Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging

  • Stina Syvänen1, 2,
  • Jonas Eriksson1, 3,
  • Tove Genchel2,
  • Örjan Lindhe1,
  • Gunnar Antoni1 and
  • Bengt Långström1, 3Email author
BMC Medical Imaging20077:6

DOI: 10.1186/1471-2342-7-6

Received: 19 March 2007

Accepted: 30 July 2007

Published: 30 July 2007

Abstract

Background

The previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171.

Methods

[1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171.

Results

All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171.

Conclusion

The propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl-analogue (I).

Background

Positron emission tomography (PET) has been used for visualisation of cerebral energy consumption and receptor distribution in the living brain using β +-emitting radioligands, i.e. tracers. A radioligand employed in brain receptor mapping is generally desired to display a rapid transport over the blood-brain barrier, a high affinity and a selective binding to the receptor. As apposed to the high affinity criteria in receptor mapping, a radioligand used in concentration measurements of endogenous transmitters in the vicinity of neuroreceptors should have an affinity which enables displacement by an endogenous ligand [14]. It is assumed that a radioligand with a very high affinity to a receptor will not enable such detection.

There is a large interest in the development of antagonists for the Neurokinin-1 (NK1) receptor system [510]. Recently Emend® (MK-869) was approved as a drug for treatment of chemotherapy-induced nausea. Other possible therapeutic areas of NK1-receptor antagonists are not fully defined yet, but their potential as drugs has been explored in a range of disorders, including pain, inflammation, depression and other psychiatric diseases [1114]. The endogenous NK1-receptor ligand, substance P, is distributed in neurons within the central nervous system [15]. The NK1-receptor system has showed a spatial overlap with neurotransmitters such as serotonin and noradrenaline [16, 17]. Substance P interacts with the serotonergic neuronal systems via interneurons which lead to an increase in synaptic availability of serotonin [18, 19].

Previous studies has shown that NK1-receptors can be visualised in vivo with the carbon-11 and fluorine-18 labelled NK1-receptor antagonists [O-methyl-11C]GR205171 and [18F]SPA-RQ [2022]. These two compounds are based on the same pharmacophore and display a very high affinity for the NK1-receptor, hence they can be used for visualisation of the receptor system. However, the compounds cannot be used for detecting changes in substance P levels due to slow dissociation from the receptor. Most attempts to develop in vivo NK1-receptor radioligands have been unsuccessful or indifferent, except for the two ligands mention above [2326].

Recent developments in 11C-chemistry have opened for new labelling methods beyond the use of methylation and cyanation reactions. Carbonylation using [11C]carbon monoxide has shown to yield 11C-labelled carbonyl compounds with high specific radioactivity and to enable the synthesis of small libraries of labelled compounds [2731]. This may be useful in the development of PET-tracers since it has been demonstrated that small changes in the structure of a receptor ligand can lead to changes in affinity and also in the ability to penetrate the blood-brain barrier [3234].

The aim of this study was to use labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of [O-methyl-11C]GR205171-analogues with different alkyl chain lengths and to compare the binding characteristics in guinea pig and rhesus monkey. We hypothesised that the increased alkyl chain length would lead to a faster dissociation rate from the NK1-receptor.

