Neural transmitters are chemicals in the brain that are used to send messages from one brain cell to another. Neurotransmitters bind to special receptor proteins in the membrane of nerve cells, like a key in a lock, triggering a chemical reaction within the cell. Serotonin (5-HT) is one form of neural transmitter.
The serotonin system in brain is an important neurotransmission network regulating various physiological functions and behavior including anxiety and affective states. Serotonin has been linked with depression and with other psychiatric disorders such as eating disorders., alcoholism, pain, anxiety, and obsessive-compulsive behavior. One of the serotonin receptor subtypes, 5-HT.sub.1A, plays an important function as the somatodendretic autoreceptor (presynaptic) in the dorsal raphe nucleus and as a postsynaptic receptor for 5-HT in terminal field areas.
A number of agonists and antagonists for 5-HT.sub.1A receptors are reported in the literature (Hillver et al., "(S)-5-Fluoro-8-Hydroxy-2-(dipropylamino)tetralin: A Putative 5-HT.sub.1A -Receptor Antagonist [letter]" J. Med. Chem. 33: 1541-1544 (1990); Raghupathi et al., "Analogues of the 5-HT.sub.1A Serotonin Antagonist 1-(2-Methoxyphenyl)-4-[4-(2-phthalimido)butyl]Piperazine with Reduced Alpha-Adrenergic Affinity" J. Med. Chem. 34:2633-2638 (1991); Glennon et al., "Arylpiperazine Derivatives as High-Affinity 5-HT.sub.1A Serotonin Ligands" J. Med. Chem. 31:1968-1971 (1988)). Examples include 8-hydroxy-2-(N,N-di-n-propyl)aminotetralin (8-OH-DPAT), (Hoyer et al., "Molecular Pharmacology of 5-HT1 and 5-HT2 Recognition Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies with [3H]5-HT, [3H]8-OH-DPAT, (-)[125I]Iodocyanopindolol, [3H]Mesulergine and [3H]Ketanserin" Eur. J. Pharmacol. 118:13-23 (1985); Hjorth et al., "8-Hydroxy-2-(di-n-propylamino)tetralin 8-OH-DPAT, A Potent and Selective Simplified Ergot Congener with Central 5-HT Receptor Stimulating Activity" J. Neural. Transmission 55: 169-188 (1982)) (R,S)trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)]aminotetralin, ((R,S)trans-8-OH-PIPAT), (Zhuang et al., "Synthesis of (R,S)trans-8-Hydroxy-2-(N-n-propyl-N-3'-iodo-2'-propenyl aminotetraline (trans-8-OH-PIPAT): A New 5-HT.sub.1A Receptor Ligand", J. Med. Chem. 36:3161-3165 (1993)), and 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190) (Greuel et al., "The Putative 5-HT.sub.1A Receptor Antagonists NAN-190 and BMY 7378 are Partial Agonists in the Rat Dorsal Raphe Nucleus In Vitro", Eur. J. Pharmacol 211: 211-219 (1992)). NAN-190 displayed high 5-HT.sub.1A affinity (Ki=0.6 nM) and with an equal potency for the .alpha.1 receptor. Replacement of the phthalimide moiety by substituted benzamides or acyl moieties provides ligands with high binding affinity and selectivity. One such agent, 4-[4-(1-adamantanecarboxamido)-butyl]1-(2-methoxyphenyl)piperazine, was found to bind to 5-HT.sub.1A receptor with high affinity (Kd=0.4 nM) and was devoid of binding affinity to other receptors.
Recently, a new arylpiperazine derivative, N-tert-butyl-3-(4-(-2-methoxyphenyl)piperazin-1-yl)-2-phenylpropionamide, (5)-WAY 100135, was reported as a selective antagonist at both somatodendritic and postsynaptic receptor (IC.sub.50 =15 nM, rat hippocampal membranes) (Fletcher et al., "A Novel, Selective Antagonist at Presynaptic and Postsynaptic 5-HT.sub.1A Receptors", Eur. J. Pharmacol. 237:283-291 (1993); Cliffe et al., "(S)-Nj-Tert-Butyl-3-(4-(2-methoxyphenyl) - piperazin-1-yl)-2phenylpropanamide, (S)-WAY-100135: A Selective Antagonist at Presynaptic and Postsynaptic 5-HT.sub.1A Receptors", J. Med. Chem. 36: 1509-1510 (1993) Fletcher, A., et al., "Silent 5-HT.sub.1A Receptor Antagonists: Utility As Research Tools and Therapeutic Agents," TIPS 4:441-448 (1993)). A related compound, 4-(2'-methoxy-) phenyl-1-[2'-(N-2"-pyridinyl)-cyclohexylamido-]ethylpiperazine, WAY 100635, displayed even higher binding affinity (IC.sub.50 =2.2 nM, rat hippocampal membranes) with high selectivity (Cliffe et al., "The Design of Selective 5-HT.sub.1A Receptor Antagonists. 206th ACS Meeting, MEDI Abs. #30 (1990)).
It is not only desirable to find new compounds selective to 5-HT.sub.1A receptors for possible pharmacological activity; such specific ligands are desired as they may be useful for monitoring the effectiveness of drugs and substances which affect brain chemistry. For instance, it is highly desirable to be able to gauge the biochemical effects of drugs administered for blocking the patient's serotonin receptors. If too little of the drug is administered, the desired blockade does not occur, and if too much of the drug is administered, there can be severe side effects.
New and powerful imaging methods which enable one to assess the living brain in vivo and thereby monitor the effectiveness of drugs and substances that affect brain chemistry have recently been developed. Methods such as positron emission tomography (PET) and single photon emission tomography (SPECT) involve the administration to a patient of radioactive tracer substances comprising a ligand that binds to presynaptic or postsynaptic neuroreceptors in the patient's brain. Emissions (primarily gamma rays which are emitted from the positrons or photons emitted from the radioactive tracer)/are measured. These emissions are indicative of the number and degree of occupancy of blocking of the neuroreceptors. The number of neuroreceptors and the degree of occupancy or blocking is calculated utilizing a mathematical model, and compared with an intra-person or inter-person control, to determine the degree of drug.-response. Further treatment of the patient with drugs is based upon the comparisons made. For these methods to be useful, however, a ligand which has high affinity and specificity for the desired receptor is required.
There is, therefore, a clear need for potent and selective ligands for 5-HT.sub.1A receptors which ligands may not only have pharmacological activity but which can also be labelled with high specific activity to aid the progress of understanding the pharmacological function and regulation of the receptor subtype in its native state.