Patent Application: US-11027905-A

Abstract:
a novel group of apomorphine derivatives are provided that are well suited as radioimaging agents upon incorporation of radionuclides . through reaction of d ring sites , the less reactive sites of the apomorphine a ring is modified in ways previously unattainable .

Description:
the present invention has utility as therapeutic targeting dopamine receptors . the radiolabeling of an inventive compound affords a pet or spect radioimaging agent specific for detecting dopamine receptors in an individual , an organ , a cellular tissue , or an individual cell . as used herein “ individual ” is defined to include a mammalian organism specifically including a human and non - humans including chimpanzees , monkeys , cows , dogs , cats , horses , rabbits , hamsters , rats and mice . a compound ( i ) optionally is able to selectively bind to one or more subtypes of dopamine receptors , such as a d1 , d2 , d3 , d4 , or d5 dopamine receptor . for example , an apomorphine compound of the invention wherein r 1 is methyl or n - propyl can have an ability to bind to a d2 dopamine receptor . as used herein , the term “ selectively ” means that the compound binds to one or more particular dopamine receptor subtypes in preference to other dopamine receptor subtypes or unrelated molecules . it is appreciated that a compound ( i ) also functions as a dopamine receptor agonist or antagonist . a dopamine receptor agonist refers to a molecule that selectively activates or increases normal signal transduction through the dopamine receptor . a dopamine receptor antagonist refers to a compound that selectively inhibits or decreases normal signal transduction through the dopamine receptor . for diagnostic applications , a dopamine receptor agonist of the invention preferably has an ec 50 , and a dopamine receptor antagonist of the invention preferably has an ic 50 , of less than about 10 − 7 m , such as less than 10 − 8 m , and more preferably less than 10 − 9 m . however , depending on the stability , selectivity and toxicity of the compound , a dopamine receptor agonist with a higher ec 50 , or a dopamine receptor antagonist with a higher ic 50 , can also be useful diagnostically . a compound of the invention that contains a radioisotopic label can be used in a variety of experimental and diagnostic applications for visualizing dopamine receptors present on a cell , including a subcellular location ; a tissue ; an organ , or an organism . such applications include both in vitro and in vivo methods . as an example of an in vitro application , a radioisotopically labeled compound of the invention can be contacted with cultured neurons to assess binding of a dopamine receptor ligand to dopamine receptor - expressing neurons . as an example of an in vivo application , a radioisotopically labeled compound of the invention can be administered to an individual in order to assess the distribution of dopamine receptor - expressing neurons in a tissue . other exemplary in vivo applications include assessing the level of dopamine receptor - expressing neurons in a particular tissue or organ ; assessing occupancy of dopamine receptors in a particular tissue or organ , for example , in the presence of another drug ; assessing subcellular localization of dopamine receptors ; and assessing the distribution of dopamine receptors or dopamine receptor - expressing neurons in a particular tissue , organ or organism . such assessments can be used for revealing suitability of a particular therapeutic drug based on dopamine receptor amount or distribution ; for providing parameters for optimizing therapeutic effects or minimizing side effects ; for validating animal models for human conditions ; for determining species differences , and for comparing functional effects of various drugs . where r 1 is h , c 1 - c 30 alkyl , or c 1 - c 30 alkyl having a substituent of c 6 - c 18 aryl , or a heteroatom containing group where the heteroatom is oxygen . nitrogen , or sulfur ; r 2 is h , x , or sn ( c 1 - c 6 alkyl ) 3 ; x is f , cl , br , or i ; r 3 is h , x or sn ( c 1 - c 6 alkyl ) 3 ; r 4 , r 5 and r 6 are each independently h , nitro , amino , hydroxyl , x , c 1 - c 30 alkyl having a substituent of c 6 - c 18 aryl , or a heteroatom containing group where the heteroatom is oxygen , nitrogen , or sulfur ; or sn ( c 1 - c 6 alkyl ) 3 with the proviso that at least one of r 4 , r 5 and r 6 is nitro , amino , hydroxyl , x or sn ( c 1 - c 6 alkyl ) 3 ; and when r 5 is nh 2 , oh or x ; r 4 is h ; and r 6 is h ; then at least one of r 2 and r 3 is x ; r 7 and r 6 are each independently h , c 1 - c 6 alkyl group , or a c 0 - c 6 alkyl group having a substituent of c 6 - c 18 aryl , or a heteroatom containing group where the heteroatom is oxygen , nitrogen , or sulfur ; where r 7 and r 8 are optionally fused to form a ring structure , the ring structure optionally having a heteroatom therein and optionally having pendent groups therefrom , the pendent groups are each independently h , c 1 - c 8 alkyl , or a c 0 - c 8 alkyl group having a substituent of hydroxyl , amine , sulfonate , thiol , carboxyl , substituted amine and quaternary amine . it is noted that iupac positions correspond with variable r groups used herein as follows : preferably , r 1 is a c 1 - c 4 alkyl group . more preferably , r 1 is a linear alkyl group . most preferably , r 1 is methyl or n - propyl . it is appreciated that a transport or solubility modifying moiety is readily incorporated into r 1 . illustrative modifying moieties include amino acids , dipeptides , sulfonates , amines , and carboxyls . it is appreciated that a radiolabel is also optionally incorporated into r 1 . optionally , r 1 also includes an unsaturated carbon - carbon bond in the form of an alkenyl , alkynyl or aryl . heteroatom containing groups operative herein as substituents of r 1 illustratively include ( och 2 ch 2 ) n or ( och 2 ch 2 ch 2 ) n , where n has a value such that there are thirty or less carbon atoms in the alkyl group of r . similar compounds having alkyl groups containing a nitrogen or sulfur atom are also encompassed by the present invention . a compound ( i ) is operative as a radioimaging agent through radioisotope labeling . considerable modification is possible when a precursor compound has r 2 and r 3 that are both bromine , both iodine , or mixed with one of r 2 or r 3 being bromine and the other being iodine . such a compound ( i ) is characterized as having a blocked “ d ring ,” and is suitable starting material for preparing an apomorphine compound having a modified “ a ring ” or modified a and d rings . alternatively , a and d rings of a compound ( i ) are made susceptible to labeling with a halogen isotope ; an example of such compound has at least one of r 4 , r 5 , or r 6 being amine or hydroxyl . in a particular compound , r 4 and r 6 are both amine , both hydroxyl , or mixed with one of r 4 and r 6 being amine and the other being hydroxyl . in still another preferred compound amenable to both a and d ring labeling , at least one of r 4 , r 5 , or r 6 is amine or hydroxyl . in other embodiments , at least one of r 4 , r 5 , or r 6 is x . as an example , both r 4 and r 6 are x in a specific compound . the x is selected from fluorine , chlorine , bromine and iodine . optionally the halogen is a radioisotope . halogen isotopes operative herein include 18 f , 75 br , 76 br , 77 br , 78 br , 121 i , 122 i , 123 i , 124 i , 126 i and 128 i . selection of a particular radioisotope for inclusion in a compound of the invention can depend , for example , on the specifics of the pet or spect used to detect or monitor the compound in vivo or in vitro . in further embodiments , r 2 and r 3 are each independently halogens . for example , r 2 and r 3 can be each independently bromine or iodine , including compounds where r 2 and r 3 are both bromine , and where r 2 and r 3 are iodine . in a particular compound , r 2 and r 3 are both hydrogen . additionally , it is appreciated that one of r 2 or r 3 is readily x while the other is hydrogen . an inventive compound ( i ) can be a radiolabeled apomorphine compound containing a detectable moiety , such as a radioisotope . specific examples of such compounds include those having halogen isotopes at r 2 , r 3 , and r 4 ; r 2 , r 3 and r 5 ; r 2 , r 3 and r 6 ; and r 2 , r 3 , r 4 and r 6 . the invention illustratively includes the following compounds . it is appreciated that each instance of 18 f in each of the following compounds is readily replaced with another halogen . exemplary specific inventive compounds illustratively include : ( r )-(−)- 1 - amino - 2 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 1 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 3 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 1 , 3 , 8 , 9 - tetra [ 18 f ] fluoroapomorphine ; ( r )-(−)- 3 - amino - 2 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 1 - amino - 2 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 1 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 3 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 1 , 3 , 8 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 3 - amino - 2 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 1 - amino - 2 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 1 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 3 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - amino - 1 , 3 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 3 - amino - 2 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 1 - hydroxy - 2 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 3 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 3 , 8 , 9 - tetra [ 18 f ] fluoroapomorphine ; ( r )-(−)- 3 - hydroxy - 2 , 8 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 1 - hydroxy - 2 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 3 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 3 , 8 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 3 - hydroxy - 2 , 8 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 1 - hydroxy - 2 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 3 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 3 , 9 - tri [ 18 f ] fluoroapomorphine ; ( r )-(−)- 3 - hydroxy - 2 , 9 - di [ 18 f ] fluoroapomorphine ; ( r )-(−)- 1 - amino - 2 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 1 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 3 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 1 , 3 , 8 , 9 - tetra [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 3 - amino - 2 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 1 - amino - 2 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 1 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 3 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 1 , 3 , 8 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 3 - amino - 2 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 1 - amino - 2 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 1 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 3 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - amino - 1 , 3 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 3 - amino - 2 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 1 - hydroxy - 2 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 3 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 3 , 8 , 9 - tetra [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 3 - hydroxy - 2 , 8 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 1 - hydroxy - 2 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 3 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 3 , 8 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 3 - hydroxy - 2 , 8 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 1 - hydroxy - 2 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 3 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 2 - hydroxy - 1 , 3 , 9 - tri [ 18 f ] fluoro - n - n - propylnorapomorphine ; ( r )-(−)- 3 - hydroxy - 2 , 9 - di [ 18 f ] fluoro - n - n - propylnorapomorphine ; (( r )-(−)- 1 - aminoapomorphine ; ( r )-(−)- 3 - aminoapomorphine ; ( r )-(−)- 1 , 3 - diaminoapomorphine ; ( r )-(−)- 1 - hydroxyapomorphine ; ( r )-(−)- 3 - hydroxyapomorphine ; ( r )-(−)- 1 , 3 - diydroxyapomorphine ; ( r )-(−)- 1 - amino - n - n - propylnorapomorphine ; ( r )-(−)- 3 - amino - n - n - propylnorapomorphine ; ( r )-(−)- 1 , 3 - diamino - n - n - propylnorapomorphine ; ( r )-(−)- 1 - hydroxy - n - n - propylnorapomorphine ; ( r )-(−)- 3 - hydroxy - n - n - propylnorapomorphine ; ( r )-(−)- 1 , 3 - dihydroxy - n - n - propylnorapomorphine . the present invention provides a method for detecting dopamine receptors in a cell , tissue , organ or body of an individual . the process involves ( a ) administering an effective amount of a compound of the invention to the individual , where the compound is radioisotopically labeled in at least one of r 1 - r 8 , and ( b ) detecting radioisotopic signal associated with the compound , wherein the signal corresponds to a dopamine receptor amount or distribution in the individual , or a cell , tissue or organ of the individual . it is appreciated that a signal is collected at regular intervals after administration to measure the kinetics of dopamine receptor association by an inventive compound ( i ) or alternatively , collected after a single time known to provide suitable receptor association . a radioisotopically labeled compound ( i ) is also operative to determine how an unlabeled drug affects selective dopamine receptor binding in a cell , tissue or organ by indicating how dopamine receptor occupancy is modified by the drug . an advantage of this approach is that dopamine receptor binding of a drug candidate is determined when the candidate that is not suitable for imaging , for example , due to low binding affinity , lack of selectivity or lack of a chemical structure that facilitates rapid labeling with a radioisotope . optionally , a clinically relevant dose of such a drug is administered prior to , concurrent with , or subsequent to the compound ( i ). screening of a drug candidate or competitive binding of a drug is assessed relative to compound ( i ) dopamine receptor occupancy in a cell , tissue , organ or body of an individual . the process involves ( a ) administering an effective amount of a radiolabeled compound ( i ) and a drug to an individual , tissue , organ or cell , and ( b ) detecting a radioisotopic signal associated with the compound ( i ), where the signal corresponds to a dopamine receptor amount or distribution . the inventive process involves detecting a radioisotopic signal associated with a compound ( i ). a variety of methods for qualitatively and quantitatively detecting radioisotopes are known in the art and include , for example , imaging methods such as pet or spect ( 24 - 26 ). in an embodiment , a compound of the invention can bind selectively to one or more dopamine receptor subtypes . to determine whether a drug of interest binds to a dopamine receptor subtype to which a particular compound of the invention binds , a variety of competition assays can be performed . well known formats for competitive ligand binding assays for drug - ligand interactions include pretreatment and displacement assays , both of which are readily performed using imaging methods such as pet or spect . a pretreatment assay involves determining radioisotopic signals associated with the radioisotopically labeled compound in the absence and presence of drug . if dopamine receptors are blocked by a drug administered prior to administration of the radioisotopically labeled compound , the compound cannot bind to the receptors , resulting in a radioisotopic signal that is reduced or ameliorated compared to the baseline signal . a displacement assay involves determining a baseline radioisotopic signal associated with a radioisotopically labeled compound , and then adding a relatively large amount of unlabeled drug to the dopamine receptors . if the administered drug binds to the same receptors , the radioisotopically labeled compound is displaced , at least in part , from dopamine receptors due to competition for dopamine receptor binding sites . an inventive displacement assay process for detecting dopamine receptors involves administering a compound ( i ) prior to administration of a drug . an inventive pretreatment assay process for detecting dopamine receptors involves administering a compound ( i ) after administration of a drug . the present invention provides a method for diagnosing a neurological disorder . the invention involves ( a ) administering an effective amount of a compound ( i ) to an individual having or suspected of having a neurological disorder , wherein the compound is radioisotopically labeled on at least one of r 1 - r 8 ; ( b ) detecting a radioisotopic signal associated with the compound ( i ), where the signal corresponds to a dopamine receptor amount or distribution , and ( c ) comparing the amount or distribution of dopamine receptor present with a control signal for a known neurological state . a disorder that can be diagnosed using a method of the invention is one in which the amount or distribution of dopamine receptors correlates with the presence or absence of the disorder . a variety of physiological systems involve dopamine receptor activity that can affect neurological and non - neurological functions of an individual . exemplary central nervous system disorders involving dopamine receptor activity include schizophrenia , depression , parkinson &# 39 ; s disease , huntington &# 39 ; s chorea , alzheimer &# 39 ; s disease , tardive dyskinesia , phobia disorder , addiction , anxiety disorder , epilepsy , attention deficit disorder and obsessive - compulsive disorder . exemplary peripheral nervous system disorders involving dopamine receptor activity include gastric and duodenal ulceration and disorders of gastrointestinal motility , gastric mucosal blood flow and gastric acid secretion , and erectile dysfunction . these and other dopamine receptor - related disorders are well known to those skilled in the art . therefore , the skilled clinician will be able to select an individual appropriate for receiving a diagnostic or prognostic method of the invention . the invention provides a method for determining a course of treatment for an individual having a neurological disorder . the method involves ( a ) administering an effective amount of a compound ( i ) to an individual undergoing medical treatment for the neurological disorder , wherein the compound ( i ) is radioisotopically labeled on at least one of r 1 - r 8 ; ( b ) detecting a radioisotopic signal associated with the compound ( i ), where the signal corresponds to a dopamine receptor amount or distribution ; ( c ) comparing the amount or distribution of dopamine receptor present in the individual with a control signal indicative of the effectiveness of the medical treatment . the dosage for an inventive composition is an effective amount of active agent and varies depending upon known factors such as the pharmacodynamic characteristics of the particular active ingredient and its mode and route of administration ; age , sex , health and weight of the recipient ; nature and extent of symptoms ; kind of concurrent treatment , frequency of treatment and the effect desired . a typical dosage of active agent is from 1 to 400 milligrams per kilogram of body weight . dosage forms suitable for internal administration contain from about 1 . 0 to about 500 milligrams of active ingredient per unit . in these pharmaceutical compositions , the active ingredient is typically present from 0 . 05 - 95 % by weight based on the total weight of the dose . administration may be by any means suitable for the condition to be treated and may include , for example , oral administration . for example , oral administration is optionally accomplished using solid dosage forms such as capsules , tablets and powders , or in liquid dosage forms such as elixirs , syrups , emulsions and suspensions . the inventive composition is , for example , parenterally administered by injection , rapid infusion , nasopharyngeal adsorption , or dermoabsorption . the inventive composition also is optionally administered intramuscularly , intravenously , intrathecally or as a suppository . gelatin capsules may contain inventive composition and powdered carriers such as lactose , sucrose , mannitol , starch , cellulose derivatives , magnesium stearate , stearic acid , and the like . similar diluents can be used to make compressed tablets . both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours . compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere , or enteric coated for selective disintegration in the gastrointestinal tract . liquid dosage forms for oral administration optionally contain coloring and flavoring to increase patient acceptance . in general , water , a suitable oil , saline , aqueous dextrose , and related sugar solutions and glycols are suitable carriers for parenteral solutions . solutions for parenteral administration may contain suitable stabilizing agents and , if necessary , buffer substances . antioxidizing agents such as sodium bisulfate , sodium sulfite or ascorbic acid either alone or combined are suitable stabilizing agents . citric acid and its salts and sodium edta are also operative herein as stabilizing agents . in addition , parenteral solutions optionally contain preservatives such as benzalkonium chloride , methyl - or propyl - paraben and chlorobutanol . suitable pharmaceutical carriers are described in remington &# 39 ; s pharmaceutical sciences , 20th edition are operative herein . additionally , standard pharmaceutical methods can be employed to control the duration of action . these illustratively include control release preparations and can include appropriate macromolecules , for example polymers , polyesters , polyaminoacids , polyvinylpyrrolidone , ethylenevinylacetate , methyl cellulose , carboxymethyl cellulose or protamine sulfate . the concentration of macromolecules as well as the methods of incorporation can be adjusted in order to control release . additionally , the inventive composition can be incorporated into particles of polymeric materials such as polyesters , polyaminoacids , hydrogels , poly ( lactic acid ) or ethylenevinylacetate copolymers . in addition to being incorporated , the inventive composition optionally is also used to trap the compound in microcapsules . suitable exemplary dosage forms for administration of the inventive composition follow . capsules are prepared by filling standard two - piece hard gelatin capsulates each with 100 milligram of powdered active ingredient , 175 milligrams of lactose , 24 milligrams of talc and 6 milligrams magnesium stearate . a soft gelatin capsule includes mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient . the capsules are then washed and dried . tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient . 0 . 2 milligrams of colloidal silicon dioxide , 5 milligrams of magnesium stearate , 275 milligrams of microcrystalline cellulose , 11 milligrams of cornstarch and 98 . 8 milligrams of lactose . appropriate coatings may be applied to increase palatability or to delay absorption . a parenteral inventive composition suitable for administration by injection is prepared by stirring 1 . 5 % by weight of active ingredients in 10 % by volume propylene glycol and water . the solution is made isotonic with sodium chloride and sterilized . an aqueous suspension of an inventive composition is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient , 200 milligrams of sodium carboxymethyl cellulose , 5 milligrams of sodium benzoate , 1 . 0 grams of sorbitol solution u . s . p . and 0 . 025 milligrams of vanillin . as an encapsulated particulate , active particles of an inventive composition are prepared from a polymer using a coacervation method , with a particle size is between about 5 nm and 750 microns , more preferably between about 10 nm and 500 microns and most preferably between about 50 nm and 800 nm . an inventive composition is complexed to the particles using various methods known to those skilled in the art . a general method for preparation of such particles is detailed in u . s . ser . no . 2003 / 0181367 a1 . the term “ effective amount ” when used in reference to a compound of the invention means that amount necessary or sufficient to render detectable a cell , tissue or organ that expresses a dopamine receptor . the effective amount varies depending on considerations illustratively including the targeted cell , tissue or organ , the particular compound being administered , the type of individual treated , including considerations of weight , sex , and age . those skilled in the art can empirically determine the effective amount of a particular compound alone or in conjunction with another agent that allows detection of a selected cell , organ or tissue . where r 1 is h , c 1 - c 30 alkyl , c 1 - c 30 alkyl having a substituent selected from the group consisting of : c 6 - c 18 aryl , or a heteroatom containing where the heteroatom is oxygen , nitrogen , or sulfur ; r 12 and r 13 are each h or x and at least one of r 12 and r 13 is h ; x is f , cl , br or i ; where r 7 and r 8 are optionally fused to form a ring structure , the ring structure optionally having a heteroatom therein and optionally having pendent groups therefrom , the pendent groups each independently selected from h , c 1 - c 8 alkyl , and a c 0 - c 8 alkyl group having a substituent selected from a group consisting of hydroxyl , amine , sulfonate , thiol , carboxyl , substituted amine and quaternary amine ; r 14 , r 15 , and r 16 are each independently h , nitro , amino , hydroxyl and x . a particularly preferred starting compound ii has r 12 - r 16 all being hydrogen and corresponds to ( r )-(−)- apomorphine . the two phenyl rings ( a and d ) of the general structure ii above differ markedly in chemical activation . it has been demonstrated for ( r )-(−)- apomorphine ( r 1 = methyl ) that the d phenyl ring r 12 and r 13 positions can be specifically brominated under mild conditions ( 2 ). this exclusive activation allows other similar halogenations including the selective fluorination , bromination and iodination of the d ring r 12 and / or r 13 positions of general structure ii for any r 1 group by standard methods using elemental fluorine , bromine and iodine respectively . the activation of the d ring allows the preparation of pet and spect ligands labeled in the r 12 and / or r 13 positions with such isotopes as 18 f , 76 br , 123 i or 124 i . 18 f inventive compounds i are directly labeled in the d ring r 2 and / or r 3 positions with this isotope using 18 f 2 ( 27 , 28 ) or by means of xe 18 f 2 ( 29 ). aromatic bromides ( 30 ) and iodides ( 31 ) are transformed into aromatic trialkyl tin ( stannyl ) derivatives via palladium catalysts . as a result a stannyl group or groups replace d ring r 12 and / or r 13 of general structure ii . such d ring stannyl derivatives of general structure i represent precursors to d ring r 2 and / or r 3 position 18 f analogues of inventive compound i using 18 f 2 ( 32 ). alternatively , 18 f analogs of general structure i are obtained by 18 f exchange with stable isotope 19 f , r 2 and / or r 3 groups ( 33 ). bromine radiolabeled compound i is directly labeled in the d ring r 12 or r 13 positions of structure ii ( 34 ). alternatively , the stannyl analogs represent a precursor for 76 br introduction at r 2 and / or r 3 ( 30 ). it is appreciated that 75 br and 77 br are also introduced in this way and likewise operative in pet and spect . in principle , these procedures should also be capable of labeling the d ring r 2 and / or r 3 positions of general structure i with any other useful pet or spect isotope of bromine including 75 br and 77 br . for 123 i or 124 i , general structure ii is directly labeled in the d ring r 12 and / or r 13 positions with either isotope by analogy with the method of devos and co - workers ( 35 ). alternatively , utilizing the stannyl analogues of general structure i , 123 i and 124 i are introduced into the d ring r 2 and / or r 3 according to the methods of john and co - workers ( 36 ) and koziorowski and co - workers ( 37 ) respectively . it is appreciated that the use of excess halogenation reagent , more than an equivalent per equivalent per d ring hydrogen of general structures i or ii , promotes labeling in both the r 2 and r 3 , and r 12 and r 13 positions , respectively . use of an equivalent or less of halogenation reagent relative to d ring hydrogen produce a mixture of r 2 and r 3 substituted halogen analogs . all d ring 8 and 9 position mono - and di - substituted halogen analogs so produced are resolved by standard hplc procedures . in order to modify the a ring of structure ii , the more active d ring is first halogenated as detailed above . with precursor sites r 12 and r 13 of structure ii blocked with halogens , x , the resulting compound is amenable to direct halogenation with isoptically natural dihalogen gases or isotopically enriched gases to produce a mixture of a ring mono -, di - and tri - halo compounds at r 4 , r 5 , and r 6 ( 38 ). specifically , addition of 18 f to the a ring creates compounds well suited as pet and spect imaging agents . the resulting compounds are optionally catalytically hydrogenated to preferentially remove the d ring halogens to produce various a ring mono -, di - and tri - halo compounds at r 4 , r 5 , and r 6 with the substitution pattern in the a ring as any possible combination of a ring positional isomers and lacking a halogen in the d ring . the a ring isotopically - unenriched halogenated compounds of formula i also serve as precursors to the corresponding radioisotope analogues by means of exchange ( 33 ). while isotopically enriched analogues of formula i would be valuable as a mixture , resolution from one another is exacted by standard hplc purification procedures . upon halogenating the d ring of general structure i various activated a ring amino , hydroxyl and combinations thereof are formed with such moieties at r 4 and / or r 5 and / or r 6 by means of the following sequence : following the halogenation of r 12 and r 13 of structure ii , the a ring is directly nitrated ( 39 ). the stoichiometry and experimental details of these nitrations are manipulated to provide a mixture of various a ring mono - and di - substituted nitro analogs of structure i with the nitro substitution pattern in the a ring as any possible combination of r 4 , r 5 , and r 6 positional isomers . due to the ring deactivating effect of the nitro groups , trinitro substitution on the a ring of these intermediates is rarely observed . the a ring mono - or di - substituted nitro analogs are then selectively reduced with stannous chloride ( 40 ) or some other nitroselective reducing reagent to yield various a ring mono - and di - substituted amine analogs with the amine substitution pattern in the a ring as any possible combination of r 4 , r 5 , and r 6 positional isomers . these mono - and di - substituted amine analogs are optionally converted to the corresponding intermediate a ring mono and di - substituted hydroxyl analogues by nitrosation / hydrolysis ( 39 ). in the case of a di - amino or di - hydroxyl compound of structure i , it is appreciated that protecting groups are readily employed to allow for the subsequent reaction of the non - protected group . selective protection occurs through control of protecting group stoichiometry relative to the number of protectable moieties per compound of structure i . in this way , an a ring having a multiple non - hydrogen moieties is produced . as detailed above , isomers are resolved by standard hplc purification procedures . an inventive compound of structure i containing amino and or hydroxyl groups is converted to pet and spect radioligands labeled with 18 f in the unsubstituted positions of the a ring . the amino and / or hydroxyl containing a ring compound is directly labeled in the unsubstituted a ring positions with 18 f 2 ( 27 , 28 ) or by means of xe 18 f 2 ( 29 ). alternatively , the amino and / or hydroxyl containing a ring compound is fluorinated in the unsubstituted a ring positions and these fluoro analogs serve as i precursors to 18 f analogs by 18 f exchange ( 33 ). after 18 f has been introduced into the a ring , r 2 and / or r 3 halogens are optionally catalytically hydrogenated to preferentially remove the d ring halogens to produce various a ring amino or hydroxyl 18 f analogs with any possible combination of 18 f , amine or hydroxyl at r 4 , r 5 , and r 6 in the a ring positions . it is appreciated that the use of excess fluorination reagent promotes multiple radioisotope ring labeling , while use of an equivalent or less of fluorination reagent tends to produce a mixture of various mono substituted 18 f analogs . such mixtures are resolved to pure isomers by appropriate standard hplc purification procedures . it is appreciated that repetition of the above nitration , after modifying the a ring represents a method by which a nitro group is added to the d ring at r 2 or r 3 . a subsequent catalytic hydrogenation reaction , as detailed converts the r 2 or r 3 nitro to an amine group . as detailed above , the amine is optionally converted to a hydroxyl group . a hydrogen remaining at r 2 or r 3 is optionally halogenated with an isotopically unenriched or radioisotope to re - insert a halogen on the d ring . a protecting group for a hydroxyl function also may prove useful in the practice of the present invention . examples of hydroxyl protecting groups illustratively include tetrahydropyranyl , 2 - methoxyprop - 2 - yl , 1 - ethoxyeth - 1 - yl , methoxymethyl , β - methoxyethoxymethyl , methylthiomethyl , t - butyl , t - amyl , trityl , 4 - methoxytrityl , 4 , 4 ′- dimethoxytrityl , 4 , 4 ′, 4 ″- trimethoxytrityl , benzyl , allyl , trimethylsilyl , ( t - butyl ) dimethylsilyl , 2 , 2 , 2 - trichloroethoxycarbonyl , and the like . further examples of hydroxy - protecting groups are described by c . b . reese and e . haslam , “ protective groups in organic chemistry ,” j . g . w . mcomie , ed ., plenum press , new york , n . y ., 1973 , chapters 3 and 4 , respectively , and t . w . greene and p . g . m . wuts , “ protective groups in organic synthesis ,” second edition , john wiley and sons , new york , n . y ., 1991 , chapters 2 and 3 . a preferred hydroxy - protecting group is the tert - butyl group . a protecting group for the amino function can be an acyl group , such as an acyl of an aliphatic , aromatic or araliphatic carboxylic acid , especially lower alkanoyl such as acetyl or propionyl , or aryl such as benzoyl , or formyl or an acyl of a carbonic acid half - ester , such as benzyloxycarbonyl or fluorenylmethyloxycarbonyl ( fmoc ). examples of amino - protecting groups illustratively include the formyl (“ for ”) group , the trityl group , the phthalimido group , the trichloroacetyl group , the trifluoroacetyl group , the chloroacetyl , bromoacetyl , and iodoacetyl groups , urethane - type protecting groups , such as t - butoxycarbonyl (“ t - boc ”), 2 -( 4 - biphenylyl ) propyl - 2 - oxycarbonyl (“ bpoc ”), 2 - phenylpropyl - 2 - oxycarbonyl (“ poc ”), 2 -( 4 - xenyl ) isopropoxycarbonyl , 1 , 1 - diphenylethyl - 1 - oxycarbonyl , 1 , 1 - diphenylpropyl - 1 - oxycarbonyl , 2 -( 3 , 5 - dimethoxyphenyl ) propyl - 2 - oxycarbonyl (“ ddz ”), 2 -( p - toluyl ) propyl - 2 - oxycarbonyl , cyclopentanyloxycarbonyl , 1 - methylcyclopentanyloxycarbonyl , cyclohexanyloxycarbonyl , 1 - methyl - cyclohexanyloxycarbonyl , 2 - methylcyclohexanyl - oxycarbonyl , 2 -( 4 - toluylsulfonyl ) ethoxycarbonyl , 2 -( methylsulfonyl ) ethoxycarbonyl , 2 -( triphenylphosphino )- ethoxycarbonyl , 9 - fluorenylmethoxycarbonyl (“ fmoc ”), 2 -( trimethylsilyl ) ethoxycarbonyl , allyloxycarbonyl , 1 -( trimethylsilylmethyl ) prop - 1 - enyloxycarbonyl , 5 - benzisoxalylmethoxycarbonyl , 4 - acetoxybenzyl - oxycarbonyl , 2 , 2 , 2 - trichloroethoxycarbonyl , 2 - ethynyl - 2 - propoxycarbonyl , cyclopropylmethoxycarbonyl , isobomyloxycarbonyl , 1 - piperidyloxycarbonyl , benzyloxycarbonyl (“ cbz ”), 4 - phenylbenzyloxycarbonyl , 2 - methylbenzyloxycarbonyl , α - 2 , 4 , 5 ,- tetramethylbenzyl - oxycarbonyl (“ tmz ”), 4 - methoxybenzyloxycarbonyl , 4 - fluorobenzyloxycarbonyl , 4 - chlorobenzyloxycarbonyl , 3 - chlorobenzyloxycarbonyl , 2 - chlorobenzyloxycarbonyl , 2 , 4 - dichlorobenzyloxycarbonyl , 4 - bromobenzyloxycarbonyl , 3 - bromobenzyloxycarbonyl , 4 - nitrobenzyloxycarbonyl , 4 - cyanobenzyloxycarbonyl , 4 -( decyloxy ) benzyloxycarbonyl and the like ; the benzoylmethylsulfonyl group , the 2 , 2 , 5 , 7 , 8 - pentamethylchroman - 6 - sulfonyl group (“ pmc ”), the dithiasuccinoyl (“ dts ”) group , the 2 -( nitro ) phenyl - sulfenyl group (“ nps ”), the diphenylphosphine oxide group , and like amino - protecting groups . the species of amino - protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction ( s ) and can be removed at the appropriate point without disrupting the remainder of the molecule . preferred amino - protecting groups are boc , cbz and fmoc . further examples of amino - protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by , for example , t . w . greene and p . g . m . wuts , “ protective groups in organic synthesis ,” 2 nd ed ., john wiley and sons , new york , n . y ., 1991 , chapter 7 ; m . bodanzsky , “ principles of peptide synthesis ,” 1 st and 2 nd revised ed ., springer - verlag , new york , n . y ., 1984 and 1993 ; and j . m . stewart and j . d . young , “ solid phase peptide synthesis ,” 2 nd ed ., pierce chemical co ., rockford , ill ., 1984 ; e . atherton and r . c . shephard , “ solid phase peptide synthesis — a practical approach ” irl press , oxford , england ( 1989 ). the cleavage of such an acyl residue serving as protecting group for an amino function can be performed by known methods , such as solvolysis exemplified by alcoholysis . moreover it can be brought about by hydrolysis in acidic or basic medium . the alcoholytic cleavage of an acyl residue can be effected , such as in presence of a basic reagent and / or at elevated temperature , e . g . from 50 ° c . to 120 ° c . with a lower alkanol such as n - butanol or ethanol . a base is used such as an alkali metal alcoholate , such as sodium or potassium ethoxide or an alkali metal hydroxide , such as sodium or potassium hydroxide . other aminoprotecting groups , such as lower alkoxy - carbonyl - groups e . g . t - butoxycarbonyl , are cleaved under mild acidic conditions , such as by treatment with trifluoroacetic acid . another group , cleavable under especially mild conditions is an ethoxycarbonyl group carrying in the β - position a silyl group substituted with three hydrocarbon residues , such as triphenylsilyl , dimethyl - butylsilyl or especially trimethylsilyl . these are cleaved by reaction with fluoride ions , especially fluoride salts of quaternary ammonium bases , such as tetraethylammonium fluoride . in order to more fully demonstrate the advantages arising from the present invention , the following examples are set forth . it is to be understood that the following is by way of example only and not intended as a limitation on the scope of the invention . the title compound is prepared according to filer et al . ( 2 ). the synthesis included dissolution of 100 milligrams of ( r )-(−)- apomorphine hydrochloride in 30 milliliters of trifluoroacetic acid . 30 microliters of bromine in 7 milliliters of trifluoroacetic acid , representing 2 mols of bromine per mol of ( r )-(−)- apomorphine , is added dropwise over 20 minutes at room temperature to yield a crystalline precipitate . filtering and washing with cold trifluoroacetic acid yielded an off - white solid corresponding to the title compound . the procedure of example 1 is repeated except an equivalent stoichiometric amount of iodine is substituted for bromine . a solid product corresponding to the title compound is obtained . 0 . 68 millimoles of xenon difluoride was added to 0 . 33 millimoles of ( r )-(−)- apomorphine hydrochloride in 50 ml of dichloromethane . the solution is heated to 40 ° celsius for one hour to yield the title compound . the dibromoapomorphine produced in example 1 is refluxed with a stoichiometric amount of hexamethyl ditin and tetrakis ( triphenylphosphine ) palladium in dioxane to obtain the title compound in about 50 % yield . the compound having trimethyl tin at the 8 and 9 positions of ( r )-(−)- apomorphine produced according to example 4 is introduced into 5 milliliters of chloroform in an amount of 100 micromoles . 0 . 5 milliliters of concentrated hcl is added . [ 18 f ] f 2 is bubbled into the reaction mixture with stirring for 10 minutes . the reaction is quenched with sodium sulfite and loaded onto a c - 18 sep - pack , washed with water and eluted with ethanol further purified by hplc ( 30 ). the title compound was obtained with a radiochemical yield of 40 %. 200 micromoles of a dibromoapomorphine as produced in example 1 is dissolved in 10 milliliters of trifluoroacetic acid through which fluorine is bubbled at room temperature for 20 minutes . the resulting reaction mixture is resolved with hplc ( 30 ) to obtain the ( r )-(−)- 1 , 2 , 3 - trifluoro - 8 , 9 dibromoapomorphine ; ( r )-(−)- 2 - fluoro - 8 , 9 dibromoapomorphine ; and 3 isomers of ( r )-(−)- difluoro - 8 , 9 dibromoapomorphine . the trifluoro dibromoapomorphine produced according to example 6 is reduced with hydrogen in 10 milliliters of ethanol using 30 milligrams of 10 % palladium / carbon at room temperature in the dark for 2 hours with stirring ( 2 ) to yield the title compound . ( r )-(−)- 8 , 9 - dibromo apomorphine as made in example 1 is dissolved in 30 milliliters of sulfuric acid with cooling . 20 milliliters of concentrated nitric acid is added dropwise with stirring to maintain the temperature below 5 ° celsius . the reaction mixture is stirred at room temperature for 16 hours and poured onto ice . the resulting solution is neutralized with aqueous ammonia and extracted with chloroform . the chloroform extract is dried over sodium sulfate and evaporated under vacuum to yield a mixture of nitrated apomorphines . the product obtained from the procedure of example 8 is dissolved in approximately 200 milliliters ethanol and subjected to catalytic hydrogenation at 60 pounds per square inch in room temperature for 20 hours in the presence of 10 % palladium on charcoal ( 1 gram ). the resulting solution is filtered and evaporated under vacuum to yield the title compound . 20 micromoles of ( r )-(−)- 1 , 3 - diamino 8 , 9 - dibromoapomorphine is reacted with an equivalent amount of fluorenylmethyloxycarbonyl chloride in the presence of 60 micromols of pyridine in dichloromethane at room temperature for 1 hour . a mix of protected groups on the 1 and 3 positions of apomorphine is noted . the resulting partially protected apomorphine is dissolved in a mixture of concentrated sulfuric acid ( 10 ml ) and ice ( 30 grams ). an aqueous solution of sodium nitrite is added dropwise over 30 minutes while the temperature is maintained about 0 ° celsius for 8 hours . urea is added thereafter and filtered . the solution is slowly added to 200 milliliters of 2 molar sulfuric acid and thereafter cooled and extracted with chloroform . the extract is washed with 10 % sodium hydroxide to yield a mixture of ( r )-(−)- 1 - amino - 3 - hydroxy - 8 , 9 dibromoapomorphine and ( r )-(−)- 1 - hydroxy - 3 - amino - 8 , 9 dibromoapomorphine . 10 micromols of ( r )-(−)- 1 - amino - 3 - hydroxyl - 8 , 9 difluoroapomorphine is reacted with n - butoxycarbonyl ether in a mixture of dry triethylamine and dimethylformamide at room temperature ( 41 ). 1 - boc - 3 - hydroxyl - 8 , 9 fluoroapomorphine is an intermediate that in turn is reacted with [ 76 br ] ammonium bromide in the presence of peracetic acid , acetic acid and a mixture of methanol in water at room temperature to afford the title product after reaction with trifluoroacetic acid to deprotect the 1 position amine . 1 . j . l . neumeyer et al ., synthesis and dopamine receptor affinity of ( r )-(−) 2 - fluoro - n - n - propylnorapomorphine : a highly potent and selective dopamine d2 agonist , j . med . chem . 33 , 3122 - 3124 ( 1990 ). 2 . c . n . filer et al ., preparation of (−)-[ 8 , 9 - 3 h ] apomorphine at high specific activity , j . org . chem . 45 , 3918 - 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