerebellum reached 6.4 at 87.5 min after injection of (R)-[(11)C]RWAY. After treatment with WAY-100635 before or after (R)-[(11)C]RWAY administration, radioactivity levels in 5-HT(1A) receptor-rich regions were reduced almost to that in cerebellum. Blood and urine radiometabolites were less lipophilic than parent and were not due to hydrolysis but to ring hydroxylations, oxidation, and dephenylation. CONCLUSION: (R)-[(11)C]RWAY is simply prepared and an effective antagonist for imaging brain 5-HT(1A) receptors. This radioligand resists hydrolysis in vivo, gives less lipophilic radiometabolites, and warrants further PET studies in human subjects.     

In vivo evaluation in rats of [(18)F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine as a potential radiotracer for PET assessment of CNS sigma-1 receptors

INTRODUCTION: Sigma-1 receptors are expressed throughout the mammalian central nervous system (CNS) and are implicated in several psychiatric disorders, including schizophrenia and depression. We have recently evaluated the high-affinity (K(D)=0.5+/-0.2 nM, log P=2.9) sigma-1 receptor radiotracer [(18)F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, [(18)F]FPS, in humans. In contrast to appropriate kinetics exhibited in baboon brain, in the human CNS, [(18)F]FPS does not reach pseudoequilibrium by 4 h, supporting the development of a lower-affinity tracer [Waterhouse RN, Nobler MS, Chang RC, Zhou Y, Morales O, Kuwabara H, et al. First evaluation of the sigma-1 receptor radioligand [(18)F]1-3-fluoropropyl-4-((4-cyanophenoxy)-methyl)piperidine ([(18)F]FPS) in healthy humans. Neuroreceptor Mapping 2004, July 15-18th, Vancouver, BC Canada 2004]. We describe herein the in vivo evaluation in rats of [(18)F]1-(2-fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([(18)F]SFE) (K(D)=5 nM, log P=2.4), a structurally similar, lower-affinity sigma-1 receptor radioligand. METHODS: [(18)F]SFE was synthesized (n=4) as previously described in good yield (54+/-6% EOB), high specific activity (2.1+/-0.6 Ci/micromol EOS) and radiochemical purity (98+/-1%) and evaluated in awake adult male rats. RESULTS: Similar to [(18)F]FPS, regional brain radioactivity concentrations [percentage of injected dose per gram of tissue (%ID/g), 15 min] for [(18)F]SFE were highest in occipital cortex (1.86+/-0.06 %ID/g) and frontal cortex (1.76+/-0.38 %ID/g), and lowest in the hippocampus (1.01+/-0.02%ID/g). Unlike [(18)F]FPS, [(18)F]SFE cleared from the brain with approximately 40% reduction in peak activity over a 90-min period. Metabolite analysis (1 h) revealed that [(18)F]SFE was largely intact in the brain. Blocking studies showed a large degree (>80%) of saturable binding for [(18)F]SFE in discrete brain regions. CONCLUSIONS: We conclude that [(18)F]SFE exhibits excellent characteristics in vivo and may provide a superior PET radiotracer for human studies due to its faster CNS clearance compared to [(18)F]FPS.     

Quantification of 5-HT1A receptors in human brain using p-MPPF kinetic modelling and PET

Serotonin-1A (5-HT(1A)) receptors are implicated in neurochemical mechanisms underlying anxiety and depression and their treatment. Animal studies have suggested that 4-(2'-methoxyphenyl)-1-[2'-[ N-(2"-pyridinyl)- p-[(18)F]fluorobenzamido] ethyl] piperazine ( p-MPPF) may be a suitable positron emission tomography (PET) tracer of 5-HT(1A) receptors. To test p-MPPF in humans, we performed 60-min dynamic PET scans in 13 healthy volunteers after single bolus injection. Metabolite quantification revealed a fast decrease in tracer plasma concentration, such that at 5 min post injection about 25% of the total radioactivity in plasma corresponded to p-MPPF. Radioactivity concentration was highest in hippocampus, intermediate in neocortex and lowest in basal ganglia and cerebellum. The interactions between p-MPPF and 5-HT(1A) receptors were described using linear compartmental models with plasma input and reference tissue approaches. The two quantification methods provided similar results which are in agreement with previous reports on 5-HT(1A) receptor brain distribution. In conclusion, our results show that p-MPPF is a suitable PET radioligand for 5-HT(1A) receptor human studies.     

Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats.

No-carrier-added [18F]altanserin was synthesized by nucleophilic substitution of the corresponding nitro compound with [18F]fluoride in the presence of kryptofix 222 and K2CO3. After purification by preparative HPLC, [18F]altanserin was produced in less than 2 hr with a radiochemical yield of 10% (EOS) and a specific activity of 0.8-1.3 Ci/mumol. In rats, the tracer localized rapidly in the whole brain (0.5% ID/g organ) with a high binding to the frontal cortex. The frontal cortex/cerebellum ratio increased with time and reached a plateau of 11 at 2 hr postinjection. This uptake in S2 receptor regions was saturable and could be blocked by pretreatment with various S2 antagonists. This radiopharmaceutical appears to be more selective for S2 receptor sites than other ligands available today and allows the study of S2 receptors under in vivo conditions.     

