Synthesis, radiofluorination, and in vitro evaluation of pyrazolo[1,5-a]pyridine-based dopamine D4 receptor ligands: discovery of an inverse agonist radioligand for PET.

A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5- a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D 4 receptor (D 4R) ligands ( 3a- 3h, K i = 1.3-28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D 4 subtype selectivity of more than 3 orders of magnitude over both congeners D 2 and D 3 combined with inverse agonism at D 4R. The corresponding (18)F-labeled radioligands revealed high serum stability in vitro and log P values of 2-3. In vitro rat brain autoradiography showed specific binding of [ (18)F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65-80%) and the selective D 4R antagonist 10 (78-93%). The observed binding pattern was mainly consistent with the known D 4R distribution in the rat brain. Thus, [(18)F]3h (FAUC F41) represents a potential radioligand for studying the D 4R in vivo by positron emission tomography (PET).

[1]  T. Svensson,et al.  Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre-clinical antipsychotic potential. , 2007, European journal of pharmacology.

[2]  Ao Zhang,et al.  Recent progress in development of dopamine receptor subtype-selective agents: potential therapeutics for neurological and psychiatric disorders. , 2007, Chemical reviews.

[3]  C. Palmier,et al.  F15063, a potential antipsychotic with D2/D3 antagonist, 5‐HT1A agonist and D4 partial agonist properties: (I) in vitro receptor affinity and efficacy profile , 2007, British journal of pharmacology.

[4]  A. Argiolas,et al.  Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: Involvement of central oxytocin , 2007, Neuropharmacology.

[5]  Torsten Kuwert,et al.  Structure-selectivity investigations of D2-like receptor ligands by CoMFA and CoMSIA guiding the discovery of D3 selective PET radioligands. , 2007, Journal of medicinal chemistry.

[6]  M. Rubinstein,et al.  Identification of brain neurons expressing the dopamine D4 receptor gene using BAC transgenic mice , 2006, The European journal of neuroscience.

[7]  Bryan L. Roth,et al.  WAY-100635 is a potent dopamine D4 receptor agonist , 2006, Psychopharmacology.

[8]  K. Ishiwata,et al.  PET tracers for imaging of the dopaminergic system. , 2006, Current medicinal chemistry.

[9]  Lars Farde,et al.  Using positron emission tomography to facilitate CNS drug development. , 2006, Trends in pharmacological sciences.

[10]  P. Gmeiner,et al.  Synthesis and biological investigations of dopaminergic partial agonists preferentially recognizing the D4 receptor subtype. , 2006, Bioorganic & medicinal chemistry letters.

[11]  R. Ebstein.  The molecular genetic architecture of human personality: beyond self-report questionnaires , 2006, Molecular Psychiatry.

[12]  William C Eckelman,et al.  Targeting proteins in vivo: in vitro guidelines. , 2006, Nuclear medicine and biology.

[13]  U. Hacksell,et al.  Intrinsic Efficacy of Antipsychotics at Human D2, D3, and D4 Dopamine Receptors: Identification of the Clozapine Metabolite N-Desmethylclozapine as a D2/D3 Partial Agonist , 2005, Journal of Pharmacology and Experimental Therapeutics.

[14]  P. Gmeiner,et al.  Synthesis and evaluation of 18F-labeled dopamine D3 receptor ligands as potential PET imaging agents. , 2005, Bioorganic & medicinal chemistry letters.

[15]  Jyh-Cheng Chen,et al.  Evaluation of F-18-labeled amino acid derivatives and [18F]FDG as PET probes in a brain tumor-bearing animal model. , 2005, Nuclear medicine and biology.

[16]  A. Argiolas,et al.  PD-168077, a selective dopamine D4 receptor agonist, induces penile erection when injected into the paraventricular nucleus of male rats , 2005, Neuroscience Letters.

[17]  Jeewoo Lee,et al.  Synthesis and evaluation of fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives for dopamine D4 receptor imaging. , 2004, Bioorganic & medicinal chemistry.

[18]  J. Feldon,et al.  FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia , 2004, Psychopharmacology.

[19]  R. Waterhouse,et al.  Determination of lipophilicity and its use as a predictor of blood-brain barrier penetration of molecular imaging agents. , 2003, Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.

[20]  H. V. Tol,et al.  The dopamine D4 receptors and mechanisms of antipsychotic atypicality , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[21]  T. Grönroos,et al.  Synthesis of 3-[[4-(4-[18F] fluorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine , 2002 .

[22]  Ming-Rong Zhang,et al.  Syntheses and pharmacological evaluation of two potent antagonists for dopamine D4 receptors: [11C]YM-50001 and N-[2-[4-(4-Chlorophenyl)-piperizin-1-yl]ethyl]-3-[11C]methoxybenzamide. , 2002, Nuclear medicine and biology.

[23]  P. Gmeiner,et al.  Synthesis and in vitro evaluation of iodine labelled pyrazolo[1,5-a]pyridines as highly selective dopamine D4 receptor ligands , 2001 .

[24]  P. Gmeiner,et al.  Rationally based efficacy tuning of selective dopamine d4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213). , 2001, Journal of medicinal chemistry.

[25]  T. Kenakin,et al.  Inverse, protean, and ligand‐selective agonism: matters of receptor conformation , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  P. Strange,et al.  Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. , 2001, Pharmacological reviews.

