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Visualization and Quantification of Neurokinin-1 (NK1) Receptors in the Human Brain

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Abstract

Purpose

This study was conducted to develop a new positron emission tomography (PET) method to visualize neurokinin-1 (NK1) receptor systems in the human brain in vivo in order to examine their neuroanatomical distribution and facilitate investigations of the role of substance P, NK1 receptors, and NK1 receptor antagonists in central nervous system (CNS) function and dysfunction.

Methods

PET studies were conducted in 10 healthy male volunteers using a novel selective, high-affinity NK1 receptor antagonist labeled with fluorine-18 to very high specific radioactivity (up to 2000 GBq/μmol) [F-18]SPA-RQ. Data were collected in 3D mode for greatest sensitivity. Different modeling methods were compared and regional receptor distributions determined for comparison with in vitro autoradiographic studies using postmortem human brain slices with [F-18]SPA-RQ.

Results

The studies showed that the highest uptake of [F-18]SPA-RQ was observed in the caudate and putamen. Lower binding was found in globus pallidus and substantia nigra. [F-18]SPA-RQ uptake was also widespread throughout the neocortex and limbic cortex including amygdala and hippocampus. There was very low specific uptake of the tracer in the cerebellar cortex. The distribution pattern was confirmed using in vitro receptor autoradiography with [F-18]SPA-RQ on postmortem human brain slices. Kinetic modeling of the [F-18]SPA-RQ uptake data indicated a binding potential between 4 and 5 in the basal ganglia and between 1.5 and 2.5 in the cortical regions.

Conclusions

[F-18]SPA-RQ is a novel tool for exploration of the functions of NK1 receptors in man. [F-18]SPA-RQ can be used to define receptor pharmacodynamics and focus dose selection of novel NK1 receptor antagonists in clinical trials thereby ensuring adequate proof of concept testing particularly in therapeutic applications related to CNS dysfunction.

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References

  1. Stout SC, Owens MJ, Nemeroff CB (2001) Neurokinin(1) receptor antagonists as potential antidepressants. Annu Rev Pharmacol Toxicol 41:877–906

    Article  PubMed  CAS  Google Scholar 

  2. Von Euler US, Gaddum JH (1931) An unidentified depressor substance in certain tissue extracts. J Physiol 72:74–87

    Google Scholar 

  3. Pernow B (1983) Substance-P. Pharmacol Rev 35:85–141

    PubMed  CAS  Google Scholar 

  4. Otsuka M, Yoshioka K (1993) Neurotransmitter functions of mammalian tachykinins. Pharmacol Rev 73:229–308

    CAS  Google Scholar 

  5. Vincent SR, Satoh K, Armstrong DM, Panula P, Vale W, Fibiger HC (1986) Neuropeptides and nadph-diaphorase activity in the ascending cholinergic reticular system of the rat. Neuroscience 17:167–182

    Article  PubMed  CAS  Google Scholar 

  6. Baker KG, Halliday GM, Hornung JP, Geffen LB, Cotton RGH, Tork I (1991) Distribution, morphology and number of monoamine-synthesizing and substance P-containing neurons in the human dorsal raphe nucleus. Neuroscience 42:757–775

    Article  PubMed  CAS  Google Scholar 

  7. Nicholas AP, Pieribone VA, Arvidsson U, Hokfelt T (1992) Serotoninlike, substance P-like and glutamate aspartate-like immunoreactivities in medullo-spinal pathways of rat and primate. Neuroscience 48:545–559

    Article  PubMed  CAS  Google Scholar 

  8. Sergeyev V, Hokfelt T, Hurd Y (1999) Serotonin and substance P coexist in dorsal raphe neurons of the human brain. NeuroReport 10:3967–3970

    Article  PubMed  CAS  Google Scholar 

  9. Ljungdahl A, Hokfelt T, Nilsson G (1978) Distribution of substance P-like immunoreactivity in central nervous system of rat. 1. Cell bodies and nerve-terminals. Neuroscience 3:861–943

    Article  PubMed  CAS  Google Scholar 

  10. Mai JK, Stephens PH, Hopf A, Cuello AC (1986) Substance-P in the human-brain. Neuroscience 17:709–739

    Article  PubMed  CAS  Google Scholar 

  11. Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE (1991) Molecular-cloning, structural characterization and functional expression of the human substance-P receptor. Mol Cell Biol Res Commun 179:1232–1240

    CAS  Google Scholar 

  12. Caberlotto L, Hurd YL, Murdock P, et al. (2003) Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain. Eur J Neurosci 17:1736–1746

    Article  PubMed  Google Scholar 

  13. De Felipe C, Herrero JF, O'Brien JA, et al. (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397

    Article  PubMed  Google Scholar 

  14. Murtra P, Sheasby AM, Hunt SP, De Felipe C (2000) Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 405:180–183

    Article  PubMed  CAS  Google Scholar 

  15. Laird JMA, Olivar T, Roza C, De Felipe C, Hunt SP, Cervero F (2000) Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachykinin NK1 receptor gene. Neuroscience 98:345–352

    Article  PubMed  CAS  Google Scholar 

  16. Rupniak NMJ, Carlson EC, Harrison T, et al. (2000) Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology 39:1413–1421

    Article  PubMed  CAS  Google Scholar 

  17. Morcuende S, Gadd CA, Peters M, et al. (2003) Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice. Eur J Neurosci 18:1828–1836

    Article  PubMed  Google Scholar 

  18. van der Hart MGC, Czeh B, de Biurrun G, et al. (2002) Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume. Mol Psychiatry 7:933–941

    Article  PubMed  CAS  Google Scholar 

  19. Bondy B, Baghai TC, Minov C, et al. (2003) Substance P serum levels are increased in major depression: Preliminary results. Biol Psychiatry 53:538–542

    Article  PubMed  CAS  Google Scholar 

  20. Navari RM, Reinhardt RR, Gralla RJ, et al. (1999) Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group. N Engl J Med 340:190–195

    Article  PubMed  CAS  Google Scholar 

  21. Hesketh PJ, Van Belle S, Aapro M, et al. (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39:1074–1080

    Article  PubMed  CAS  Google Scholar 

  22. Hesketh PJ, Grunberg SM, Gralla RJ, et al. (2003) The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: A multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatinVThe Aprepitant Protocol 052 Study Group. J Clin Oncol 21:4112–4119

    Article  PubMed  CAS  Google Scholar 

  23. De Wit R, Herrstedt J, Rapoport B, et al. (2003) Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol 21:4105–4111

    Article  PubMed  CAS  Google Scholar 

  24. Kramer MS, Cutler N, Feighner J, et al. (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640–1645

    Article  PubMed  CAS  Google Scholar 

  25. Kramer MS, Winokur A, Kelsey J, et al. (2004) Demonstration of the efficacy and safety of a novel substance P (NK1) receptor antagonist in major depression. Neuropsychopharmacology 29:385–392

    Article  PubMed  CAS  Google Scholar 

  26. Rimon R, Legreves P, Nyberg F, Heikkila L, Salmela L, Terenius L (1984) Elevation of substance P-like peptides in the CSF of psychiatric-patients. Biol Psychiatry 19:509–516

    PubMed  CAS  Google Scholar 

  27. Snider RM, Constantine JW, Lowe JA, et al. (1991) A potent nonpeptide antagonist of the substance-P (Nk1) receptor. Science 251:435–437

    Article  PubMed  CAS  Google Scholar 

  28. McLean S, Ganong A, Seymour PA, et al. (1996) Characterization of CP-122,721; A nonpeptide antagonist of the neurokinin NK1 receptor. J Pharmacol Exp Ther 277:900–908

    PubMed  CAS  Google Scholar 

  29. Rupniak NMJ, Kramer MS (1999) Discovery of the anti-depressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol Sci 20:485–490

    Article  PubMed  CAS  Google Scholar 

  30. Tattersall FD, Rycroft W, Francis B, et al. (1996) Tachykinin NK1 receptor antagonists act centrally to inhibit emesis induced by the chemotherapeutic agent cisplatin in ferrets. Neuropharmacology 35:1121–1129

    Article  PubMed  CAS  Google Scholar 

  31. Tattersall FD, Rycroft W, Cumberbatch M, et al. (2000) The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L758,298, inhibit acute and delayed cisplatininduced emesis in ferrets. Neuropharmacology 39:652–663

    Article  PubMed  CAS  Google Scholar 

  32. Solin O, Eskola O, Hamill TG, et al. (2004) Synthesis and characterization of a potent, selective, radiolabeled substance-P antagonist for NK(1) receptor quantitation: ([(18)F]SPA-RQ). Mol Imaging Biol 6:373–384

    Article  PubMed  Google Scholar 

  33. Bergman J, Eskola O, Lehikoinen P, Solin O (2001) Automated synthesis and purification of [18F]bromofluoromethane at high specific radioactivity. Appl Radiat Isotopes 54:927–933

    Article  CAS  Google Scholar 

  34. Gunn RN, Sargent PA, Bench CJ, et al. (1998) Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET. NeuroImage 8:426–440

    Article  PubMed  CAS  Google Scholar 

  35. Hietala J, Syvalahti E, Vuorio K, et al. (1995) Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 346:1130–1131

    Article  PubMed  CAS  Google Scholar 

  36. Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ (1984) A quantitative model for the in vivo assessment of drug-binding sites with positron emission tomography. Ann Neurol 15:217–227

