Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

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

Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl... Background: The previously validated NK -receptor ligand [O-methyl- C]GR205171 binds with a high affinity to the NK -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 NK -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 NK -receptor ligands with chemical structures based on [O-methyl- C]GR205171. 11 11 Methods: [1- C]Ethyl and [1- C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl- C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1- C]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- C]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- C]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- C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl- C]GR205171. Conclusion: The propyl-analogue (II) cannot be used for detecting changes in NK -ligand levels, while further studies should be performed with the ethyl-analogue (I). Page 1 of 6 (page number not for citation purposes) BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 The aim of this study was to use labelled ethyl and propyl Background Positron emission tomography (PET) has been used for iodide with high specific radioactivity in the synthesis of C]GR205171-analogues with different alkyl visualisation of cerebral energy consumption and receptor [O-methyl- distribution in the living brain using β -emitting radiolig- chain lengths and to compare the binding characteristics ands, i.e. tracers. A radioligand employed in brain recep- in guinea pig and rhesus monkey. We hypothesised that tor mapping is generally desired to display a rapid the increased alkyl chain length would lead to a faster dis- transport over the blood-brain barrier, a high affinity and sociation rate from the NK -receptor. a selective binding to the receptor. As apposed to the high affinity criteria in receptor mapping, a radioligand used in Methods concentration measurements of endogenous transmitters The radioligand [O-methyl- C]GR205171 was synthe- in the vicinity of neuroreceptors should have an affinity sized from [ C]methyl iodide and O-desmethyl which enables displacement by an endogenous ligand [1- GR205171 as previously described [20]. The ethyl ana- 4]. It is assumed that a radioligand with a very high affin- logue (2S,3S)-N-(1-(2- [1- C]ethoxy-5-(3-(trifluorome- ity to a receptor will not enable such detection. thyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2- phenylpiperidin-3-amine (I) and the propyl analogue There is a large interest in the development of antagonists (2S,3S)-2-phenyl-N-(1-(2- [1- C]propoxy-5-(3-(trifluor- for the Neurokinin-1 (NK ) receptor system [5-10]. omethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin- Recently Emend (MK-869) was approved as a drug for 3-amine (II) were synthesized via alkylation of O-desme- 11 11 treatment of chemotherapy-induced nausea. Other possi- thyl GR205171 with [1- C]ethyl iodide and [1- C]pro- ble therapeutic areas of NK -receptor antagonists are not pyl iodide, Figure 1. The following procedure was used; fully defined yet, but their potential as drugs has been dimethylformamide (300 μl) was added to O-desmethyl explored in a range of disorders, including pain, inflam- GR205171 (1.0 mg, 2.3 μmol) and cesium carbonate (3.2 mation, depression and other psychiatric diseases [11- mg, 9.8 μmol) [35]. The solution was vortexed for approx- 11 11 14]. The endogenous NK -receptor ligand, substance P, is imately 20 min before [1- C]ethyl iodide or [1- C]pro- distributed in neurons within the central nervous system pyl iodide was transferred in a flow of nitrogen gas (30 [15]. The NK -receptor system has showed a spatial over- mL/min) to the vial. The vial was then heated for 5 min at lap with neurotransmitters such as serotonin and 140°C to yield the alkylated product. The product was noradrenaline [16,17]. Substance P interacts with the ser- purified on a semi-preparative HPLC consisting of a Beck- -1 otonergic neuronal systems via interneurons which lead man 126 pump at 4 mL min , a Beckman 166 UV detec- to an increase in synaptic availability of serotonin [18,19]. tor at 254 nm, a Bioscan β -flow count detector, Gilson 231 XL auto injector, and a Beckman Ultrasphere ODS dp Previous studies has shown that NK -receptors can be vis- 5 μcolumn (250 × 10 mm). The mobile phase used was A) ualised in vivo with the carbon-11 and fluorine-18 0.05 M ammonium formate pH 3.5 and B) acetonitrile. labelled NK-receptor antagonists [O-methyl- Compound (I): Gradient from 35% B to 48% over 8 min. 11 18 C]GR205171 and [ F]SPA-RQ [20-22]. These two com- R.t 14.7 min. Compound (II): Isocratic elution 52% B, R.t pounds are based on the same pharmacophore and dis- 7.6 min. The mobile phase was removed using a rotavapor play a very high affinity for the NK -receptor, hence they at 90°C and reduced pressure. The product was formu- can be used for visualisation of the receptor system. How- lated in saline (2 mL), propylene glycol (2 mL), HCl (0.3 ever, the compounds cannot be used for detecting changes mL, 0.3 M) and ethanol (0.42 mL) and transferred from in substance P levels due to slow dissociation from the the evaporator to a vial. The pH was adjusted to 7.0 with receptor. Most attempts to develop in vivo NK -receptor phosphate/sodium hydroxide buffer prior to sterile filtra- radioligands have been unsuccessful or indifferent, except tion (Acrodisc Syringe Filters, 0.2 μm HT Tuffryn Mem- for the two ligands mention above [23-26]. brane). Analytical HPLC used to assess the radiochemical purity was performed on a similar Beckman system Recent developments in C-chemistry have opened for equipped with a Beckman Ultrasphere ODS dp 5 μcol- new labelling methods beyond the use of methylation umn (250 × 4.6 mm) and with the UV detector set to 254 and cyanation reactions. Carbonylation using [ C]car- nm. The mobile phase used was A) 0.05 M ammonium bon monoxide has shown to yield C-labelled carbonyl formate pH 3.5, B) acetonitrile. Compound (I): Isocratic -1 compounds with high specific radioactivity and to enable elution 50% B, 1 mL min , R.t. 7.9 min, radiochemical the synthesis of small libraries of labelled compounds purity 97%. Compound (II): Isocratic elution 55% B, 1 -1 [27-31]. This may be useful in the development of PET- mL min , r.t. 6.9 min, radiochemical purity 98%. tracers since it has been demonstrated that small changes in the structure of a receptor ligand can lead to changes in Male guinea-pigs weighing 350–500 g were housed under affinity and also in the ability to penetrate the blood-brain standard laboratory conditions (20°C and 50% humid- barrier [32-34]. ity), maintained