A retrospect on the discovery of WAY-100635 and the prospect for improved 5-HT(1A) receptor PET radioligands

Abstract. An outline is given of the developments that led to the identification of [O-methyl-(11)C]WAY-100635 (4) as the first useful PET ligand for imaging serotonin(1A) (5-HT(1A)) receptors in the living human brain. Recent attempts to develop 5-HT(1A) receptor radioligands superior to 4 are reviewed, and [carbonyl-(11)C]WAY-100635 (6) has been shown to be the best currently available radioligand for human studies. Of other (11)C-radiolabelled compounds, [O-methyl-(11)C](R,S)-CPC-222 (9), DWAY (8), and [(11)C]NAD-299 (14) all demonstrate specific binding to 5-HT(1A) receptors in animals and warrant further expedited studies in humans. The trans-fluorocyclohexane, 12, and fluorobenzene, [(18)F]p-MPPF 13, are highlighted as examples of promising (18)F-labelled ligands.     

An automated one-step one-pot [(18)F]FCWAY synthesis: development and minimization of chemical impurities

[(18)F]FCWAY (N-{2-[4-(2-methoxyphenyl)piperazino]}-N-(2-pyridinyl)trans-4-fluorocyclohexanecarboxamide) has been prepared routinely as a serotonin 5-HT(1A) receptor ligand for clinical human studies. We have developed an automated one-step radiosynthesis using a modified Nuclear Interface C-11 Methylation System. The chemical synthesis of an appropriate methanesulfonate precursor for single-step nucleophilic substitution with [(18)F]fluoride ion and the adaptation of radiochemical synthesis to an automated production module were accomplished. Following purification of a substrate using countercurrent chromatography, radiochemical yield increased from 18.9+/-0.3% to 21.9+/-2.2%. In addition, reduction of chemical impurities from about 40% to about 20% of total mass was observed. Further improvements in chemical purity were achieved by minimization of side reactions by modification of reaction conditions and optimization of the high-performance liquid chromatography method for the purification of the final radiopharmaceutical. Optimized automated synthesis produced [(18)F]FCWAY in a radiochemical yield of 28+/-6% at a chemical purity of 99.3% based on the absorbance of FCWAY at 254 nm and with a specific activity of 3433+/-1015 mCi/micromol at the end of bombardment, all calculated from the same 50 runs.     

Quantitative imaging of 5-HT(1A) receptor binding in healthy volunteers with [(18)f]p-MPPF

Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido+ ++] ethylpiperazine ([(18)F]p-MPPF) can be used for 5-hydroxytryptamine(1A) (5-HT(1A)) receptor imaging. The aim of this study was to develop a method for the quantitative imaging of 5-HT(1A) receptors in healthy volunteers with [(18)F]p-MPPF. After injection of [(18)F]p-MPPF radioactivity was rapidly taken up in the brain, with the highest accumulation in the medial temporal cortex. Low levels of radioactivity were found in cerebellum and basal ganglia. Plasma clearance and metabolism of [(18)F]p-MPPF resulted in only about 1% of the radioactivity in plasma as parent radioligand after 10 min. Using a linear graphical method (Logan-Patlak), binding potentials were calculated in several brain areas. A good correlation (r = 0.95) was found between the obtained binding potentials and literature values for 5-HT(1A) receptor densities. A good correlation (r = 0.96) was also found between the body weight-corrected region/cerebellum ratios and the respective binding potentials. Moreover, a blocking experiment with pindolol (n = 3) showed a decrease of 40% in the region/cerebellum ratios of the target areas. Compared to those of [carbonyl-(11)C]WAY-100635, the binding potentials were four to six times lower, indicating that [(18)F]p-MPPF has a lower in vivo affinity for 5-HT(1A) receptors. In conclusion, [(18)F]p-MPPF can be used for the quantitative analysis of 5-HT(1A) receptor distribution in human brain.     

Synthesis,radiofluorination and first evaluation of [18F]fluorophenylsulfonyl- and [18F]fluorophenylsulfinyl-piperidines as serotonin 5-HT2A receptor antagonists for PET

In psychiatric disorders, 5-HT_2A receptors play an important role. In order to study these receptors in vivo by positron emission tomography (PET), there is an increasing interest for subtype selective and high affinity radioligands. Up to now, no optimal radiotracer is available. Thus, 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfonyl)piperidine (9), possessing high affinity and sufficient subtype selectivity for 5-HT_2A receptors, and 1-(2,4-difluorophenethyl)-4-(4-fluorophenylsulfinyl)piperidine (15) have been ¹⁸F-labelled by a nucleophilic one-step reaction. Both radiotracers could be prepared and isolated within 45 min, [¹⁸F]9 in a radiochemical yield (RCY) of 34.5±8% and [¹⁸F]15 of 9.5±2.5%. The K_i values of 9 and 15 at 5-HT_2A receptors towards [³H]ketanserin were determined to be 1.9±0.6 and 198±8 nM, respectively. Autoradiography with [¹⁸F]9 and [¹⁸F]15 on rat brain sections showed a very high nonspecific binding of >80% for [¹⁸F]9 and 30% to 40% nonspecific binding for [¹⁸F]15; however, it is still too high in order to compensate for its lower affinity. Even though the affinity of 9 is more promising compared with 15, the high nonspecific binding of both radiofluorinated tracers in rat brain does not recommend those as an in vivo PET imaging agent for serotonin 5-HT_2A receptors in humans.