Methods

The radioligand [O-methyl-11C]GR205171 was synthesized from [11C]methyl iodide and O-desmethyl GR205171 as previously described [20]. The ethyl analogue (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and the propyl analogue (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) were synthesized via alkylation of O-desmethyl GR205171 with [1-11C]ethyl iodide and [1-11C]propyl iodide, Figure 1. The following procedure was used; dimethylformamide (300 μl) was added to O-desmethyl GR205171 (1.0 mg, 2.3 μmol) and cesium carbonate (3.2 mg, 9.8 μmol) [35]. The solution was vortexed for approximately 20 min before [1-11C]ethyl iodide or [1-11C]propyl iodide was transferred in a flow of nitrogen gas (30 mL/min) to the vial. The vial was then heated for 5 min at 140°C to yield the alkylated product. The product was purified on a semi-preparative HPLC consisting of a Beckman 126 pump at 4 mL min-1, a Beckman 166 UV detector at 254 nm, a Bioscan β+-flow count detector, Gilson 231 XL auto injector, and a Beckman Ultrasphere ODS dp 5 μcolumn (250 × 10 mm). The mobile phase used was A) 0.05 M ammonium formate pH 3.5 and B) acetonitrile. Compound (I): Gradient from 35% B to 48% over 8 min. R.t 14.7 min. Compound (II): Isocratic elution 52% B, R.t 7.6 min. The mobile phase was removed using a rotavapor at 90°C and reduced pressure. The product was formulated in saline (2 mL), propylene glycol (2 mL), HCl (0.3 mL, 0.3 M) and ethanol (0.42 mL) and transferred from the evaporator to a vial. The pH was adjusted to 7.0 with phosphate/sodium hydroxide buffer prior to sterile filtration (Acrodisc Syringe Filters, 0.2 μm HT Tuffryn Membrane). Analytical HPLC used to assess the radiochemical purity was performed on a similar Beckman system equipped with a Beckman Ultrasphere ODS dp 5 μcolumn (250 × 4.6 mm) and with the UV detector set to 254 nm. The mobile phase used was A) 0.05 M ammonium formate pH 3.5, B) acetonitrile. Compound (I): Isocratic elution 50% B, 1 mL min-1, R.t. 7.9 min, radiochemical purity 97%. Compound (II): Isocratic elution 55% B, 1 mL min-1, r.t. 6.9 min, radiochemical purity 98%.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2342-7-6/MediaObjects/12880_2007_Article_38_Fig1_HTML.jpg
Figure 1

Synthesis of [O-methyl-11C]GR205171 and O-ethyl and O-propyl analogues.

Male guinea-pigs weighing 350–500 g were housed under standard laboratory conditions (20°C and 50% humidity), maintained on a 12 h:12 h light/dark cycle and with free access to food and water. The guinea-pig was placed in a Plexiglass container and anesthetized with 3.8 % isoflurane prior to each experiment. When unconscious, the animal was taken from the container and kept anesthetized with 2.8% isoflurane via mask during the PET-scan. A warm water pad was used to maintain the body temperature at 36–37°C throughout the experiment. To assess the status of the guinea pigs during anaesthesia the breathing frequency was monitored and blood samples were analysed for the following parameters: pH, HCO3, pCO2, TCO2, sO2, pO2, Na, K, iCa, Hct and Hb. A catheter for intravenous injection was inserted into the left femoral vein. [O-methyl-11C]GR205171 (62, 59 and 29 MBq) and (I) (8, 13 and 38 MBq) was administered to three animals each and (II) (25 and 35 MBq) was administered to two animals. The studies were performed using a microPET R4 tomograph (Concorde Microsystems) [36]. A transmission scan with rotating 57Co source was used to correct the emission scan for the attenuation of 511 keV photons through the tissue and scanner bed. The emission scan was started when the radioligand was injected and continued for 90 min.

Two female rhesus monkeys, 8.0 kg and 9.5 kg, were sedated with 100 mg intramuscular ketamine (Ketaminol, Vetpharm AB) and transported to the investigation site at Uppsala Imanet in the morning of the experiment. Venous catheters were inserted in both hind legs of the rhesus monkey. The catheters were used for administration of the radioligand, Ringer-Acetate (2 mL/kg/h, Frensenius Kabi AB) and propofol (50 mg, Propofil-Lipuro, B/Brown) to induce anaesthesia. Anaesthesia was maintained with 1.3 – 2.5% sevoflurane via tracheal intubation during the PET-scan. A femoral artery catheter was inserted for blood sampling. Three PET-scans were carried out 2 hrs apart in each monkey. Monkey 1 received [O-methyl-11C]GR205171 (215 MBq), ligand (I) (54 MBq) and ligand (I) (30 MBq). Isotopically unmodified GR205171 (0.5 mg/kg) was administered as a 10 min infusion prior to the third scan. The same protocol was used for monkey 2 which received [O-methyl-11C]GR205171 (134 MBq), ligand (II) (36 MBq) and GR205171 (0.5 mg/kg) 10 min prior to administration of ligand (II) (39 MBq). Arterial blood samples were obtained at 1, 2.5, 5, 10, 20, 40, 60 and 90 min after radioligand administration. Ventilation was supported with 30% oxygen in air and the body temperature was maintained at 37–38°C with heating pads. The studies were performed using a PET/CT tomograph (Discovery ST16, GE Healthcare). A CT scan was obtained to correct the emission scan for the attenuation of 511 keV photons through the tissue and head supports. The emission scan began when the radioligand was injected and continued for 90 min. The animal experiments were approved by the Uppsala Animal Ethics Committee (C117/4).