on a 12 h:12 h light/dark cycle and with Page 2 of 6 (page number not for citation purposes) BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 C]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 radi- oligand administration. Ventilation was supported with 30% oxygen in air and the body temperature was main- tained 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 p Figure 1 Synthesis of [ yl analoguesO-methyl- C]GR205171 and O-ethyl and O-pro- emission scan for the attenuation of 511 keV photons Synthesis of [O-methyl- C]GR205171 and O-ethyl and O-pro- through the tissue and head supports. The emission scan pyl analogues. began when the radioligand was injected and continued for 90 min. The animal experiments were approved by the Uppsala Animal Ethics Committee (C117/4). free access to food and water. The guinea-pig was placed in a Plexiglass container and anesthetized with 3.8 % iso- The PET images were reconstructed using filtered backpro- flurane prior to each experiment. When unconscious, the jection after correction for attenuation and scattered radi- animal was taken from the container and kept anesthe- ation. The frame images were summarized and regions of tized with 2.8% isoflurane via mask during the PET-scan. interest (ROI) were drawn in the striatum and cerebellum, A warm water pad was used to maintain the body temper- using rhesus monkey brain atlas for guidance (The rhesus ature at 36–37°C throughout the experiment. To assess monkey brain in stereotaxic coordinates. Paxinos et al., the status of the guinea pigs during anaesthesia the breath- 2000). The tissue radioactivity was expressed as SUV ing frequency was monitored and blood samples were (Standardized Uptake Value). analysed for the following parameters: pH, HCO , pCO , 3 2 TCO , sO , pO , Na, K, iCa, Hct and Hb. A catheter for 2 2 2 intravenous injection was inserted into the left femoral Measured Radioactivity in tissue 11 SUV = C]GR205171 (62, 59 and 29 MBq) and vein. [O-methyl- Injected Radioactivity / / Body Weight (I) (8, 13 and 38 MBq) was administered to three animals each and (II) (25 and 35 MBq) was administered to two Results and Discussion 11 11 animals. The studies were performed using a microPET R4 [1- C]Ethyl iodide and [1- C]propyl iodide was synthe- tomograph (Concorde Microsystems) [36]. A transmis- sized within 15 min from [ C]carbon monoxide, Figure sion scan with rotating Co source was used to correct the 2. [1- C]Ethyl iodide was synthesized via hydroxycarbo- emission scan for the attenuation of 511 keV photons nylation of methyl iodide with a decay-corrected radio- through the tissue and scanner bed. The emission scan chemical yield of 55% [37]. [1- C]Propyl iodide was was started when the radioligand was injected and contin- synthesized via hydroformylation of ethene with a decay ued for 90 min. corrected radiochemical yield of 58% [38]. The specific radioactivities at end of synthesis were 90 GBq/μmol and Two female rhesus monkeys, 8.0 kg and 9.5 kg, were 270 GBq/μmol, respectively. The alkylation of O-desme- sedated with 100 mg intramuscular ketamine (Ketaminol, thyl GR205171 led to O-alkylated and N-alkylated prod- Vetpharm AB) and transported to the investigation site at ucts in 1:7 ratio for both ethyl and propyl iodide. Based Uppsala Imanet in the morning of the experiment. on [ C]carbon monoxide, (I) and (II) were obtained in Venous catheters were inserted in both hind legs of the 5.1 ± 0.6% (n = 6) and 4.7 ± 0.8% (n = 7) isolated radio- rhesus monkey. The catheters were used for administra- chemical yield, respectively. When the reaction tempera- tion of the radioligand, Ringer-Acetate (2 mL/kg/h, ture was lowered from 140°C to 110°C the yield of (I) Frensenius Kabi AB) and propofol (50 mg, Propofil- was reduced to 2.3 ± 0.6% (n = 5). The use of tetrabuty- Lipuro, B/Brown) to induce anaesthesia. Anaesthesia was lammonium hydroxide instead of cesium carbonate maintained with 1.3 – 2.5% sevoflurane via tracheal intu- resulted in poorer radiochemical yield due to hydrolysis bation during the PET-scan. A femoral artery catheter was of the labelled alkyl halides and a lower selectivity inserted for blood sampling. Three PET-scans were carried towards O-alkylation compared to N-alkylation. Despite out 2 hrs apart in each monkey. Monkey 1 received [O- the low selectivity of the alkylation reaction, a sufficient methyl- C]GR205171 (215 MBq), ligand (I) (54 MBq) amount of product was obtained for PET imaging in and ligand (I) (30 MBq). Isotopically unmodified guinea pig and rhesus monkey. GR205171 (0.5 mg/kg) was administered as a 10 min infusion prior to the third scan. The same protocol was [O-methyl- C]GR205171 and the two analogues were dis- used for monkey 2 which received [O-methyl- tributed into the guinea pig brain in a similar pattern. The Page 3 of 6 (page number not for citation purposes) BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 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- C]GR205171. The striatum could not be visual- ised with (I) after predosing with GR205171. A small decrease in cerebellum uptake was also seen after predos- ing. With the more lipophilic propyl-analogue (II) the striatum could not be distinguished in the images either with or without predosing. The maximum SUV-values for [O-methyl- C]GR205171 11 11 Synthesis of [1- Figure 2 C]ethyl iodide and [1- C]propyl iodide were 4.2 and 3.1 in monkey 1 and 2, respectively, Figure 11 11 Synthesis of [1- C]ethyl iodide and [1- C]propyl iodide. 5. The SUV values did not decline during the 90 min PET- scan indicating that the binding was not reversible during time-activity profiles obtained from the guinea pig PET the investigation time. This was in accordance with earlier images showed an increase in striatum uptake throughout reported results [20]. The uptake profiles were different the investigation for both analogues and [O-methyl- for the two analogues compared to [O-methyl- 11 11 C]GR205171, Figure 3. C]GR205171. The maximum SUV, 2.7 and 1.5 for the ethyl- and propyl-analogues, respectively, was reached The SUV-values in guinea pig striatum were around 0.35– within minutes after administration. Furthermore, the 0.85 at the end of the investigation. The values were low analogues had a brain half-life of around 60 min and were compared to earlier studies with [O-methyl- eliminated from the striatum, in difference to [O-methyl- 11 11 C]GR205171 in rhesus monkeys which showed SUV- C]GR205171. The SUV-values for (I) were slightly values between 2 and 3 and similar shaped time-activity decreased when the NK -receptors were blocked by pre- curves [20]. The cerebellum uptake in the guinea pigs dosing with GR205171. On the other hand, no such increased during the first 30 min and remained constant change in SUV-values was observed for (II) after predos- -receptor during the rest of the investigation with SUV-values ing with GR205171. This indicated specific NK around 0.1 or less. Rupniak and co-workers have shown binding for the ethyl-analogue, while the propyl-analogue that GR205171 brain uptake in P-glycoprotein deficient was mainly unspecifically bound in the brain. The plasma mice was considerably higher than in wild type mice indi- kinetics were similar for [O-methyl- C]GR205171 and the cating active efflux of GR205171 from the brain [39]. Sim- two analogues with a short distribution half-life and an ilarly, the low brain uptake of [O-methyl- C]GR205171 in elimination phase half-life above 3 hrs. guinea pig might be explained by active efflux mecha- nisms. PET images obtained from the studies in rhesus monkeys are shown in Figure 4. [O-methyl- C]GR205171 and the two analogues were transported into the brain in a much 0.8 0.6 0.4 0.2 0 15 3045 6075 90 Time (min) PET-images over the tr le Figure 4 vel of striatum ansaxial rhesus monkey brain at the PET-images over the transaxial rhesus monkey brain at the 11 11 Figure 3 (I) Time-ac tion of [ (squares) t O ivity profiles in -methyl and pr - C]GR205 opyl-a guinea nalogue 171 (diamonds), ethyl-ana pig str (II) iatu (triangles) m after adminliogue stra- level of striatum. Monkey 1: A. [O-methyl- C]GR205171, B. Time-activity profiles in guinea pig striatum after administra- Ethyl-analogue (I), C. Ethyl-analogue (I) after predosing with 11 11 tion of [O-methyl- C]GR205171 (diamonds), ethyl-analogue GR205171. Monkey 2: D. [O-methyl- C]GR205171, E. Pro- (I) (squares) and propyl-analogue (II) (triangles). Each line pyl-analogue (II), F. Propyl-analogue (II) after predosing with represents uptake in one guinea pig. GR205171. Page 4 of 6 (page number not for citation purposes) SUV BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 3. Innis RB, Malison RT, al-Tikriti M, Hoffer PB, Sybirska EH, Seibyl JP, 4.5 4.5 Zoghbi SS, Baldwin RM, Laruelle M, Smith EO: Amphetamine- 4.0 4.0 stimulated dopamine release competes in vivo for 3.5 3.5 [123I]IBZM binding to the D2 receptor in nonhuman pri- 3.0 3.0 mates. Synapse 1992, 10(3):177-184. 2.5 2.5 4. Laruelle M, D'Souza CD, Baldwin RM, Abi-Dargham A, Kanes SJ, Fin- 2.0 2.0 gado CL, Seibyl JP, Zoghbi SS, Bowers MB, Jatlow P, Charney DS, Innis 1.5 1.5 RB: Imaging D2 receptor occupancy by endogenous 1.0 1.0 dopamine in humans. Neuropsychopharmacology 1997, 0.5 17(3):162-174. 0.5 A B 5. Shue HJ, Chen X, Shih NY, Blythin DJ, Paliwal S, Lin L, Gu D, Schwerdt 0.0 0.0 0 1530 4560 7590 0 1530 4560 7590 JH, Shah S, Reichard GA, Piwinski JJ, Duffy RA, Lachowicz JE, Coffin Time (min) Time (min) VL, Liu F, Nomeir AA, Morgan CA, Varty GB: Cyclic urea deriva- tives as potent NK1 selective antagonists. Bioorg Med Chem Lett 2005, 15(17):3896-3899. Time-ac Figure 5 tivity profiles in rhesus monkey striatum 6. Thomson CG, Carlson E, Chicchi GG, Kulagowski JJ, Kurtz MM, Swain CJ, Tsao KL, Wheeldon A: Synthesis and structure-activity Time-activity profiles in rhesus monkey striatum. A. Monkey relationships of 8-azabicyclo[3.2.1]octane benzylamine NK1 1. [O-methyl- C]GR205171 (diamonds), ethyl-analogue (I) antagonists. Bioorg Med Chem Lett 2006, 16(4):811-814. (squares) and ethyl-analogue (I) after predosing with 7. Huscroft IT, Carlson EJ, Chicchi GG, Kurtz MM, London C, Raubo P, GR205171 (triangles). B. Monkey 2. [O-methyl- Wheeldon A, Kulagowski JJ: 1-Phenyl-8-azabicyclo[3.2.1]octane 11 ethers: a novel series of neurokinin (NK1) antagonists. Bioorg C]GR205171 (diamonds), propyl-analogue (II) (squares) Med Chem Lett 2006, 16(7):2008-2012. and propyl-analogue (II) after predosing with GR205171(tri- 8. Meurer LC, Finke PE, Owens KA, Tsou NN, Ball RG, Mills SG, Mac- angles). coss M, Sadowski S, Cascieri MA, Tsao KL, Chicchi GG, Egger LA, Luell S, Metzger JM, Macintyre DE, Rupniak NM, Williams AR, Har- greaves RJ: Cyclopentane-based human NK1 antagonists. Part 2: development of potent, orally active, water-soluble deriv- Conclusion atives. Bioorg Med Chem Lett 2006, 16(17):4504-4511. 9. Elliott JM, Carlson EJ, Chicchi GG, Dirat O, Dominguez M, Gerhard The rhesus monkey studies indicated that the order of lig- U, Jelley R, Jones AB, Kurtz MM, Tsao K, Wheeldon A: NK1 antag- and affinities for the NK -receptor was [O-methyl- onists based on seven membered lactam scaffolds. Bioorg Med C]GR205171 > (I) > (II). The ethyl-analogue had a sim- Chem Lett 2006, 16(11):2929-2932. 10. Hoffmann-Emery F, Hilpert H, Scalone M, Waldmeier P: Efficient ilar binding pattern as [O-methyl- C]GR205171, while no synthesis of novel NK1 receptor antagonists: selective 1,4- specific binding to striatum could be detected for the pro- addition of grignard reagents to 6-chloronicotinic acid deriv- atives. J Org Chem 2006, 71(5):2000-2008. pyl-analogue. The propyl-analogues can therefore not be 11. Rupniak NM: New insights into the antidepressant actions of used for detecting changes in NK -ligand levels, while fur- substance P (NK1 receptor) antagonists. Can J Physiol Pharmacol ther studies should be performed with the ethyl analogue. 2002, 80(5):489-494. 12. Hokfelt T, Pernow B, Wahren J: Substance P: a pioneer amongst neuropeptides. J Intern Med 2001, 249(1):27-40. Competing interests 13. Rupniak NM, Kramer MS: Discovery of the antidepressant and The author(s) declare that they have no competing inter- anti-emetic efficacy of substance P receptor (NK1) antago- nists. Trends Pharmacol Sci 1999, 20(12):485-490. ests. 14. Gardner CJ, Armour DR, Beattie DT, Gale JD, Hawcock AB, Kil- patrick GJ, Twissell DJ, Ward P: GR205171: a novel antagonist with high affinity for the tachykinin NK1 receptor, and Authors' contributions potent broad-spectrum anti-emetic activity. Regul Pept 1996, BL and GA supervised the development of the radiolig- 65(1):45-53. ands. JE developed and synthesized the radioligands. SS 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, Mac- and OL organized and SS and TG performed the animal Coss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri studies. SS and OL performed the data analysis. SS and JE MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carl- wrote the manuscript. All authors read and approved the son EJ, Hargreaves RJ, Rupniak NM: Distinct mechanism for anti- depressant activity by blockade of central substance P final manuscript. receptors. Science 1998, 281(5383):1640-1645. 16. Baker KG, Halliday GM, Hornung JP, Geffen LB, Cotton RG, Tork I: Distribution, morphology and number of monoamine-syn- Acknowledgements thesizing and substance P-containing neurons in the human This work was conducted in collaboration with Imanet, GE Healthcare and dorsal raphe nucleus. Neuroscience 1991, 42(3):757-775. was supported by grants from The Swedish Research Council and Len- 17. Sergeyev V, Hokfelt T, Hurd Y: Serotonin and substance P co- nanders stiftelse. We are grateful to the staff at Uppsala Imanet, particularly exist in dorsal raphe neurons of the human brain. Neuroreport 1999, 10(18):3967-3970. to Tora Sundin for assistance with the PET/CT scanner and Gudrun Nylén 18. Blier P, Gobbi G, Haddjeri N, Santarelli L, Mathew G, Hen R: Impact for assistance with the rhesus monkeys. of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/ References anxiolytic response. J Psychiatry Neurosci 2004, 29(3):208-218. 19. Haddjeri N, Blier P: Effect of neurokinin-I receptor antagonists 1. Carson RE, Breier A, de Bartolomeis A, Saunders RC, Su TP, Schmall on the function of 5-HT and noradrenaline neurons. Neurore- B, Der MG, Pickar D, Eckelman WC: Quantification of ampheta- port 2000, 11(6):1323-1327. mine-induced changes in [11C]raclopride binding with con- 20. Bergström M, Fasth KJ, Kilpatrick G, Ward P, Cable KM, Wipperman tinuous infusion. J Cereb Blood Flow Metab 1997, 17(4):437-447. MD, Sutherland DR, Långström B: Brain uptake and receptor 2. Dewey SL, Smith GS, Logan J, Brodie JD, Fowler JS, Wolf AP: Striatal binding of two [11C]labelled selective high affinity NK1- binding of the PET ligand 11C-raclopride is altered by drugs antagonists, GR203040 and GR205171--PET studies in rhe- that modify synaptic dopamine levels. Synapse 1993, sus monkey. Neuropharmacology 2000, 39(4):664-670. 13(4):350-356. Page 5 of 6 (page number not for citation purposes) SUV SUV BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 21. Solin O, Eskola O, Hamill TG, Bergman J, Lehikoinen P, Gronroos T, 37. Eriksson J, Antoni G, Långström B: Synthesis of [1-11C]ethyl Forsback S, Haaparanta M, Viljanen T, Ryan C, Gibson R, Kiec- iodide from [11C]carbon monoxide and its application in zykowski G, Hietala J, Hargreaves R, Burns HD: Synthesis and alkylation reactions. J Labelled Compd Radiopharm 2004, characterization of a potent, selective, radiolabeled sub- 47(11):723-731. stance-P antagonist for NK1 receptor quantitation: 38. Eriksson J, Antoni G, Långström B: Synthesis of [1-11C]propyl ([18F]SPA-RQ). Mol Imaging Biol 2004, 6(6):373-384. and [1-11C]butyl iodide from [11C]carbon monoxide and 22. Hietala J, Nyman MJ, Eskola O, Laakso A, Gronroos T, Oikonen V, their use in alkylation reactions. J Labelled Compd Radiopharm Bergman J, Haaparanta M, Forsback S, Marjamaki P, Lehikoinen P, 2006, 49(12):1105-1116. Goldberg M, Burns D, Hamill T, Eng WS, Coimbra A, Hargreaves R, 39. Rupniak NM, Fisher A, Boyce S, Clarke D, Pike A, O'Connor D, Watt Solin O: Visualization and quantification of neurokinin-1 A: P-Glycoprotein efflux reduces the brain concentration of (NK1) receptors in the human brain. Mol Imaging Biol 2005, the substance P (NK1 receptor) antagonists SR140333 and 7(4):262-272. GR205171: a comparative study using mdr1a-/- and mdr1a+/ 23. Del Rosario RB, Mangner TJ, Gildersleeve DL, Shreve PD, Weiland + mice. Behav Pharmacol 2003, 14(5-6):457-463. DM, Lowe JA 3rd, Drozda SE, Snider RM: Synthesis of a nonpep- tide carbon-11 labeled substance P antagonist for PET stud- Pre-publication history ies. Nucl Med Biol 1993, 20(4):545-547. The pre-publication history for this paper can be accessed 24. Livni E, Babich JW, Desai MC, Godek DM, Wilkinson RA, Rubin RH, Fischman AJ, Del Rosario RB, Mangner TJ, Gildersleeve DL, Shreve here: PD, Weiland DM, Lowe JA 3rd, Drozda SE, Snider RM: Synthesis of a 11C-labeled NK1 receptor ligand for PET studies. Nucl Med Biol 1995, 22(1):31-36. http://www.biomedcentral.com/1471-2342/7/6/prepub 25. Bender D, Olsen AK, Marthi MK, Smith DF, Cumming P: PET eval- uation 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. 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. 27. Kihlberg T, Karimi F, Långström B: [11C] Carbon monoxide in selenium-mediated synthesis of [11C]-carbamoyl com- pounds. J Org Chem 2002, 67(11):3687-3692. 28. Rahman O, Kihlberg T, Långstrom B: Synthesis of [11C]/ [13C]Ketones by Suzuki Coupling. Eur J Org Chem 2004, 3:474-478. 29. Doi H, Barletta J, Suzuki M, Noyori R, Watanabe Y, Långstrom B: Synthesis of 11C-labelled N,N'-diphenylurea and ethyl phe- nylcarbamate by a rhodium-promoted carbonylation via [11C]isocyanatobenzene using phenyl azide and [11C]car- bon monoxide. Org Biomol Chem 2004, 2:3063-3066. 30. Itsenko O, Långström B: Radical Mediated Carboxylation of Alkyl Iodides with [11C]Carbon Monoxide in Solvent Mix- tures. J Org Chem 2005, 70:2244-2249. 31. Karimi F, Barletta J, Långstrom B: Palladium-Mediated [11C]Car- bonylative Cross-Coupling of Alkyl/Aryl Iodides with Orga- nostannanes: An Efficient Synthesis of Unsymmetrical Alkyl/ Aryl [11C-carbonyl]Ketones. Eur J Org Chem 2005, 11:2374-2378. 32. Nishiyama S, Tsukada H, Sato K, Kakiuchi T, Ohba H, Harada N, Takahashi K: Evaluation of PET ligands (+)N-[11C]ethyl-3-pip- eridyl benzilate and (+)N-[11C]propyl-3-piperidyl benzilate for muscarinic cholinergic receptors: a PET study with microdialysis in comparison with (+)N-[11C]methyl-3-pip- eridyl benzilate in the conscious monkey brain. Synapse 2001, 40(3):159-169. 33. Wagner HN Jr., 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, Publish with Bio Med Central and every 221(4617):1264-1266. scientist can read your work free of charge 34. Mach RH, Jackson JR, Luedtke RR, Ivins KJ, Molinoff PB, Ehrenkaufer RL: Effects of N-Alkylation on the Affinities of Analogues of "BioMed Central will be the most significant development for Spiperone for Dopamine D2 and Serotonin 5-HT2 Recep- disseminating the results of biomedical researc h in our lifetime." tors. J Med Chem 1992, 35:423-430. Sir Paul Nurse, Cancer Research UK 35. Långström B, Kihlberg T, Bergstrom M, Antoni G, Bjorkman M, Forn- gren BH, Forngren T, Hartvig P, Markides K, Yngve U, Ogren M: Your research papers will be: Compounds labelled with short-lived beta(+)-emitting radi- available free of charge to the entire biomedical community onuclides and some applications in life sciences. The impor- tance of time as a parameter. Acta Chem Scand 1999, peer reviewed and published immediately upon acceptance 53(9):651-669. cited in PubMed and archived on PubMed Central 36. Knoess C, Siegel S, Smith A, Newport D, Richerzhagen N, Winkeler A, Jacobs A, Goble RN, Graf R, Wienhard K, Heiss WD: Perform- yours — you keep the copyright ance evaluation of the microPET R4 PET scanner for BioMedcentral rodents. Eur J Nucl Med Mol Imaging 2003, 30(5):737-747. Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Medical Imaging Springer Journals

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

Loading next page...
