‘US 201002 iON (10) Pub. No.: US 2010/0260685 Al us United States c2) Patent Application Publica ‘Wynn et al, (4s) Pub, Dat Oct. 14, 2010 (St) CONTRAST AGENTS 0) Foreign Application Priority Data (76) twesors x1.30,2007 (NO) 20075474 (Gb). lan Martin Newington, Publication Classification Aterstam (GB), Harry Joh ce Wadsworth, Amersham (GB) ain aan fanaa cme dyin d0001) Comespondence Ades Copavis ooo) GE HEALTHCARE, INC, (52) US.CL 424/9.44; 564/51; 544/86, IP DEPARTMENT i01 CARNEGIE CENTER PRINCETON, NJ 08540-6231 (US) on oe The reson invention relates ta cas of compounds and to i i fer diagnostic options containing such compounds we (21) Appl aa the compounds are iodine containing compounds ofthe fo mb Y XZ Reber cach ewusa cided ee ee pheny| residue further substituted by hydrophilic moieties. Y {in Z are reo and trehane poups andX ia alglene group (85) PCTNo Pevmposiesss2 ‘which may be fre ubsae, The invention also rites sa71@u, indiognost imaging and in parteaarn Xr) moging and (2),(4)Date: Apr. 27,2010 to contrast media containing such compoundsUS 2010/0260685 AI CONTRAST AGENTS ‘TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to a class of com- foundsandto diagnos compositons containing such ome Pounds here the compounds are ioe conning com founds. Mor special the fodine containing compounds fre chemical compounds containing to linked iodinated pha rps {0003} The invention also relates tothe use of such ding- note compositions sx contrast agents in diagnostic maging and in particular in Xray imaging, and fo Conrast media contig soc compounds DESCRIPTION OF RELATED ART 10003] All diagnostic imaging is based on the achievement ‘of different signal levels from diferent sractares within the body. Thus in X-ray imaging for example, for a given body strocture tobe visible in the image, the X-ray attemation by ing issues. signal Bebween the body structire and its surroundings is frequently termed contrast and mueh effort has been devoted to means of enhancing contrast in diagnos tic imaging sinee the greater the contrast between a body structure and its suroundings the higher the quality of the mags and the greater theie valueto the physician performing the diagnosis. Moreover, the greater the contrast the smaller the body’ structures that may be visualized in the imaging procedures, ic. inereased contrast can lead to increase spa {al esolution. [0003] The disynostc quality oFimages is strongly depen- ‘dent on the inherent noise level in theimaging procedure, and the ratio ofthe contrast level tothe noise level eanthus he seen torepresent an effective diagnostic quality factor for diagnos: tie images [0005] Achieving improvement in sucha diganostic quality actor has long been and sil remains an important goa. [a techniques suclias X-ray, magnetic resonance imaging (MRD) and ultrasound, one approach to improving the diagnostic ‘quality Faetor has boon to intluce contrast enhancing mate ‘als formulated as contrast media into the body region being imaged 10006] Thus in X-ray early examples of contrast agents ‘were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distribute. For the last 50 years the field of X-ray contrast agents has been ‘dominated by soluble iodine containing compounds, Com- ‘mercial available contrast media containing iodinated con- trast quents are usually elassfied as ionie monomers such as sdatizoate (marketed eg. under the trade mame Gastro- trafen"™), ionic dimers such as ioxaglate (marketed eg. under the wade name Hexabrix™) nonionic monomers such as iohexyl (marketed eg. under the wade name ‘Omnipague™), iopamidol (marketed eg. under the wade name Tsovue™), jomeprot (marketed eg under the trade ‘ame lomeron™) and the son-ionie dimer iodxano! (mar- keted under the trade name and Visipaque™) [0007] The most widely used commercial non-ionic X-ray ‘contrast agents sch as those mentioned above are considered safe. Contrast media containing iodinated contrast agents are used in more that 20 millions of X-ray extminations annually ‘nthe USA and the numberof adverse reaction is