    Article  PubMed  CAS  Google Scholar 

  37. Slifstein M, Laruelle M (2001) Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. Nucl Med Biol 28:595–608

    Article  PubMed  CAS  Google Scholar 

  38. Parsey RV, Slifstein M, Hwang DR, et al. (2000) Validation and reproducibility of measurement of 5-HT1A receptor parameters with [carbonyl-C-11]WAY-100635 in humans: Comparison of arterial and reference tissue input functions. J Cereb Blood Flow Metab 20:1111–1133

    Article  PubMed  CAS  Google Scholar 

  39. Ito H, Hietala J, Blomqvist G, Halldin C, Farde L (1998) Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [C-11]raclopride binding. J Cereb Blood Flow Metab 18:941–950

    Article  PubMed  CAS  Google Scholar 

  40. Cunningham VJ, Hume SP, Price GR, Ahier RG, Cremer JE, Jones AKP (1991) Compartmental analysis of diprenorphine binding to opiate receptors in the rat in vivo and its comparison with equilibrium data in vitro. J Cereb Blood Flow Metab 11:1–9

    PubMed  CAS  Google Scholar 

  41. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. NeuroImage 4:153–158

    Article  PubMed  CAS  Google Scholar 

  42. Sudo Y, Suhara T, Inoue M, et al. (2001) Reproducibility of [C-11]FLB 457 binding in extrastriatal regions. Nucl Med Commun 22:1215–1221

    Article  PubMed  CAS  Google Scholar 

  43. Bergstrom M, Hargreaves RJ, Burns HD, et al. (2004) Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry 55:1007–1012

    Article  PubMed  CAS  Google Scholar 

  44. Oikonen V, Allonen T, Nagren K, Kajander J, Hietala J (2000) Quantification of [carbonyl-C-11]WAY-100635 binding: Considerations on the cerebellum. Nucl Med Biol 27:483–486

    Article  PubMed  CAS  Google Scholar 

  45. Goto T, Kido MA, Yamaza T, Tanaka T (2001) Substance P and substance P receptors in bone and gingival tissues. Med Electron Microsc 34:77–85

    Article  PubMed  CAS  Google Scholar 

  46. Maeno H, Kiyama H, Tohyama M (1993) Distribution of the substance P receptor (NK-1 receptor) in the central nervous system. Brain Res Mol Brain Res 18:43–58

    Article  PubMed  CAS  Google Scholar 

  47. Hokfelt T, Broberger C, Xu ZQD, Sergeyev V, Ubink R, Diez M (2000) Neuropeptides—An overview. Neuropharmacology 39:1337–1356

    Article  PubMed  CAS  Google Scholar 

  48. Mantyh PW, Hunt SP, Maggio JE (1984) Substance-P receptors—Localization by light microscopic autoradiography in rat-brain using [H-3]Sp as the radioligand. Brain Res 307:147–165

    Article  PubMed  CAS  Google Scholar 

  49. Parent A, Cicchetti F, Beach TG (1995) Striatal neurones displaying substance P (NK1) receptor immunoreactivity in human and nonhuman primates. NeuroReport 6:721–724

    Article  PubMed  CAS  Google Scholar 

  50. Mounir S, Parent A (2002) The expression of neurokinin-1 receptor at striatal and pallidal levels in normal human brain. Neurosci Res 44:71–81

    Article  PubMed  CAS  Google Scholar 

  51. Gerfen CR (1991) Substance P (neurokinin-1) receptor mRNA is selectively expressed in cholinergic neurons in the striatum and basal forebrain. Brain Res 556:165–170

    Article  PubMed  CAS  Google Scholar 

  52. Chen LW, Wei LC, Liu HL, Qiu Y, Chan YS (2001) Cholinergic neurons expressing substance P receptor (NK1) in the basal forebrain of the rat: A double immunocytochemical study. Brain Res 904:161–166

    Article  PubMed  CAS  Google Scholar 

  53. Kaneko T, Shigemoto R, Nakanishi S, Mizuno N (1993) Substance P receptor-immunoreactive neurons in the rat neostriatum are segregated into somatostatinergic and cholinergic aspiny neurons. Brain Res 631:297–303

    Article  PubMed  CAS  Google Scholar 

  54. Whitty CJ, Paul MA, Bannon MJ (1997) Neurokinin receptor mRNA localization in human midbrain dopamine neurons. J Comp Neurol 382:394–400

    Article  PubMed  CAS  Google Scholar 

  55. Whitty CJ, Walker PD, Goebel DJ, Poosch MS, Bannon MJ (1995) Quantitation, cellular-localization and regulation of neurokinin receptor gene-expression within the rat substantia-nigra. Neuroscience 64:419–425

    Article  PubMed  CAS  Google Scholar 

  56. Futami T, Hatanaka Y, Matsushita K, Furuya S (1998) Expression of substance P receptor in the substantia nigra. Mol Brain Res 54:183–198

    Article  PubMed  CAS  Google Scholar 

  57. Feuerstein TJ, Gleichauf O, Landwehrmeyer GB (1996) Modulation of cortical acetylcholine release by serotonin: The role of substance P interneurons. Naunyn-Schmiedeberg's Arch Pharmacol 354:618–626

    CAS  Google Scholar 

  58. Lejeune F, Gobert A, Millan MJ (2002) The selective neurokinin (NK)(1) antagonist, GR205,171, stereo specifically enhances mesocortical dopaminergic transmission in the rat: A combined dialysis and electrophysiological study. Brain Res 935:134–139

    Article  PubMed  CAS  Google Scholar 

  59. Kus L, Mazzone SB, Paxinos G, Geraghty DP (1998) Autoradiographic localisation of substance P (NK1) receptors in human primary visual cortex. Brain Res 794:309–312

    Article  PubMed  CAS  Google Scholar 

  60. Smith DW, Hewson L, Fuller P, Williams AR, Wheeldon A, Rupniak NM (1999) The substance P antagonist L-760,735 inhibits stressinduced NK(1) receptor internalisation in the basolateral amygdala. Brain Res 848:90–95

    Article  PubMed  CAS  Google Scholar 

  61. Nomura H, Shiosaka S, Tohyama M (1987) Distribution of substance P-like immunoreactive structures in the brain-stem of the adult humanbrain—An immunocytochemical study. Brain Res 404:365–370

    Article  PubMed  CAS  Google Scholar 

  62. Conley RK, Cumberbatch MJ, Mason GS, et al. (2002) Substance P (neurokinin 1) receptor antagonists enhance dorsal raphe neuronal activity. J Neurosci 22:7730–7736

    PubMed  CAS  Google Scholar 

  63. Maubach KA, Martin K, Chicchi G, et al. (2002) Chronic substance P (NK1) receptor antagonist and conventional antidepressant treatment increases burst firing of monoamine neurones in the locus coeruleus. Neuroscience 109:609–617

    Article  PubMed  CAS  Google Scholar 

  64. Froger N, Gardier AM, Moratalla R, et al. (2001) 5-Hydroxytryptamine (5-HT)1A autoreceptor adaptive changes in substance P (neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization. J Neurosci 21:8188–8197

    PubMed  CAS  Google Scholar 

  65. Watson JW, Gonsalves SF, Fossa AA, et al. (1995) The antiemetic effects of Cp-99,994 in the ferret and the dog—Role of the Nk1 receptor. Br J Pharmacol 115:84–94

    PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by Merck Research Laboratories, USA. The help of the staff in the Turku PET laboratory and in MRI unit is appreciated. We thank Drs. Jari Tiihonen, Erkki Tupala (Kuopio University), and Terttu Särkioja (Oulu University) for their help with postmortem human brain slices. The authors would also like to thank Dr. David Sciberras for oversight of the studies during his tenure at Merck.

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Authors and Affiliations

  1. Neuropsychiatric Imaging, Turku PET Centre, Turku University Central Hospital, Kiinamyllynkatu 4-8, 20520, Turku, Finland

    Jarmo Hietala MD, PhD, Mikko J. Nyman MD, Aki Laakso MD, PhD & Vesa Oikonen MSc

  2. Department of Psychiatry, Turku University Central Hospital, 20520, Turku, Finland

    Jarmo Hietala MD, PhD

  3. Accelerator Laboratory, Turku PET Centre, 20520, Turku, Finland

    Olli Eskola MSc, Tove Grönroos MSc, Jörgen Bergman PhD, Pertti Lehikoinen PhD & Olof Solin PhD

  4. Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, Fin-20520, Turku, Finland

    Aki Laakso MD, PhD

  5. Medicity PET, Turku PET Centre, 20520, Turku, Finland

    Merja Haaparanta MSc, Sarita Forsback MSc & Päivi Marjamäki MSc

  6. Merck Research Laboratories, Rahway, NJ, USA

    Michael Goldberg MD, Donald Burns PhD, Terence Hamill PhD, Wai-Si Eng PhD, Alexandre Coimbra PhD & Richard Hargreaves PhD

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  1. Jarmo Hietala MD, PhD
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  2. Mikko J. Nyman MD
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  11. Pertti Lehikoinen PhD
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  13. Donald Burns PhD
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  18. Olof Solin PhD
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Correspondence to Jarmo Hietala MD, PhD.

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Hietala, J., Nyman, M.J., Eskola, O. et al. Visualization and Quantification of Neurokinin-1 (NK1) Receptors in the Human Brain. Mol Imaging Biol 7, 262–272 (2005). https://doi.org/10.1007/s11307-005-7001-6

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