 
/lp/springer-journals/synthesis-of-two-potential-nk1-receptor-ligands-using-1-11c-ethyl-gHQPQJLWS9
Publisher
Springer Journals
Copyright
Copyright © 2007 by Syvänen et al; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Imaging / Radiology
eISSN
1471-2342
DOI
10.1186/1471-2342-7-6
pmid
17663770
Publisher site
See Article on Publisher Site

Abstract

Background: The previously validated NK -receptor ligand [O-methyl- C]GR205171 binds with a high affinity to the NK -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 NK -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 NK -receptor ligands with chemical structures based on [O-methyl- C]GR205171. 11 11 Methods: [1- C]Ethyl and [1- C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl- C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1- C]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- C]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- C]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- C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl- C]GR205171. Conclusion: The propyl-analogue (II) cannot be used for detecting changes in NK -ligand levels, while further studies should be performed with the ethyl-analogue (I). Page 1 of 6 (page number not for citation purposes) BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 The aim of this study was to use labelled ethyl and propyl Background Positron emission tomography (PET) has been used for iodide with high specific radioactivity in the synthesis of C]GR205171-analogues with different alkyl visualisation of cerebral energy consumption and receptor [O-methyl- distribution in the living brain using β -emitting radiolig- chain lengths and to compare the binding characteristics ands, i.e. tracers. A radioligand employed in brain recep- in guinea pig and rhesus monkey. We hypothesised that tor mapping is generally desired to display a rapid the increased alkyl chain length would lead to a faster dis- transport over the blood-brain barrier, a high affinity and sociation rate from the NK -receptor. a selective binding to the receptor. As apposed to the high affinity criteria in receptor mapping, a radioligand used in Methods concentration measurements of endogenous transmitters The radioligand [O-methyl- C]GR205171 was synthe- in the vicinity of neuroreceptors should have an affinity sized from [ C]methyl iodide and O-desmethyl which enables displacement by an endogenous ligand [1- GR205171 as previously described [20]. The ethyl ana- 4]. It is assumed that a radioligand with a very high affin- logue (2S,3S)-N-(1-(2- [1- C]ethoxy-5-(3-(trifluorome- ity to a receptor will not enable such detection. thyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2- phenylpiperidin-3-amine (I) and the propyl analogue There is a large interest in the development of antagonists (2S,3S)-2-phenyl-N-(1-(2- [1- C]propoxy-5-(3-(trifluor- for the Neurokinin-1 (NK ) receptor system [5-10]. omethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin- Recently Emend (MK-869) was approved as a drug for 3-amine (II) were synthesized via alkylation of O-desme- 11 11 treatment of chemotherapy-induced nausea. Other possi- thyl GR205171 with [1- C]ethyl iodide and [1- C]pro- ble therapeutic areas of NK -receptor antagonists are not pyl iodide, Figure 1. The following procedure was used; fully defined yet, but their potential as drugs has been dimethylformamide (300 μl) was added to O-desmethyl explored in a range of disorders, including pain, inflam- GR205171 (1.0 mg, 2.3 μmol) and cesium carbonate (3.2 mation, depression and other psychiatric diseases [11- mg, 9.8 μmol) [35]. The solution was vortexed for approx- 11 11 14]. The endogenous NK -receptor ligand, substance P, is imately 20 min before [1- C]ethyl iodide or [1- C]pro- distributed in neurons within the central nervous system pyl iodide was transferred in a flow of nitrogen gas (30 [15]. The NK -receptor system has showed a spatial over- mL/min) to the vial. The vial was then heated for 5 min at lap with neurotransmitters such as serotonin and 140°C to yield the alkylated product. The product was noradrenaline [16,17]. Substance P interacts with the ser- purified on a semi-preparative HPLC consisting of a Beck- -1 otonergic neuronal systems via interneurons which lead man 126 pump at 4 mL min , a Beckman 166 UV detec- to an increase in synaptic availability of serotonin [18,19]. tor at 254 nm, a Bioscan β -flow count detector, Gilson 231 XL auto injector, and a Beckman Ultrasphere ODS dp Previous studies has shown that NK -receptors can be vis- 5 μcolumn (250 × 10 mm). The mobile phase used was A) ualised in vivo with the carbon-11 and fluorine-18 0.05 M ammonium formate pH 3.5 and B) acetonitrile. labelled NK-receptor antagonists [O-methyl- Compound (I): Gradient from 35% B to 48% over 8 min. 11 18 C]GR205171 and [ F]SPA-RQ [20-22]. These two com- R.t 14.7 min. Compound (II): Isocratic elution 52% B, R.t pounds are based on the same pharmacophore and dis- 7.6 min. The mobile phase was removed using a rotavapor play a very high affinity for the NK -receptor, hence they at 90°C and reduced pressure. The product was formu- can be used for visualisation of the receptor system. How- lated in saline (2 mL), propylene glycol (2 mL), HCl (0.3 ever, the compounds cannot be used for detecting changes mL, 0.3 M) and ethanol (0.42 mL) and transferred from in substance P levels due to slow dissociation from the the evaporator to a vial. The pH was adjusted to 7.0 with receptor. Most attempts to develop in vivo NK -receptor phosphate/sodium hydroxide buffer prior to sterile filtra- radioligands have been unsuccessful or indifferent, except tion (Acrodisc Syringe Filters, 0.2 μm HT Tuffryn Mem- for the two ligands mention above [23-26]. brane). Analytical HPLC used to assess the radiochemical purity was performed on a similar Beckman system Recent developments in C-chemistry have opened for equipped with a Beckman Ultrasphere ODS dp 5 μcol- new labelling methods beyond the use of methylation umn (250 × 4.6 mm) and with the UV detector set to 254 and cyanation reactions. Carbonylation using [ C]car- nm. The mobile phase used was A) 0.05 M ammonium bon monoxide has shown to yield C-labelled carbonyl formate pH 3.5, B) acetonitrile. Compound (I): Isocratic -1 compounds with high specific radioactivity and to enable elution 50% B, 1 mL min , R.t. 7.9 min, radiochemical the synthesis of small libraries of labelled compounds purity 97%. Compound (II): Isocratic elution 55% B, 1 -1 [27-31]. This may be useful in the development of PET- mL min , r.t. 6.9 min, radiochemical purity 98%. tracers since it has been demonstrated that small changes in the structure of a receptor ligand can lead to changes in Male guinea-pigs weighing 350–500 g were housed under affinity and also in the ability to penetrate the blood-brain standard laboratory conditions (20°C and 50% humid- barrier [32-34]. ity), maintained on a 12 h:12 h light/dark cycle and with Page 2 of 6 (page number not for citation purposes) BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 C]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 radi- oligand administration. Ventilation was supported with 30% oxygen in air and the body temperature was main- tained 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 p Figure 1 Synthesis of [ yl analoguesO-methyl- C]GR205171 and O-ethyl and O-pro- emission scan for the attenuation of 511 keV photons Synthesis of [O-methyl- C]GR205171 and O-ethyl and O-pro- through the tissue and head supports. The emission scan pyl analogues. began when the radioligand was injected and continued for 90 min. The animal experiments were approved by the Uppsala Animal Ethics Committee (C117/4). free access to food and water. The guinea-pig was placed in a Plexiglass container and anesthetized with 3.8 % iso- The PET images were reconstructed using filtered backpro- flurane prior to each experiment. When unconscious, the jection after correction for attenuation and scattered radi- animal was taken from the container and kept anesthe- ation. The frame images were summarized and regions of tized with 2.8% isoflurane via mask during the PET-scan. interest (ROI) were drawn in the striatum and cerebellum, A warm water pad was used to maintain the body temper- using rhesus monkey brain atlas for guidance (The rhesus ature at 36–37°C throughout the experiment. To assess monkey brain in stereotaxic coordinates. Paxinos et al., the status of the guinea pigs during anaesthesia the breath- 2000). The tissue radioactivity was expressed as SUV ing frequency was monitored and blood samples were (Standardized Uptake Value). analysed for the following parameters: pH, HCO , pCO , 3 2 TCO , sO , pO , Na, K, iCa, Hct and Hb. A catheter for 2 2 2 intravenous injection was inserted into the left femoral Measured Radioactivity in tissue 11 SUV = C]GR205171 (62, 59 and 29 MBq) and vein. [O-methyl- Injected Radioactivity / / Body Weight (I) (8, 13 and 38 MBq) was administered to three animals each and (II) (25 and 35 MBq) was administered to two Results and Discussion 11 11 animals. The studies were performed using a microPET R4 [1- C]Ethyl iodide and [1- C]propyl iodide was synthe- tomograph (Concorde Microsystems) [36]. A transmis- sized within 15 min from [ C]carbon monoxide, Figure sion scan with rotating Co source was used to correct the 2. [1- C]Ethyl iodide was synthesized via hydroxycarbo- emission scan for the attenuation of 511 keV photons nylation of methyl iodide with a decay-corrected radio- through the tissue and scanner bed. The emission scan chemical yield of 55% [37]. [1- C]Propyl iodide was was started when the radioligand was injected and contin- synthesized via hydroformylation of ethene with a decay ued for 90 min. corrected radiochemical yield of 58% [38]. The specific radioactivities at end of synthesis were 90 GBq/μmol and Two female rhesus monkeys, 8.0 kg and 9.5 kg, were 270 GBq/μmol, respectively. The alkylation of O-desme- sedated with 100 mg intramuscular ketamine (Ketaminol, thyl GR205171 led to O-alkylated and N-alkylated prod- Vetpharm AB) and transported to the investigation site at ucts in 1:7 ratio for both ethyl and propyl iodide. Based Uppsala Imanet in the morning of the experiment. on [ C]carbon monoxide, (I) and (II) were obtained in Venous catheters were inserted in both hind legs of the 5.1 ± 0.6% (n = 6) and 4.7 ± 0.8% (n = 7) isolated radio- rhesus monkey. The catheters were used for administra- chemical yield, respectively. When the reaction tempera- tion of the radioligand, Ringer-Acetate (2 mL/kg/h, ture was lowered from 140°C to 110°C the yield of (I) Frensenius Kabi AB) and propofol (50 mg, Propofil- was reduced to 2.3 ± 0.6% (n = 5). The use of tetrabuty- Lipuro, B/Brown) to induce anaesthesia. Anaesthesia was lammonium hydroxide instead of cesium carbonate maintained with 1.3 – 2.5% sevoflurane via tracheal intu- resulted in poorer radiochemical yield due to hydrolysis bation during the PET-scan. A femoral artery catheter was of the labelled alkyl halides and a lower selectivity inserted for blood sampling. Three PET-scans were carried towards O-alkylation compared to N-alkylation. Despite out 2 hrs apart in each monkey. Monkey 1 received [O- the low selectivity of the alkylation reaction, a sufficient methyl- C]GR205171 (215 MBq), ligand (I) (54 MBq) amount of product was obtained for PET imaging in and ligand (I) (30 MBq). Isotopically unmodified guinea pig and rhesus monkey. GR205171 (0.5 mg/kg) was administered as a 10 min infusion prior to the third scan. The same protocol was [O-methyl- C]GR205171 and the two analogues were dis- used for monkey 2 which received [O-methyl- tributed into the guinea pig brain in a similar pattern. The Page 3 of 6 (page number not for citation purposes) BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 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- C]GR205171. The striatum could not be visual- ised with (I) after predosing with GR205171. A small decrease in cerebellum uptake was also seen after predos- ing. With the more lipophilic propyl-analogue (II) the striatum could not be distinguished in the images either with or without predosing. The maximum SUV-values for [O-methyl- C]GR205171 11 11 Synthesis of [1- Figure 2 C]ethyl iodide and [1- C]propyl iodide were 4.2 and 3.1 in monkey 1 and 2, respectively, Figure 11 11 Synthesis of [1- C]ethyl iodide and [1- C]propyl iodide. 5. The SUV values did not decline during the 90 min PET- scan indicating that the binding was not reversible during time-activity profiles obtained from the guinea pig PET the investigation time. This was in accordance with earlier images showed an increase in striatum uptake throughout reported results [20]. The uptake profiles were different the investigation for both analogues and [O-methyl- for the two analogues compared to [O-methyl- 11 11 C]GR205171, Figure 3. C]GR205171. The maximum SUV, 2.7 and 1.5 for the ethyl- and propyl-analogues, respectively, was reached The SUV-values in guinea pig striatum were around 0.35– within minutes after administration. Furthermore, the 0.85 at the end of the investigation. The values were low analogues had a brain half-life of around 60 min and were compared to earlier studies with [O-methyl- eliminated from the striatum, in difference to [O-methyl- 11 11 C]GR205171 in rhesus monkeys which showed SUV- C]GR205171. The SUV-values for (I) were slightly values between 2 and 3 and similar shaped time-activity decreased when the NK -receptors were blocked by pre- curves [20]. The cerebellum uptake in the guinea pigs dosing with GR205171. On the other hand, no such increased during the first 30 min and remained constant change in SUV-values was observed for (II) after predos- -receptor during the rest of the investigation with SUV-values ing with GR205171. This indicated specific NK around 0.1 or less. Rupniak and co-workers have shown binding for the ethyl-analogue, while the propyl-analogue that GR205171 brain uptake in P-glycoprotein deficient was mainly unspecifically bound in the brain. The plasma mice was considerably higher than in wild type mice indi- kinetics were similar for [O-methyl- C]GR205171 and the cating active efflux of GR205171 from the brain [39]. Sim- two analogues with a short distribution half-life and an ilarly, the low brain uptake of [O-methyl- C]GR205171 in elimination phase half-life above 3 hrs. guinea pig might be explained by active efflux mecha- nisms. PET images obtained from the studies in rhesus monkeys are shown in Figure 4. [O-methyl- C]GR205171 and the two analogues were transported into the brain in a much 0.8 0.6 0.4 0.2 0 15 3045 6075 90 Time (min) PET-images over the tr le Figure 4 vel of striatum ansaxial rhesus monkey brain at the PET-images over the transaxial rhesus monkey brain at the 11 11 Figure 3 (I) Time-ac tion of [ (squares) t O ivity profiles in -methyl and pr - C]GR205 opyl-a guinea nalogue 171 (diamonds), ethyl-ana pig str (II) iatu (triangles) m after adminliogue stra- level of striatum. Monkey 1: A. [O-methyl- C]GR205171, B. Time-activity profiles in guinea pig striatum after administra- Ethyl-analogue (I), C. Ethyl-analogue (I) after predosing with 11 11 tion of [O-methyl- C]GR205171 (diamonds), ethyl-analogue GR205171. Monkey 2: D. [O-methyl- C]GR205171, E. Pro- (I) (squares) and propyl-analogue (II) (triangles). Each line pyl-analogue (II), F. Propyl-analogue (II) after predosing with represents uptake in one guinea pig. GR205171. Page 4 of 6 (page number not for citation purposes) SUV BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 3. Innis RB, Malison RT, al-Tikriti M, Hoffer PB, Sybirska EH, Seibyl JP, 4.5 4.5 Zoghbi SS, Baldwin RM, Laruelle M, Smith EO: Amphetamine- 4.0 4.0 stimulated dopamine release competes in vivo for 3.5 3.5 [123I]IBZM binding to the D2 receptor in nonhuman pri- 3.0 3.0 mates. Synapse 1992, 10(3):177-184. 2.5 2.5 4. Laruelle M, D'Souza CD, Baldwin RM, Abi-Dargham A, Kanes SJ, Fin- 2.0 2.0 gado CL, Seibyl JP, Zoghbi SS, Bowers MB, Jatlow P, Charney DS, Innis 1.5 1.5 RB: Imaging D2 receptor occupancy by endogenous 1.0 1.0 dopamine in humans. Neuropsychopharmacology 1997, 0.5 17(3):162-174. 0.5 A B 5. Shue HJ, Chen X, Shih NY, Blythin DJ, Paliwal S, Lin L, Gu D, Schwerdt 0.0 0.0 0 1530 4560 7590 0 1530 4560 7590 JH, Shah S, Reichard GA, Piwinski JJ, Duffy RA, Lachowicz JE, Coffin Time (min) Time (min) VL, Liu F, Nomeir AA, Morgan CA, Varty GB: Cyclic urea deriva- tives as potent NK1 selective antagonists. Bioorg Med Chem Lett 2005, 15(17):3896-3899. Time-ac Figure 5 tivity profiles in rhesus monkey striatum 6. Thomson CG, Carlson E, Chicchi GG, Kulagowski JJ, Kurtz MM, Swain CJ, Tsao KL, Wheeldon A: Synthesis and structure-activity Time-activity profiles in rhesus monkey striatum. A. Monkey relationships of 8-azabicyclo[3.2.1]octane benzylamine NK1 1. [O-methyl- C]GR205171 (diamonds), ethyl-analogue (I) antagonists. Bioorg Med Chem Lett 2006, 16(4):811-814. (squares) and ethyl-analogue (I) after predosing with 7. Huscroft IT, Carlson EJ, Chicchi GG, Kurtz MM, London C, Raubo P, GR205171 (triangles). B. Monkey 2. [O-methyl- Wheeldon A, Kulagowski JJ: 1-Phenyl-8-azabicyclo[3.2.1]octane 11 ethers: a novel series of neurokinin (NK1) antagonists. Bioorg C]GR205171 (diamonds), propyl-analogue (II) (squares) Med Chem Lett 2006, 16(7):2008-2012. and propyl-analogue (II) after predosing with GR205171(tri- 8. Meurer LC, Finke PE, Owens KA, Tsou NN, Ball RG, Mills SG, Mac- angles). coss M, Sadowski S, Cascieri MA, Tsao KL, Chicchi GG, Egger LA, Luell S, Metzger JM, Macintyre DE, Rupniak NM, Williams AR, Har- greaves RJ: Cyclopentane-based human NK1 antagonists. Part 2: development of potent, orally active, water-soluble deriv- Conclusion atives. Bioorg Med Chem Lett 2006, 16(17):4504-4511. 9. Elliott JM, Carlson EJ, Chicchi GG, Dirat O, Dominguez M, Gerhard The rhesus monkey studies indicated that the order of lig- U, Jelley R, Jones AB, Kurtz MM, Tsao K, Wheeldon A: NK1 antag- and affinities for the NK -receptor was [O-methyl- onists based on seven membered lactam scaffolds. Bioorg Med C]GR205171 > (I) > (II). The ethyl-analogue had a sim- Chem Lett 2006, 16(11):2929-2932. 10. Hoffmann-Emery F, Hilpert H, Scalone M, Waldmeier P: Efficient ilar binding pattern as [O-methyl- C]GR205171, while no synthesis of novel NK1 receptor antagonists: selective 1,4- specific binding to striatum could be detected for the pro- addition of grignard reagents to 6-chloronicotinic acid deriv- atives. J Org Chem 2006, 71(5):2000-2008. pyl-analogue. The propyl-analogues can therefore not be 11. Rupniak NM: New insights into the antidepressant actions of used for detecting changes in NK -ligand levels, while fur- substance P (NK1 receptor) antagonists. Can J Physiol Pharmacol ther studies should be performed with the ethyl analogue. 2002, 80(5):489-494. 12. Hokfelt T, Pernow B, Wahren J: Substance P: a pioneer amongst neuropeptides. J Intern Med 2001, 249(1):27-40. Competing interests 13. Rupniak NM, Kramer MS: Discovery of the antidepressant and The author(s) declare that they have no competing inter- anti-emetic efficacy of substance P receptor (NK1) antago- nists. Trends Pharmacol Sci 1999, 20(12):485-490. ests. 14. Gardner CJ, Armour DR, Beattie DT, Gale JD, Hawcock AB, Kil- patrick GJ, Twissell DJ, Ward P: GR205171: a novel antagonist with high affinity for the tachykinin NK1 receptor, and Authors' contributions potent broad-spectrum anti-emetic activity. Regul Pept 1996, BL and GA supervised the development of the radiolig- 65(1):45-53. ands. JE developed and synthesized the radioligands. SS 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, Mac- and OL organized and SS and TG performed the animal Coss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri studies. SS and OL performed the data analysis. SS and JE MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carl- wrote the manuscript. All authors read and approved the son EJ, Hargreaves RJ, Rupniak NM: Distinct mechanism for anti- depressant activity by blockade of central substance P final manuscript. receptors. Science 1998, 281(5383):1640-1645. 16. Baker KG, Halliday GM, Hornung JP, Geffen LB, Cotton RG, Tork I: Distribution, morphology and number of monoamine-syn- Acknowledgements thesizing and substance P-containing neurons in the human This work was conducted in collaboration with Imanet, GE Healthcare and dorsal raphe nucleus. Neuroscience 1991, 42(3):757-775. was supported by grants from The Swedish Research Council and Len- 17. Sergeyev V, Hokfelt T, Hurd Y: Serotonin and substance P co- nanders stiftelse. We are grateful to the staff at Uppsala Imanet, particularly exist in dorsal raphe neurons of the human brain. Neuroreport 1999, 10(18):3967-3970. to Tora Sundin for assistance with the PET/CT scanner and Gudrun Nylén 18. Blier P, Gobbi G, Haddjeri N, Santarelli L, Mathew G, Hen R: Impact for assistance with the rhesus monkeys. of substance P receptor antagonism on the serotonin and norepinephrine systems: relevance to the antidepressant/ References anxiolytic response. J Psychiatry Neurosci 2004, 29(3):208-218. 19. Haddjeri N, Blier P: Effect of neurokinin-I receptor antagonists 1. Carson RE, Breier A, de Bartolomeis A, Saunders RC, Su TP, Schmall on the function of 5-HT and noradrenaline neurons. Neurore- B, Der MG, Pickar D, Eckelman WC: Quantification of ampheta- port 2000, 11(6):1323-1327. mine-induced changes in [11C]raclopride binding with con- 20. Bergström M, Fasth KJ, Kilpatrick G, Ward P, Cable KM, Wipperman tinuous infusion. J Cereb Blood Flow Metab 1997, 17(4):437-447. MD, Sutherland DR, Långström B: Brain uptake and receptor 2. Dewey SL, Smith GS, Logan J, Brodie JD, Fowler JS, Wolf AP: Striatal binding of two [11C]labelled selective high affinity NK1- binding of the PET ligand 11C-raclopride is altered by drugs antagonists, GR203040 and GR205171--PET studies in rhe- that modify synaptic dopamine levels. Synapse 1993, sus monkey. Neuropharmacology 2000, 39(4):664-670. 13(4):350-356. Page 5 of 6 (page number not for citation purposes) SUV SUV BMC Medical Imaging 2007, 7:6 http://www.biomedcentral.com/1471-2342/7/6 21. Solin O, Eskola O, Hamill TG, Bergman J, Lehikoinen P, Gronroos T, 37. Eriksson J, Antoni G, Långström B: Synthesis of [1-11C]ethyl Forsback S, Haaparanta M, Viljanen T, Ryan C, Gibson R, Kiec- iodide from [11C]carbon monoxide and its application in zykowski G, Hietala J, Hargreaves R, Burns HD: Synthesis and alkylation reactions. J Labelled Compd Radiopharm 2004, characterization of a potent, selective, radiolabeled sub- 47(11):723-731. stance-P antagonist for NK1 receptor quantitation: 38. Eriksson J, Antoni G, Långström B: Synthesis of [1-11C]propyl ([18F]SPA-RQ). Mol Imaging Biol 2004, 6(6):373-384. and [1-11C]butyl iodide from [11C]carbon monoxide and 22. Hietala J, Nyman MJ, Eskola O, Laakso A, Gronroos T, Oikonen V, their use in alkylation reactions. J Labelled Compd Radiopharm Bergman J, Haaparanta M, Forsback S, Marjamaki P, Lehikoinen P, 2006, 49(12):1105-1116. Goldberg M, Burns D, Hamill T, Eng WS, Coimbra A, Hargreaves R, 39. Rupniak NM, Fisher A, Boyce S, Clarke D, Pike A, O'Connor D, Watt Solin O: Visualization and quantification of neurokinin-1 A: P-Glycoprotein efflux reduces the brain concentration of (NK1) receptors in the human brain. Mol Imaging Biol 2005, the substance P (NK1 receptor) antagonists SR140333 and 7(4):262-272. GR205171: a comparative study using mdr1a-/- and mdr1a+/ 23. Del Rosario RB, Mangner TJ, Gildersleeve DL, Shreve PD, Weiland + mice. Behav Pharmacol 2003, 14(5-6):457-463. DM, Lowe JA 3rd, Drozda SE, Snider RM: Synthesis of a nonpep- tide carbon-11 labeled substance P antagonist for PET stud- Pre-publication history ies. Nucl Med Biol 1993, 20(4):545-547. The pre-publication history for this paper can be accessed 24. Livni E, Babich JW, Desai MC, Godek DM, Wilkinson RA, Rubin RH, Fischman AJ, Del Rosario RB, Mangner TJ, Gildersleeve DL, Shreve here: PD, Weiland DM, Lowe JA 3rd, Drozda SE, Snider RM: Synthesis of a 11C-labeled NK1 receptor ligand for PET studies. Nucl Med Biol 1995, 22(1):31-36. http://www.biomedcentral.com/1471-2342/7/6/prepub 25. Bender D, Olsen AK, Marthi MK, Smith DF, Cumming P: PET eval- uation 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. 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. 27. Kihlberg T, Karimi F, Långström B: [11C] Carbon monoxide in selenium-mediated synthesis of [11C]-carbamoyl com- pounds. J Org Chem 2002, 67(11):3687-3692. 28. Rahman O, Kihlberg T, Långstrom B: Synthesis of [11C]/ [13C]Ketones by Suzuki Coupling. Eur J Org Chem 2004, 3:474-478. 29. Doi H, Barletta J, Suzuki M, Noyori R, Watanabe Y, Långstrom B: Synthesis of 11C-labelled N,N'-diphenylurea and ethyl phe- nylcarbamate by a rhodium-promoted carbonylation via [11C]isocyanatobenzene using phenyl azide and [11C]car- bon monoxide. Org Biomol Chem 2004, 2:3063-3066. 30. Itsenko O, Långström B: Radical Mediated Carboxylation of Alkyl Iodides with [11C]Carbon Monoxide in Solvent Mix- tures. J Org Chem 2005, 70:2244-2249. 31. Karimi F, Barletta J, Långstrom B: Palladium-Mediated [11C]Car- bonylative Cross-Coupling of Alkyl/Aryl Iodides with Orga- nostannanes: An Efficient Synthesis of Unsymmetrical Alkyl/ Aryl [11C-carbonyl]Ketones. Eur J Org Chem 2005, 11:2374-2378. 32. Nishiyama S, Tsukada H, Sato K, Kakiuchi T, Ohba H, Harada N, Takahashi K: Evaluation of PET ligands (+)N-[11C]ethyl-3-pip- eridyl benzilate and (+)N-[11C]propyl-3-piperidyl benzilate for muscarinic cholinergic receptors: a PET study with microdialysis in comparison with (+)N-[11C]methyl-3-pip- eridyl benzilate in the conscious monkey brain. Synapse 2001, 40(3):159-169. 33. Wagner HN Jr., 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, Publish with Bio Med Central and every 221(4617):1264-1266. scientist can read your work free of charge 34. Mach RH, Jackson JR, Luedtke RR, Ivins KJ, Molinoff PB, Ehrenkaufer RL: Effects of N-Alkylation on the Affinities of Analogues of "BioMed Central will be the most significant development for Spiperone for Dopamine D2 and Serotonin 5-HT2 Recep- disseminating the results of biomedical researc h in our lifetime." tors. J Med Chem 1992, 35:423-430. Sir Paul Nurse, Cancer Research UK 35. Långström B, Kihlberg T, Bergstrom M, Antoni G, Bjorkman M, Forn- gren BH, Forngren T, Hartvig P, Markides K, Yngve U, Ogren M: Your research papers will be: Compounds labelled with short-lived beta(+)-emitting radi- available free of charge to the entire biomedical community onuclides and some applications in life sciences. The impor- tance of time as a parameter. Acta Chem Scand 1999, peer reviewed and published immediately upon acceptance 53(9):651-669. cited in PubMed and archived on PubMed Central 36. Knoess C, Siegel S, Smith A, Newport D, Richerzhagen N, Winkeler A, Jacobs A, Goble RN, Graf R, Wienhard K, Heiss WD: Perform- yours — you keep the copyright ance evaluation of the microPET R4 PET scanner for BioMedcentral rodents. Eur J Nucl Med Mol Imaging 2003, 30(5):737-747. Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 6 of 6 (page number not for citation purposes)

Journal

BMC Medical ImagingSpringer Journals

Published: Jul 30, 2007

References