considered ‘acceptable, However, since contrast enhanced X-ray exa Oct. 14, 2010 ‘tion wil quire up about 200ml contrast msi nine Jord ia a total dose, hee is. continous di Jproved contast media {0008} Thewtiity ofthe contrast media is wovered largely byit toxicity, by its dagpostic efficacy by averse effet may have on the subject to which the contast medium is ‘xministred, and by the ease of storage ad ease of adie ‘nation. Since sock media are conventionally used for dag- nostic purposes rather than wo ahieve dint thezpeutic et, iis generally desirable o provide media having as Tinlas possible effet onthe varions biologieal mechanisms ote cells o the body as this wll ead to lower oii ad lower adverse clinial effect. The tonicity and adverse bine logical elects ofa contrast mem ae contrite aby the ceampontets ofthe formulation media, e the solvent or Carrier well sth conirst agent sel adits components Such as ions forthe ionic contrast agents and also by is metabolites {0009} ‘The major conebuting factors tothe toxeityof the contrast medium’ ae identifies the chemotoxiity ofthe conast ant, the osmoltity ofthe contrast medium andthe Jonie composition or lack thereof o the contrast medium. (0010) Desiable characteristics ofan iodinated contrast gent are Jw toxicity ofthe compound isl (hemotoxi= 4) low wsconiy ofthe contrast medium wherein the come pound i disolved, low osmolality ofthe eontast medium nd ahigh iodine content (Irsqunlly measured iodine per ri of the formulated contrast medium for administration) ‘Taeiodinated conrast agent sus ao be completely soluble {nthe formulation medium, usualy an. aqueous medium, nd remain in soltion ding storage {0011} Theosmoalites ofthe commercial peedets, anda paticularof the non-ionic compornds seceptble fr most Inedia conning dimers and on-ionie monomers although {hore stil om fr improvement In coronary angograpiy for example injection into the eiteulatory system of bolus closcoeantrast msi hs ose ever sie elects Inthe procedure contrast medi rather than blood flows through the syst fora short period of tne, and difrences inthe chenical and physiochemical nature of the contest medi tnd the blood that replaces can cause undesirable adverse effects suchasathythmias, QT prolongation and redetion in carac cntractive lore. Sch effects are seen in paticular ‘ith sonic contrast agents where osmotoxic elects ae ass0- Ciated with hypertonicity ofthe injected contrast medi, Contrast mediathat at isotonic or sighty hypotonic withthe body hide are puriclary desired, Low osmolar contest media have low rena toxicity whichis particularly desirable ‘The osmolality a function of the umber of particles per ‘volume tit of the formulated contest medion, {0012] Ia patients wis acute real flue. nephropathy Jndweed by contast meium remains one ofthe most ein callyimpertant complications of tus of diate conrast ‘medium: Aspli, Petal, The Nev England Jounal of Mesi- eine, Vol, 348:491-499 (2003) coneled tht nephropathy Jndueed by contrast medium may be es likely to develop in igh sis potent when odixano etme ater than ow csmola, non-ionic contrast medi {0013} "Theparofthepaten population consiersdas high Fisk pint is increasing. To moet the ned for continuous improvement fin vivo X-ray disgnostc agents for the entire patient population, there is a continuous dive in fading ray contas agents that has improved propentizs, also with rogands fo contrast induced aepheotoicit (CIN).US 2010/0260685 AI 10014] To keep the injection volume ofthe contrast media 285 Iow as possible itis highly desirable o formulate contrast ‘media with high concentration of ioine!ml, and still maintain the osmolality of the media ata low level, preferably below or close to isotonicty. The development of nan-ionie mono meric contest agents and in particular non-ionic bis(ei ‘odophenyl) dimers such a iodixanol (EP patent 108638) has provided contrast media with reduced osmeroxieity allowing ‘contrast eflective iodine conceateation to be achieved with hypotonic solution, and has even alowed correction of ionic ‘imbalance by inelusionof plasma ions while still maintsining the contrast medium Visipague™ atthe desiced osmolality (WO 90101194 and WO 91/13636). [0015] |The X-ray contrast media t commercial high iodine ‘concentration have relative high viscosity, ringing. fom ‘about 150 abou 60 mPas at ambienttemperatute, Generally, ‘contrast media where the conteastenhaneing agent isa dimer has higher viseosty than the corresponding contrast media ‘where the contrast enhancing agent is the monomer corre sponding to the dimer. Such high viscosities may pose prob- Jems tothe administrators ofthe contrast medium, requiring relatively laze bore needles orhigh applied pressure, and are panicularly pronounced in podiaric radiography” and in radiographic techniques which require raid bolus adasinis- tration, ©. in angiography. [0016] X-ray contrast media containing a chemical com- pound asthe ative pharmaceutical ingredients) having wo jodinated phenyl groups linked by linking group are ust- ally referred to as dimeric contrast agents or dimers. During the years a wide variety of iodinated dimers lave been pro- posed. Relevant patent publications comprises EP 1186305, EP 686046, EPIOS638, EP OO974S, EP 0023992, WO 2003080854, WO2000026179, WO 1997000240, WO 5208691, U.S, Pat, No. 3,804,892, US. Pat No. 4,239,747, US. Pat. No. 3,763.226, US. Pat No. 3.763.227, US. Pat. No. 3,660,464 and U.S. Pat. No. 3,678,152. At this time, one ‘contrast medium having an iodinated non-ionic dimer ae the ‘active pharmaceutical ingredients one the market, the prod ct Visipaque™ containing the compound iodixanol. The ‘compound Hexabrix™, containing the ionic dimeric com- pouuid ioxaglie acid is also on the market. [0017] Hence there still exists a desire to develop contrast ‘agents that solves one or more of the problems discussed above, Such agents should ideally have improved properties ‘over the soluble iodine containing compounds on the market in one or more of the following properties: renal toxicity, ‘osmolality, viscosity, solubility, injection volumesfiodine ‘concentration and atenuation/adiation dose and any ad tional adverse elect known or discovered for such iodinated ‘compounds SUMMARY OF THE INVENTION 10018] The preseat invention provides compounds useful asconrast media having improved properties over the known tsa with regards to at last one of the criteria mentioned above andi particular to renal texiety, osmolality, viscosity and solubility: The contrast media comprises iodine contain- ing contrast enhaneing compounds where iodine containing ‘compourals are chemical compousds containing 10 Finke Fodinated phenyl groups DETAILED DESCRIPTION OF THE INVENTION [0019] The new compounds ofthe invention, their use as X-ray contrast agents and their formulation and production fare specified inthe attached claims and in the specification hereialer Oct. 14, 2010 [0020] The contrast enhancing compounds are synthe chemical compounds of formula (1) and salts or optical ative isomers thereof, wherein X denotes a C, t0 Cy sraght of branched alkylene moiety ‘optionally interrupted by aneto two oxy3ien atoms or sup ‘toms and wherein the alkylene mosety optionally is subs fhted by up to4-OR groups Yana independently denote urea groups or urethane groups ‘optionally N substituted with C, 10 C, straight or branched aly! groups: RR denotes a hydrogen atom oeaC, 1oC. straight of branched alkyl group: and teach R independently are the same or different and denote a {iodinated phesy] group, prelenbly # 2dtriiodinated phenyl group furler substituted by two groups R? where ‘ach Rae the same or different and denote aliydrogen at nie hydrophilic moiety, provided that at least one 1 group inthe compound of oman) is hdrptiic {0021} In formula) above, X preferably deotesa straight (0,40 alkylene chain optionally subsite by one to three ‘OR’ groups [0022] " More preferred X denotes a siriight O, to C, alky- Jene chain having atleast one OR" group, preferably at east one hydroxyl proup in a postin that fs not vieinl 1 nitrogen atoms of the urea functions. More prelerably the alkylene chin is substituted by one or owo hydroxyl groups. Particular preferred groups X comprise elylene, propylene, Dhyeroxy” propylene, 2ibydroxymethyl) propylene and 2-methy-2-hydroxy propylene. When the group X contains ‘an symmetric carbon atom such as eg. the 2-Nydroxy’pro- pylene moiety, then enantiomers ean exist and can be sepa rated, [0023] R" preferably donotesa hydrogen oramethy! group, ‘most prefered a hydrogen atom, [024]. Y and Z are represented by ures groups of formula N(R})—CON(R))— and urethane proups of formula —N(R'}—CO_O-, Preferably the nitrogen stom in the ‘urethane group is linked fo the moiety R, Zand Y may be the same, each representing urea groups or each representing ethane groups, orZ andY may be different where one ofthe Zand eotties represents a-aree group. a the other ofthe Zand entities represent urethane {0025} “Thesubstiment denotes hydrogen atom oraC, {0C, straight of branched alkyl group, Preferably R? denotes ‘hydrogen tomoramethyl group, When R denotes analky! soup, the ally] group is preferably bound to the nitrogen atom that js bound tothe moiety X. [0026] Hence, particularly prefered groups Y and Z are ‘unsubstituted urea and urethane groups and the group of {formula —NH—CO—N(CH,)— 0027} Fach ofthe iodinated R groups can be the same or ‘ifferent and preferably denote 2.,6-riiodimated phenyl group, further substituted by two groups R? inthe remaining 'Sand 5 postions inthe phenyl moiety [0028] The non-ionic hydrophilic moieties R® may be any of the non-ionizing groups egnventionally used to enhance ‘water solubility. Heneo, the R° substituents may'be the same ‘ordiferent and shal preferably all denote non-ionic hyde Dhilic moiety comprising esters, amides and amine moieties, ‘optionally Further substituted by a straight ehain or branched chain, alkyl groups, preferably C, alkyl groups, where the alkyi'groups also may have one or more CH, or CH noieties replaced by oxygen or nitrogen atoms. The R? sub- slituents may also further containoneormore groups selectedUS 2010/0260685 AI from oxo, hydroxy, amiao or carbon derivative, sd oxo substituted sulphir and phosphionss atoms. Each of the staat or branch allyl groups preferably contains 110 6 hydroxy groupe and more rctembly 1 to 3 deoxy aon, “heefore, ns furer prefer sspoct, the R? subsites fe the some or diflerat and are polybydroxy C, aly Iydroxyalhonyaliyl with Ito §earbon atoms aad bydroxy= polvalkonyalkyl wit Ito S earbonatoms, and areatachedto the iodinated phenyl group via an aide or a carbamoyl linkage, preferably amide linkages {0029} TheR* groups ofthe formulas Tisted below are pa Sevlarly prefers CONH CH, CH, OH —CONH—CH,—CHOH—cH,—on —CON(CH,)CH,—CHOH—CH, OH —CONHCH_(CH, 01), —CON(CH, CHO), —CON—(CH—CHON—CH;—O1, —CONH, —CONHICH, CON(CH,-CHOH-cH, —CONH—C(CH,OH), —CONH—CH(CH,—OH)(CHOH—CH,—-OF) —CONH—CH(CH,-OH)(CHOH—CH,—O8), and 10030) OHV(CH, CH, on) -morpholine-4-carbonyl. Oct. 14, 2010 [0031] Even more preferably the RB? groups will beequal or silent and denote amide group compounds, eeferably one ‘of more moieties of the formulas. —CONH—CH,— (CHOH CH, On, —CON(CH,)CH.— CHOH— CHOH, —CONH—cR_(cH,—O1}),, -CON—(CH,— CHOH}), and CON (CH, “CHOH” CH, —OH),. Sil more preferably both R groups re the same andthe R° groups in each R are the same or dflerent and denote — CONE CH, CHOR CH, OH and CON—(CH CHZOH—CH,OF),- Most preferred all substituents R® are the same, [0032] Thus, preferred structures according to the inven- tion include the compounds of fm (I) Font RNII-CO-NR)- XN) —CONIR aw R-NII-CO-0-K-0-CO-NI-R tm) R-NII-€O-O-X-NB}-CO-NI-R aw) {0033} In formulas (1), ach group R lass the meaning ahove, more preferably each odopheny! groups Rare the Same und the R groupe all denote nonsonie hydrophilic moieties, and preferably the R groups are inked 0 oinated ‘hon moicy by amie linkages, RY and X as the meanings Shove and X preferably denotes staight chain alkylene fnvups with 210 5 carbon atoms and straight oe branched ‘mono-hydoxylatedalkylene groups where thehydroxylsub- Stent are at positions that are nt uljcent othe mitogen funtion (0034) Preferred examples the stctures according wo the Jnventoninelude the compounds of formes (1) (Hn) below. | 7 Receeee . A Y 1Oct. 14, 2010 US 2010/0260685 AI zee & &. e SyUS 2010/0260685 AI Oct. 14, 2010 continued Foal Font : 1 KAY Aw on ‘ ‘ OH mA Be on On ' a ° * \ on ~ : A, “ Ay Roe oa ! 8 hoUS 2010/0260685 AI Oct. 14, 2010 6 -continued foot Fons ce ot it 6 a comes aces s Bn a oy See x0" OE grat mop Spon bn I on . on Fortin o ros < aaUS 2010/0260685 AI 10035] Acaniodine concentration of 320 mpl, which isa ‘common conceatraion for commercially available iodinated ‘contrast media, the concentration ofthecompound of formula () will be approximately 0.42 M (Molar). The contrast ‘medium will also be bypoosmolur at this iodine eoncentra- tion, and this is an advantageous property with regards to the nephrotoxicity of the contrast medium. Its also possible 0 ad electolyes othe contrast medium to lower the cardio- vascular effects as explained in WO 90/0194 and WO 91/13636. 10036] | Compounds of formula (I also comprises optical sctive isomers and may exist in several isomeric forms de to chiral carbon atoms, Both enantiomerically pure produess as ‘well as mixtures of optical isomers are ince 10037] The compounds of the invention may be used as ‘contrast agents and may be formulated with conventional ‘carters and excipients to produce diagnostic contrast media, 10038) Thus viewed from a further aspect the invention providesa diagnostic composition comprising a eompoundol formula (1) as deseribod above together with at least one physiologically tolerable carrier or excipient, ein aqueous solution for injection optionally together with added plasma fons or dissolved oxygen, [0039] The contrast agent composition of the invention may be in ready 1 use concentration or may bea concen- teat fom for dilution prior administration. Generally com- positions in a eady to se form will have iodine concentra- ‘ions of atleast 100 mg Vint, preferably at least 150 mg Vin, ith concentrations of at last 300 mg Ul, eg. 320 mg Vm being prefered. The higher the jodine concentration, the higher isthe diagnostic value in the form of X-mry attenuation ‘of thecontrast media. However, the higher the iodine concen tration the higher isthe viscosity and the osmolality of the ‘composition. Normally the maximum iodine concentration Tora given contrast media wll be determined by the solubility ‘ofthe contrast enhancing agente. the iodinated compound, ‘andthe tolerable limits for viseosity and osmolaliy [0040] Forcontrast media which are administered by in tion or infusion, the desired upper limit for the solution's viscosity at ambient temperature (20° C.)is about 30 mPa, however viscosities of upto 500 60 mPas andeven more than 60 mPas can be tolerated. For contrast media given by bolus injection, ¢. in aigiographic procedures, osmotoxic elects sist be considered and preferably the osmolality should be below 1 Osivkg HO, preferably below 850 mOsm/kg HO ‘and more preferably about 300 mOsm 11,0. [0041] _ Withthe compounds the invention such visosiy, ‘osmolality and iodine concentrations targets can be met Indeed, effective iodine concentrations ean he reached With hypotonic solutions. It may ths be desirable to make up the solution's tonieity by the addition of plasma cations 80 8 10 reduce the toxicity contribution that derives from the imbal- ‘ance effects Following bolus injetion. Such cations will, desirably be included in the ranges suggested in WO 90101194 and WO 91/13636, [0042] Inparieular, addition of sodium andealeium ions 0 provide a contrast medium isotonic with blood fr all iodine ‘concentrations is desiable andl obtainable, The plasma eat ons may be proved inthe form ofsats with physiologically tolerable counterions, eg chloride, sulphate, phosphate hydrogen carbonate et. with plasma anions preferably being sed, Oct. 14, 2010 [043] The contrast media containing compounds of for ‘mula (1) can be administered by injection or infusion, eg. by intevasculae administration, Altematvely, contest