[27]  I. Lucki,et al.  Quantitative autoradiographic mapping of rat brain dopamine D3 binding with [(125)I]7-OH-PIPAT: evidence for the presence of D3 receptors on dopaminergic and nondopaminergic cell bodies and terminals. , 2000, The Journal of pharmacology and experimental therapeutics.

[28]  P. Gmeiner,et al.  Cyanoindole derivatives as highly selective dopamine D(4) receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments. , 2000, Journal of medicinal chemistry.

[29]  J. Sandell,et al.  Carbon-11 pb-12: an attempt to visualize the dopamine d(4) receptor in the primate brain with positron emission tomography. , 2000, Nuclear medicine and biology.

[30]  H. V. Van Tol,et al.  The dopamine D(4) receptor: one decade of research. , 2000, European journal of pharmacology.

[31]  A. IJzerman,et al.  Inverse agonism at G protein‐coupled receptors: (patho)physiological relevance and implications for drug discovery , 2000, British journal of pharmacology.

[32]  F. Fazio,et al.  Synthesis and in vivo evaluation of 3-[11C]methyl-(3-methoxy-naphthalen)-2-yl-(1-benzyl-piperidin)-4-yl-acetate (SB-235753), as a putative Dopamine D4 receptors antagonist for PET , 2000 .

[33]  P. Gmeiner,et al.  Conjugated enynes as nonaromatic catechol bioisosteres: synthesis, binding experiments, and computational studies of novel dopamine receptor agonists recognizing preferentially the D(3) subtype. , 2000, Journal of medicinal chemistry.

[34]  M. Low,et al.  Quantitative analysis of the dopamine D4 receptor in the mouse brain , 2000, Journal of neuroscience research.

[35]  F. Tarazi,et al.  Effects of alkylating agents on dopamine D3 receptors in rat brain: selective protection by dopamine , 1999, Brain Research.

[36]  B. Sommer,et al.  NGD 94-1 as an agonist at human recombinant dopamine D4.4 receptors expressed in HEK293 cells. , 1999, European journal of pharmacology.

[37]  P. Gmeiner,et al.  Azaindole derivatives with high affinity for the dopamine D4 receptor: synthesis, ligand binding studies and comparison of molecular electrostatic potential maps. , 1999, Bioorganic & medicinal chemistry letters.

[38]  A. Rivera,et al.  Differential regional and cellular distribution of dopamine D2‐like receptors: An immunocytochemical study of subtype‐specific antibodies in rat and human brain , 1998, The Journal of comparative neurology.

[39]  Hans Herzog,et al.  Imaging dopamine D4 receptors in the living primate brain: A positron emission tomography study using the novel D1/ D4 antagonist [11C]SDZ GLC 756 , 1998, Synapse.

[40]  F. Tarazi,et al.  Regional distribution of dopamine D4 receptors in rat forebrain , 1997, Neuroreport.

[41]  J. Tallman,et al.  I. NGD 94-1: identification of a novel, high-affinity antagonist at the human dopamine D4 receptor. , 1997, The Journal of pharmacology and experimental therapeutics.

[42]  J. Tallman,et al.  II. Localization and characterization of dopamine D4 binding sites in rat and human brain by use of the novel, D4 receptor-selective ligand [3H]NGD 94-1. , 1997, The Journal of pharmacology and experimental therapeutics.

[43]  M. Antonelli,et al.  Autoradiographic Localization of the Putative D4 Dopamine Receptor in Rat Brain , 1997, Neurochemical Research.

[44]  E. Malchiodi,et al.  Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. , 1997, Brain research. Molecular brain research.

[45]  D. Sibley,et al.  Cellular distribution of the rat D4 dopamine receptor protein in the CNS using anti-receptor antisera , 1997, Brain Research.

[46]  H. V. Van Tol,et al.  Modulation of Intracellular Cyclic AMP Levels by Different Human Dopamine D4 Receptor Variants , 1995, Journal of neurochemistry.

[47]  P. Sokoloff,et al.  Novel dopamine receptors half a decade later. , 1995, Trends in pharmacological sciences.

[48]  P. Seeman,et al.  Dopamine D4 receptors elevated in schizophrenia , 1993, Nature.

[49]  T. Biden,et al.  Structural subtypes of the dopamine D2 receptor are functionally distinct: expression of the cloned D2A and D2B subtypes in a heterologous cell line. , 1992, Molecular Endocrinology.

[50]  Philip Seeman,et al.  Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine , 1991, Nature.

[51]  Bruno Giros,et al.  Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics , 1990, Nature.

[52]  H. Coenen,et al.  The N.C.A. nucleophilic 18F‐fluorination of 1,N‐disubstituted alkanes as fluoroalkylation agents , 1987 .

[53]  K. Hamacher,et al.  Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. , 1986, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[54]  Y. Cheng,et al.  Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. , 1973, Biochemical pharmacology.

[55]  R. Tietze,et al.  Syntheses and radiofluorination of two derivatives of 5‐cyano‐indole as selective ligands for the dopamine subtype‐4 receptor , 2006 .

[56]  P. Gmeiner,et al.  Tissue distribution of radioiodinated FAUC113 , 2006, Nuklearmedizin.

[57]  K. Neve,et al.  Dopamine Receptors , 2008 .

[58]  M. E. Lajiness,et al.  Activation of heterologously expressed D3 dopamine receptors: comparison with D2 dopamine receptors. , 1994, Molecular pharmacology.

[59]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .