USOO5853696A United States Patent (19) 11 Patent Number: 5,853,696 Elmaleh et al. (45) Date of Patent: Dec. 29, 1998 54 SUBSTITUTED 2-CARBOXYALKYL-3 Carroll et al., “Synthesis, Ligand Binding, QSAR, and (FLUOROPHENYL)-8-(3-HALOPROPEN-2- CoMFA Study . , Journal of Medicinal Chemistry YL) NORTROPANES AND THEIR USE AS 34:2719-2725, 1991. IMAGING AGENTS FOR Madras et al., “N-Modified Fluorophenyltropane Analogs. NEURODEGENERATIVE DISORDERS ... ", Pharmcology, Biochemistry & Behavior 35:949–953, 1990. 75 Inventors: David R. Elmaleh; Bertha K. Madras, Milius et al., “Synthesis and Receptor Binding of N-Sub both of Newton; Peter Meltzer, stituted Tropane Derivatives . , Journal of Medicinal Lexington; Robert N. Hanson, Newton, Chemistry 34:1728-1731, 1991. all of Mass. Boja et al. “New, Potent Cocaine Analogs: Ligand Binding 73 Assignees: Organix, Inc., Woburn; The General and Transport Studies in Rat Striatum' European J. of Hospital Corporation, Boston; The Pharmacology, 184:329–332 (1990). President and Fellows of Harvard Brownell et al. *Use of C-11 College, Cambridge; Northeastern 2B-Carbomethoxy-3B-4-Fluorophenyl Tropane (C-11 University, Boston, all of Mass. CFT) in Studying Dopamine Fiber Loss in a Primate Model of Parkinsonism” J. Nuclear Med. Abs., 33:946 (1992). 21 Appl. No.: 605,332 Canfield et al. “Autoradiographic Localization of Cocaine Binding Sites by HICFT (I HIWIN 35,428) in the 22 Filed: Feb. 20, 1996 Monkey Brain” Synapse, 6:189-195 (1990). Carroll et al. “Probes for the Cocaine Receptor. Potentially Related U.S. Application Data Irreversible Ligands for the Dopamine Transporter” J. Med. 62 Division of Ser. No. 142.584, Oct. 25, 1993, Pat. No. Chem., 35:1813–1817 (1992). 5,493,026. Carroll et al. “Cocaine Receptor: Biochemical Characteriza tion and Structure-Activity Relationships of Cocaine Ana (51) Int. Cl." ..................................................... A61K 51/04 logues at the Dopamine Transporter” J. Med. Chem., 52 U.S. Cl. .......................................... 424/1.85; 424/1.89 35:969–981 (1992). 58 Field of Search .................................. 424/1.85, 1.89, Carroll et al. “Synthesis, Ligand Binding, QSAR, and 424/1.65; 546/132; 514/304 COMFA Study of 3.3-(p-Substituted phenyl)tropane-2B-carboxylic Acid Methyl Esters' J. Med. 56 References Cited Chem., 34:2719–2725 (1991). U.S. PATENT DOCUMENTS (List continued on next page.) 3,452,029 6/1969 Childress et al. ....................... 260/292 5,128,118 7/1992 Carroll et al. ... ... 424/1.1 Primary Examiner John Kight 5,268,480 12/1993 Kozikowski .............................. 546/23 Assistant Examiner-Lara Chapman Kelley 5,310,912 5/1994 Neumeyer et al. .. ... 546/132 Attorney, Agent, or Firm Fish & Richardson P.C. 5,413,779 5/1995 Kuhar et al. ............. ... 424/1.85 5,439,666 8/1995 Neumeyer et al. ...... ... 424/1.85 57 ABSTRACT 5,493,026 2/1996 Elmaleh et al. ..... ... 346/132 5,496,953 3/1996 Kuhar et al. ............................ 54.6/125 Disclosed are certain cocaine analogs useful for imaging of cocaine receptors and dopamine receptors. Also disclosed OTHER PUBLICATIONS are analogs useful for imaging diagnostics for Parkinson's Abstract #275, “Radioiodinated 2beta-Carbomethoxy disease. 3beta (4-Chlorophenyl)-8-(3E-and 3Z-Iodopropen-2-yl) Nortropanes”, Journal of Nuclear Medicine 33:890, 1992. 4 Claims, 3 Drawing Sheets H YN (Bu)3Sn COOCH3 YTN ci Y COOCH3 --al-e- F 7.1% F 5 6 NS 87% Atropane 5,853,696 Page 2 OTHER PUBLICATIONS Milius et al. “Synthesis and Receptor Binding of N-Substi tuted Tropane Derivatives. High-Affinity Ligands for the Elmaleh et al. “PET Imaging Probes for the Cocaine Recep tors: A Validation Study in a Nonhuman Primate Model” J. Cocaine Receptor" J. Med. Chem., 34:1728-1731 (1991). Nuclear Med. Abs., 33:946 (1992). Reith et al. “Radiolabeling of Dopamine Uptake Sites in Goodman et al. "Radioiodinated Mouse Striatum: Comparison of Binding Sites for Cocaine, 2B-Carbomethoxy-3?-(4-Chlorophenyl)-8-(3E-and MaZindol, and GBR 12935” Arch. of Pharmacol., 3Z-Iodopropen-2-YL)Nortropanes: Synthesis of Potential 345:309-318 (1992). Radioligands for Mapping Cocaine Receptor...' J. Nuclear Reith et al. “Structural Requirements for Cocaine Congeners Med. Abs., 33:890 (1992). to Interact with Dopamine and Serotonin Uptake Sites in Kaufman et al. “Severe Depletion of Cocaine Recognition Mouse Brain and to Induce Sterotyped Behavior Biochem. Sites Associated With the Dopamine Transporter in Pharmacol., 35:1123–1129 (1986). Parkinson’s-Diseased Striatum' Synapse, 9:43–49 (1991). Isacson, “Clinical and Preclinical PET Correlates of Parkin Madras “' C-WIN35,428 for Detecting Dopamine Deple sonism with '' C-Win 35,428” Annals of Neurology, tion in Mild Parkinson's Disease' Annals of Neuro., 35:377-378 (1994). 35;376-379 (1994). Meyer et al. “Intravenously Administered Dopamine Trans Madras et al. “N-Modified Fluorophenyltropane Analogs of porter Site Radioligand Is Not Significantly Retained in Cocaine With High Affinity for Cocaine Receptors' Phar Mouse Substantia Nigra or Other Sites Outside of Basal macol. Biochem. & Behav., 35:949–953 (1990). Ganglia.” Annals of Neurology, 35:378-379 (1994). Meltzer et al. “Substituted 3-Phenyltropane Analogs of Van der Zee et al., “A comparison of the inhibitory effects of Cocaine: Synthesis, Inhibition of Binding at Cocaine Rec aromatic Substituted benzhydryl . into Synaptosomal ognition Sites, and Positron Emission Tomography Imag preparations of the rat brain”, Neuropharmacology, 17(7), ing” J. Med. Chem., 36:855–862 (1993). 483-90, 1978. U.S. Patent Dec. 29, 1998 Sheet 2 of 3 5,853,696 U.S. Patent Dec. 29, 1998 Sheet 3 of 3 5,853,696 SIN %/8 5,853,696 1 2 SUBSTITUTED 2-CARBOXYALKYL-3 ('I-iodopropene-2yl) nortropane. The selectivity of this (FLUOROPHENYL)-8-(3-HALOPROPEN-2- analog for the dopamine over the Serotonin transporter is not YL) NORTROPANES AND THEIR USE AS discussed. IMAGINGAGENTS FOR CFT or WIN 35,428 is approximately 15 times more NEURODEGENERATIVE DISORDERS Selective for the dopamine over the Serotonin transporter. The 4-chloro analog is 4-fold selective. See Carroll et al., J. This is a divisional of application Ser. No. 08/142.584, Med. Chem. 35:969 (1992); and Meltzer et al., J. Med. filed Oct. 25, 1993, now U.S. Pat. No. 5,493,026. Chem. 36:855–862 (1993). SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION 1O We have discovered that fluorination of the phenyl Sub Stituent of N-haloallyl phenyl nortropanes yields compounds The invention relates to Substituted nortropanes and their that are unusually effective for several purposes. The 3E and use to image: a) dopamine-transporter-containing neurons, 3Z isomers of 2-f-carbomethoxy-3-3-(4-fluorophenyl)-8- particularly in connection with diagnosis and Study of cer (3-I-iodopropen-2-yl) nortropane are particularly preferred. tain neurodegenerative disorders; and b) cocaine receptors. 15 We have designated this preferred compound Iodoaltropane There is a need for diagnostic agents and markers of or IACFT. Most preferably, the compounds according to the neurogenerative disorderS Such as Parkinson's disease. For invention are labeled with radionuclides of the halogen example, exclusion at an early stage of Parkinson's disease series, such as 'I or 'I. as the cause of Symptoms may be useful information in The Special properties of the claimed compounds are best diagnosing other conditions. Moreover, early diagnosis of understood with the following background. Cocaine recog Parkinson's disease can facilitate the introduction of puta nition sites are localized on the dopamine transporter, which tive prophylactic drug therapy (e.g., deprenyl) prior to the itself is localized on dopamine nerve terminals. Drugs that onset of more Severe Symptoms. See, Kaufman and Madras bind to these sites therefore have potential uses which (1991) Synapse 9:43-49. Detection of nerve cell depletion in include: (i) imaging probes for neurodegenerative disorders; the presymptomatic phase in an animal model of Parkin 25 and (ii) imaging probes for dopamine transporter/cocaine Son's disease would also be useful, e.g., when using the binding Sites. model to evaluate therapies for Parkinson's disease. See, Because of the unique anatomical location of the cocaine Hantraye et al. (1992) Neuro Reports 3:265-268; and recognition Sites, a high affinity probe for imaging of these sites in vivo in the brain can be carried out using PET or Hantraye et al. (1992) Soc. Neurosci. Abstra. 18:935. SPECT imaging. Such imaging is useful for diagnosing or There is a particular need for diagnostic agents and monitoring Parkinson's disease, a neurological disorder markers of neurogenerative disorders that Selectively target characterized by the degeneration of dopamine nerve termi a dopamine transporting protein (the dopamine transporter) nals or by aging. in preference to another protein known as the Serotonin Accordingly, one aspect of the invention features a com transporter. In normal brain tissue, the dopamine:Serotonin pound of formula: transporter density ratio is approximately 10:1. In certain 35 neurodegenerative disorders, Such as Parkinson's disease, I nerve cells that produce dopamine (and on which the dopamine transporter is located) undergo Severe depletion, HC=CHCH while Serotonin nerve cells are leSS affected. The dopamine: N COR serotonin transporter ratio can fall to 50% in Parkinson's 40 disease. Various Substances (particularly cocaine and cocaine congeners) are potent inhibitors of dopamine transport in the striatum of the brain because they bind to the dopamine F transporter. The more Strongly these Substances block 45 dopamine transport, the more Strongly they bind to Sites on wherein the following condition is imposed on that formula: the dopamine transporter which have been labeled by H) R is -CH, -CH2CH (C. configuration; f configuration cocaine or by a compound known as HICFT (also known or both), -CH(CH), -(CH), CH, -(CH2)CHX, as HIWIN 35.428). See, Madras et al., (1989) J.