The PET images were reconstructed using filtered backprojection after correction for attenuation and scattered radiation. The frame images were summarized and regions of interest (ROI) were drawn in the striatum and cerebellum, using rhesus monkey brain atlas for guidance (The rhesus monkey brain in stereotaxic coordinates. Paxinos et al., 2000). The tissue radioactivity was expressed as SUV (Standardized Uptake Value).
S U V = M e a s u r e d R a d i o a c t i v i t y i n t i s s u e I n j e c t e d R a d i o a c t i v i t y / B o d y W e i g h t MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacqWGtbWucqWGvbqvcqWGwbGvcqGH9aqpdaWcaaqaaiabd2eanjabdwgaLjabdggaHjabdohaZjabdwha1jabdkhaYjabdwgaLjabdsgaKjabbccaGiabdkfasjabdggaHjabdsgaKjabdMgaPjabd+gaVjabdggaHjabdogaJjabdsha0jabdMgaPjabdAha2jabdMgaPjabdsha0jabdMha5jabbccaGiabdMgaPjabd6gaUjabbccaGiabdsha0jabdMgaPjabdohaZjabdohaZjabdwha1jabdwgaLbqaaiabdMeajjabd6gaUjabdQgaQjabdwgaLjabdogaJjabdsha0jabdwgaLjabdsgaKjabbccaGiabdkfasjabdggaHjabdsgaKjabdMgaPjabd+gaVjabdggaHjabdogaJjabdsha0jabdMgaPjabdAha2jabdMgaPjabdsha0jabdMha5jabc+caViabdkeacjabd+gaVjabdsgaKjabdMha5jabbccaGiabdEfaxjabdwgaLjabdMgaPjabdEgaNjabdIgaOjabdsha0baaaaa@873A@

Results and Discussion

[1-11C]Ethyl iodide and [1-11C]propyl iodide was synthesized within 15 min from [11C]carbon monoxide, Figure 2. [1-11C]Ethyl iodide was synthesized via hydroxycarbonylation of methyl iodide with a decay-corrected radiochemical yield of 55% [37]. [1-11C]Propyl iodide was synthesized via hydroformylation of ethene with a decay corrected radiochemical yield of 58% [38]. The specific radioactivities at end of synthesis were 90 GBq/μmol and 270 GBq/μmol, respectively. The alkylation of O-desmethyl GR205171 led to O-alkylated and N-alkylated products in 1:7 ratio for both ethyl and propyl iodide. Based on [11C]carbon monoxide, (I) and (II) were obtained in 5.1 ± 0.6% (n = 6) and 4.7 ± 0.8% (n = 7) isolated radiochemical yield, respectively. When the reaction temperature was lowered from 140°C to 110°C the yield of (I) was reduced to 2.3 ± 0.6% (n = 5). The use of tetrabutylammonium hydroxide instead of cesium carbonate resulted in poorer radiochemical yield due to hydrolysis of the labelled alkyl halides and a lower selectivity towards O-alkylation compared to N-alkylation. Despite the low selectivity of the alkylation reaction, a sufficient amount of product was obtained for PET imaging in guinea pig and rhesus monkey.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2342-7-6/MediaObjects/12880_2007_Article_38_Fig2_HTML.jpg
Figure 2

Synthesis of [1-11C]ethyl iodide and [1-11C]propyl iodide.

[O-methyl-11C]GR205171 and the two analogues were distributed into the guinea pig brain in a similar pattern. The time-activity profiles obtained from the guinea pig PET images showed an increase in striatum uptake throughout the investigation for both analogues and [O-methyl-11C]GR205171, Figure 3.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2342-7-6/MediaObjects/12880_2007_Article_38_Fig3_HTML.jpg
Figure 3

Time-activity profiles in guinea pig striatum after administration of [O-methyl-11C]GR205171 (diamonds), ethyl-analogue (I) (squares) and propyl-analogue (II) (triangles). Each line represents uptake in one guinea pig.

The SUV-values in guinea pig striatum were around 0.35–0.85 at the end of the investigation. The values were low compared to earlier studies with [O-methyl-11C]GR205171 in rhesus monkeys which showed SUV-values between 2 and 3 and similar shaped time-activity curves [20]. The cerebellum uptake in the guinea pigs increased during the first 30 min and remained constant during the rest of the investigation with SUV-values around 0.1 or less. Rupniak and co-workers have shown that GR205171 brain uptake in P-glycoprotein deficient mice was considerably higher than in wild type mice indicating active efflux of GR205171 from the brain [39]. Similarly, the low brain uptake of [O-methyl-11C]GR205171 in guinea pig might be explained by active efflux mechanisms.

PET images obtained from the studies in rhesus monkeys are shown in Figure 4. [O-methyl-11C]GR205171 and the two analogues were transported into the brain in a much higher extent than in the guinea pigs. The ethyl-analogue (I) showed binding in the striatum, but the ratio between specific and unspecific binding was smaller than with [O-methyl-11C]GR205171. The striatum could not be visualised with (I) after predosing with GR205171. A small decrease in cerebellum uptake was also seen after predosing. With the more lipophilic propyl-analogue (II) the striatum could not be distinguished in the images either with or without predosing.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2342-7-6/MediaObjects/12880_2007_Article_38_Fig4_HTML.jpg
Figure 4

PET-images over the transaxial rhesus monkey brain at the level of striatum. Monkey 1: A. [O-methyl-11C]GR205171, B. Ethyl-analogue (I), C. Ethyl-analogue (I) after predosing with GR205171. Monkey 2: D. [O-methyl-11C]GR205171, E. Propyl-analogue (II), F. Propyl-analogue (II) after predosing with GR205171.

The maximum SUV-values for [O-methyl-11C]GR205171 were 4.2 and 3.1 in monkey 1 and 2, respectively, Figure 5. The SUV values did not decline during the 90 min PET-scan indicating that the binding was not reversible during the investigation time. This was in accordance with earlier reported results [20]. The uptake profiles were different for the two analogues compared to [O-methyl-11C]GR205171. The maximum SUV, 2.7 and 1.5 for the ethyl- and propyl-analogues, respectively, was reached within minutes after administration. Furthermore, the analogues had a brain half-life of around 60 min and were eliminated from the striatum, in difference to [O-methyl-11C]GR205171. The SUV-values for (I) were slightly decreased when the NK1-receptors were blocked by predosing with GR205171. On the other hand, no such change in SUV-values was observed for (II) after predosing with GR205171. This indicated specific NK1-receptor binding for the ethyl-analogue, while the propyl-analogue was mainly unspecifically bound in the brain. The plasma kinetics were similar for [O-methyl-11C]GR205171 and the two analogues with a short distribution half-life and an elimination phase half-life above 3 hrs.
https://static-content.springer.com/image/art%3A10.1186%2F1471-2342-7-6/MediaObjects/12880_2007_Article_38_Fig5_HTML.jpg
Figure 5

Time-activity profiles in rhesus monkey striatum. A. Monkey 1. [O-methyl-11C]GR205171 (diamonds), ethyl-analogue (I) (squares) and ethyl-analogue (I) after predosing with GR205171 (triangles). B. Monkey 2. [O-methyl-11C]GR205171 (diamonds), propyl-analogue (II) (squares) and propyl-analogue (II) after predosing with GR205171(triangles).

Conclusion

The rhesus monkey studies indicated that the order of ligand affinities for the NK1-receptor was [O-methyl-11C]GR205171 > (I) > (II). The ethyl-analogue had a similar binding pattern as [O-methyl-11C]GR205171, while no specific binding to striatum could be detected for the propyl-analogue. The propyl-analogues can therefore not be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl analogue.

Declarations

Acknowledgements

This work was conducted in collaboration with Imanet, GE Healthcare and was supported by grants from The Swedish Research Council and Lennanders stiftelse. We are grateful to the staff at Uppsala Imanet, particularly to Tora Sundin for assistance with the PET/CT scanner and Gudrun Nylén for assistance with the rhesus monkeys.

Authors’ Affiliations

(1)
Uppsala Imanet, GE Healthcare
(2)
Department of Pharmaceutical Biosciences, Uppsala University
(3)
Department of Biochemistry and Organic Chemistry, Uppsala University

References

  1. Carson RE, Breier A, de Bartolomeis A, Saunders RC, Su TP, Schmall B, Der MG, Pickar D, Eckelman WC: Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion. J Cereb Blood Flow Metab. 1997, 17 (4): 437-447. 10.1097/00004647-199704000-00009.View ArticlePubMedGoogle Scholar
  2. Dewey SL, Smith GS, Logan J, Brodie JD, Fowler JS, Wolf AP: Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels. Synapse. 1993, 13 (4): 350-356. 10.1002/syn.890130407.View ArticlePubMedGoogle Scholar
  3. Innis RB, Malison RT, al-Tikriti M, Hoffer PB, Sybirska EH, Seibyl JP, Zoghbi SS, Baldwin RM, Laruelle M, Smith EO: Amphetamine-stimulated dopamine release competes in vivo for [123I]IBZM binding to the D2 receptor in nonhuman primates. Synapse. 1992, 10 (3): 177-184. 10.1002/syn.890100302.View ArticlePubMedGoogle Scholar
  4. Laruelle M, D'Souza CD, Baldwin RM, Abi-Dargham A, Kanes SJ, Fingado CL, Seibyl JP, Zoghbi SS, Bowers MB, Jatlow P, Charney DS, Innis RB: Imaging D2 receptor occupancy by endogenous dopamine in humans. Neuropsychopharmacology. 1997, 17 (3): 162-174. 10.1016/S0893-133X(97)00043-2.View ArticlePubMedGoogle Scholar
  5. Shue HJ, Chen X, Shih NY, Blythin DJ, Paliwal S, Lin L, Gu D, Schwerdt JH, Shah S, Reichard GA, Piwinski JJ, Duffy RA, Lachowicz JE, Coffin VL, Liu F, Nomeir AA, Morgan CA, Varty GB: Cyclic urea derivatives as potent NK1 selective antagonists. Bioorg Med Chem Lett. 2005, 15 (17): 3896-3899. 10.1016/j.bmcl.2005.05.111.View ArticlePubMedGoogle Scholar
  6. Thomson CG, Carlson E, Chicchi GG, Kulagowski JJ, Kurtz MM, Swain CJ, Tsao KL, Wheeldon A: Synthesis and structure-activity relationships of 8-azabicyclo[3.2.1]octane benzylamine NK1 antagonists. Bioorg Med Chem Lett. 2006, 16 (4): 811-814. 10.1016/j.bmcl.2005.11.026.View ArticlePubMedGoogle Scholar
  7. Huscroft IT, Carlson EJ, Chicchi GG, Kurtz MM, London C, Raubo P, Wheeldon A, Kulagowski JJ: 1-Phenyl-8-azabicyclo[3.2.1]octane ethers: a novel series of neurokinin (NK1) antagonists. Bioorg Med Chem Lett. 2006, 16 (7): 2008-2012. 10.1016/j.bmcl.2005.12.069.View ArticlePubMedGoogle Scholar
  8. Meurer LC, Finke PE, Owens KA, Tsou NN, Ball RG, Mills SG, Maccoss M, Sadowski S, Cascieri MA, Tsao KL, Chicchi GG, Egger LA, Luell S, Metzger JM, Macintyre DE, Rupniak NM, Williams AR, Hargreaves RJ: Cyclopentane-based human NK1 antagonists. Part 2: development of potent, orally active, water-soluble derivatives. Bioorg Med Chem Lett. 2006, 16 (17): 4504-4511. 10.1016/j.bmcl.2006.06.044.View ArticlePubMedGoogle Scholar
  9. Elliott JM, Carlson EJ, Chicchi GG, Dirat O, Dominguez M, Gerhard U, Jelley R, Jones AB, Kurtz MM, Tsao K, Wheeldon A: NK1 antagonists based on seven membered lactam scaffolds. Bioorg Med Chem Lett. 2006, 16 (11): 2929-2932. 10.1016/j.bmcl.2006.02.080.View ArticlePubMedGoogle Scholar
  10. Hoffmann-Emery F, Hilpert H, Scalone M, Waldmeier P: Efficient synthesis of novel NK1 receptor antagonists: selective 1,4-addition of grignard reagents to 6-chloronicotinic acid derivatives. J Org Chem. 2006, 71 (5): 2000-2008. 10.1021/jo0523666.View ArticlePubMedGoogle Scholar
  11. Rupniak NM: New insights into the antidepressant actions of substance P (NK1 receptor) antagonists. Can J Physiol Pharmacol. 2002, 80 (5): 489-494. 10.1139/y02-048.View ArticlePubMedGoogle Scholar
  12. Hokfelt T, Pernow B, Wahren J: Substance P: a pioneer amongst neuropeptides. J Intern Med. 2001, 249 (1): 27-40. 10.1046/j.0954-6820.2000.00773.x.View ArticlePubMedGoogle Scholar
  13. Rupniak NM, Kramer MS: Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol Sci. 1999, 20 (12): 485-490. 10.1016/S0165-6147(99)01396-6.View ArticlePubMedGoogle Scholar
  14. Gardner CJ, Armour DR, Beattie DT, Gale JD, Hawcock AB, Kilpatrick GJ, Twissell DJ, Ward P: GR205171: a novel antagonist with high affinity for the tachykinin NK1 receptor, and potent broad-spectrum anti-emetic activity. Regul Pept. 1996, 65 (1): 45-53. 10.1016/0167-0115(96)00071-7.View ArticlePubMedGoogle Scholar
  15. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM: Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998, 281 (5383): 1640-1645. 10.1126/science.281.5383.1640.View ArticlePubMedGoogle Scholar
  16. Baker KG, Halliday GM, Hornung JP, Geffen LB, Cotton RG, Tork I: Distribution, morphology and number of monoamine-synthesizing and substance P-containing neurons in the human dorsal raphe nucleus. Neuroscience. 1991, 42 (3): 757-775. 10.1016/0306-4522(91)90043-N.View ArticlePubMedGoogle Scholar
  17. Sergeyev V, Hokfelt T, Hurd Y: Serotonin and substance P co-exist in dorsal raphe neurons of the human brain. Neuroreport. 1999, 10 (18): 3967-3970. 10.1097/00001756-199912160-00044.View ArticlePubMedGoogle Scholar
  18. Blier P, Gobbi G, Haddjeri N, Santarelli L, Mathew G, Hen R: Impact of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/anxiolytic response. J Psychiatry Neurosci. 2004, 29 (3): 208-218.PubMedPubMed CentralGoogle Scholar
  19. Haddjeri N, Blier P: Effect of neurokinin-I receptor antagonists on the function of 5-HT and noradrenaline neurons. Neuroreport. 2000, 11 (6): 1323-1327. 10.1097/00001756-200004270-00035.View ArticlePubMedGoogle Scholar
  20. Bergström M, Fasth KJ, Kilpatrick G, Ward P, Cable KM, Wipperman MD, Sutherland DR, Långström B: Brain uptake and receptor binding of two [11C]labelled selective high affinity NK1-antagonists, GR203040 and GR205171--PET studies in rhesus monkey. Neuropharmacology. 2000, 39 (4): 664-670. 10.1016/S0028-3908(99)00182-3.View ArticlePubMedGoogle Scholar
  21. Solin O, Eskola O, Hamill TG, Bergman J, Lehikoinen P, Gronroos T, Forsback S, Haaparanta M, Viljanen T, Ryan C, Gibson R, Kieczykowski G, Hietala J, Hargreaves R, Burns HD: Synthesis and characterization of a potent, selective, radiolabeled substance-P antagonist for NK1 receptor quantitation: ([18F]SPA-RQ). Mol Imaging Biol. 2004, 6 (6): 373-384. 10.1016/j.mibio.2004.08.001.View ArticlePubMedGoogle Scholar
  22. Hietala J, Nyman MJ, Eskola O, Laakso A, Gronroos T, Oikonen V, Bergman J, Haaparanta M, Forsback S, Marjamaki P, Lehikoinen P, Goldberg M, Burns D, Hamill T, Eng WS, Coimbra A, Hargreaves R, Solin O: Visualization and quantification of neurokinin-1 (NK1) receptors in the human brain. Mol Imaging Biol. 2005, 7 (4): 262-272. 10.1007/s11307-005-7001-6.View ArticlePubMedGoogle Scholar
  23. Del Rosario RB, Mangner TJ, Gildersleeve DL, Shreve PD, Weiland DM, Lowe JA, Drozda SE, Snider RM: Synthesis of a nonpeptide carbon-11 labeled substance P antagonist for PET studies. Nucl Med Biol. 1993, 20 (4): 545-547. 10.1016/0969-8051(93)90085-9.View ArticlePubMedGoogle Scholar
  24. Livni E, Babich JW, Desai MC, Godek DM, Wilkinson RA, Rubin RH, Fischman AJ, Del Rosario RB, Mangner TJ, Gildersleeve DL, Shreve PD, Weiland DM, Lowe JA, Drozda SE, Snider RM: Synthesis of a 11C-labeled NK1 receptor ligand for PET studies. Nucl Med Biol. 1995, 22 (1): 31-36. 10.1016/0969-8051(94)00080-4.View ArticlePubMedGoogle Scholar
  25. Bender D, Olsen AK, Marthi MK, Smith DF, Cumming P: PET evaluation of the uptake of N-[11C]methyl CP-643,051, an NK1 receptor antagonist, in the living porcine brain. Nucl Med Biol. 2004, 31 (6): 699-704. 10.1016/j.nucmedbio.2004.03.005.View ArticlePubMedGoogle Scholar
  26. Gao M, Mock BH, Hutchins GD, Zheng QH: Synthesis and initial PET imaging of new potential NK1 receptor radioligands 1-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-4-[11C]methyl-pip erazine and {4-[2-(3,5-bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazine-1-yl} -acetic acid [11C]methyl ester. Nucl Med Biol. 2005, 32 (5): 543-552. 10.1016/j.nucmedbio.2005.03.012.View ArticlePubMedGoogle Scholar
  27. Kihlberg T, Karimi F, Långström B: [11C] Carbon monoxide in selenium-mediated synthesis of [11C]-carbamoyl compounds. J Org Chem. 2002, 67 (11): 3687-3692. 10.1021/jo016307d.View ArticlePubMedGoogle Scholar
  28. Rahman O, Kihlberg T, Långstrom B: Synthesis of [11C]/[13C]Ketones by Suzuki Coupling. Eur J Org Chem. 2004, 3: 474-478. 10.1002/ejoc.200300527.View ArticleGoogle Scholar
  29. Doi H, Barletta J, Suzuki M, Noyori R, Watanabe Y, Långstrom B: Synthesis of 11C-labelled N,N'-diphenylurea and ethyl phenylcarbamate by a rhodium-promoted carbonylation via [11C]isocyanatobenzene using phenyl azide and [11C]carbon monoxide. Org Biomol Chem. 2004, 2: 3063-3066. 10.1039/b409294e.View ArticlePubMedGoogle Scholar
  30. Itsenko O, Långström B: Radical Mediated Carboxylation of Alkyl Iodides with [11C]Carbon Monoxide in Solvent Mixtures. J Org Chem. 2005, 70: 2244-2249. 10.1021/jo047806s.View ArticlePubMedGoogle Scholar
  31. Karimi F, Barletta J, Långstrom B: Palladium-Mediated [11C]Carbonylative Cross-Coupling of Alkyl/Aryl Iodides with Organostannanes: An Efficient Synthesis of Unsymmetrical Alkyl/Aryl [11C-carbonyl]Ketones. Eur J Org Chem. 2005, 11: 2374-2378. 10.1002/ejoc.200400883.View ArticleGoogle Scholar
  32. Nishiyama S, Tsukada H, Sato K, Kakiuchi T, Ohba H, Harada N, Takahashi K: Evaluation of PET ligands (+)N-[11C]ethyl-3-piperidyl benzilate and (+)N-[11C]propyl-3-piperidyl benzilate for muscarinic cholinergic receptors: a PET study with microdialysis in comparison with (+)N-[11C]methyl-3-piperidyl benzilate in the conscious monkey brain. Synapse. 2001, 40 (3): 159-169. 10.1002/syn.1038.View ArticlePubMedGoogle Scholar
  33. Wagner HN, Burns HD, Dannals RF, Wong DF, Långström B, Duelfer T, Frost JJ, Ravert HT, Links JM, Rosenbloom SB, Lukas SE, Kramer AV, Kuhar MJ: Imaging dopamine receptors in the human brain by positron tomography. Science. 1983, 221 (4617): 1264-1266. 10.1126/science.6604315.View ArticlePubMedGoogle Scholar
  34. Mach RH, Jackson JR, Luedtke RR, Ivins KJ, Molinoff PB, Ehrenkaufer RL: Effects of N-Alkylation on the Affinities of Analogues of Spiperone for Dopamine D2 and Serotonin 5-HT2 Receptors. J Med Chem. 1992, 35: 423-430. 10.1021/jm00081a002.View ArticlePubMedGoogle Scholar
  35. Långström B, Kihlberg T, Bergstrom M, Antoni G, Bjorkman M, Forngren BH, Forngren T, Hartvig P, Markides K, Yngve U, Ogren M: Compounds labelled with short-lived beta(+)-emitting radionuclides and some applications in life sciences. The importance of time as a parameter. Acta Chem Scand. 1999, 53 (9): 651-669.View ArticlePubMedGoogle Scholar
  36. Knoess C, Siegel S, Smith A, Newport D, Richerzhagen N, Winkeler A, Jacobs A, Goble RN, Graf R, Wienhard K, Heiss WD: Performance evaluation of the microPET R4 PET scanner for rodents. Eur J Nucl Med Mol Imaging. 2003, 30 (5): 737-747.View ArticlePubMedGoogle Scholar
  37. Eriksson J, Antoni G, Långström B: Synthesis of [1-11C]ethyl iodide from [11C]carbon monoxide and its application in alkylation reactions. J Labelled Compd Radiopharm. 2004, 47 (11): 723-731. 10.1002/jlcr.855.View ArticleGoogle Scholar
  38. Eriksson J, Antoni G, Långström B: Synthesis of [1-11C]propyl and [1-11C]butyl iodide from [11C]carbon monoxide and their use in alkylation reactions. J Labelled Compd Radiopharm. 2006, 49 (12): 1105-1116. 10.1002/jlcr.1119.View ArticleGoogle Scholar
  39. Rupniak NM, Fisher A, Boyce S, Clarke D, Pike A, O'Connor D, Watt A: P-Glycoprotein efflux reduces the brain concentration of the substance P (NK1 receptor) antagonists SR140333 and GR205171: a comparative study using mdr1a-/- and mdr1a+/+ mice. Behav Pharmacol. 2003, 14 (5-6): 457-463.PubMedGoogle Scholar
  40. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2342/7/6/prepub

Copyright

© Syvänen et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.