medi ‘containing compounds of formu (1) may also be ada tered orally. For oral administration the contrast medium may be in the form ofa capsule, tblet or as liquid solution [0044] In a farther embodiment the invention provides agnostic agents comprising compound af formals (I) and siagnostie compositions comprising » compound of formula ) together with phamaccutically acceptable cariers oF excipients, The diagnostic agents and composition are pref- feb for we in X-ray diagnosis [0048] "Hence, the invention further embraces useofadiag- nostic ageat and a diagnostic composition containing a com- pound of formula (1) in X-ray contrast examinations and use ‘fa compound of formula (forthe manufacture of a diag- ‘nostic composition for use as an X-ray contrat agent [0046] method of disunosis comprising administration ‘of compounds of formula (1) the human or animal body, ‘examining the body with «diagnostic device and compiling {ata from the examination is also provided, In the method of diagnosis the body may also be preadminisrated with com- pounds of formula (I). [047] Furthermore, method of imaging, specifically ‘X-ray imaging is provided, which comprises administration fof compounds of formula (1) the human or ania body. ‘examining the body with diagnostic device and compiling data from the examination an optionally analysing the data Tn the method of imaging the body may also be preadmini ‘rated with compounds of Formula (D, Preparation {0048} The compounds of the general formula (1) can be synthesized by multistep procedures from starting materials are either known fom the state of at or that are commer [oos9} {ormula (1s illustrated in Examples 1 to 14 [050] tn genera, compounds of formula (Il), (1b) and le) (collectively denotes formula (1) ‘General procedure for preparation of compounds of B_NIL-CO_N@)_ X_N) CO_NIE-R a) R-NII-€O-0-X-0-CO-NI-R aw) NIL CO_0-X_NR)CO_N a can be prepared by reacting a compound of formula (IV) witha compound of formula (V) wherein B' denotes R ora precursor or protected derivative thereol; 1X’ denotes X or a precursor or protected derivative thereof; A denotes an isocyanate residue: and cach B are the same or different denotes a primary amine, secondary amine or an alcool [0051] solution of compound of formula (IV) is added 0 ‘solution of 0.5 equivalents of a compound of forma (Via ‘ichloromethane. The mixture is stimed at 25° C. for 18 h ‘when analysis indicates complete reaction, Solvent is removed under vacttim and the product is isolated by ehro- natography on silica gelUS 2010/0260685 AI ipsa ih emg of rule I a ea Feta ne coe aun ae ee abe Bou Soamtercal supplcns oem feces el cme sama a 2 (0054) us YT I 1 Ay 10055] _ To a solution of acetic acid I-acetoxymethyl-2-[3- amino-S-(2-diacetoxy-propylearbamoyl)-2.4,6-ilodo- benzoylamino}-etiyl ester (13 g, 17 mimoi) in 1-4dioxane (20 ml) was adda auton of 20% phosgene in lene then feaiod to 60°C: Tor 13 hours The reaction mixture Was ‘cooled to ambient temperature and then ‘concentrated at ‘cal peste o ae a ll White sa Droxane (30 mL x2) was added and removed slowhy’at reduced pressure to five an oll-white slid which was placed on a vac ine to Femove any rosiial solvent. The material was Used without further punieation [0086] © "HNMR (CDI,}: 7.02 (s, br, 2H), $29-5.21 (m, 2D) 480438, 2) 430-419 (21), 982-348 (, 411) 2.05 6. 1210 Io IM (CPCB): 170.7, 170.3, 169.7, 149.8, 123 92.2, 100, 633, 39.9,21'3, 207 16088)" “Using the same procedure the following isoeyan- ates Were prepa: NNN INV Tetruallyl-246triiodo-S-isveyanato- : [0059] 7 we AL [0060] "HNMR (CDCI): 5.91-5.84 (m, 41), 5.38-4.91 BHD, 4.28-4.02 (m, AF, 3.68 (4 4, 1-62) (6rjodo-S-isceyanato-N.N'-in- ‘eliylisophiblamide Oct. 14, 2010 [0062] | AINMR (CCL): $:86.0(m, 2H), 5.2-5.4(m, 41, 4.16 and 2.76 4,411), 3.68 and 3.08 (8, 6), [063] “CNM (CDCI, )- 169.50, 169.20, 168.77, 131.96, 131-55, 131-42, 120.19, 119.31, 119.23, 91.70, 90.93, 67.08, 53.63, 49.53, $4.79, 3453 and 31.20, N.N-Dially-2,46-tiodo--isoeyanatoisophthala- ike [0064 okey [0065] _'H NMR (46DMSO}: 8.61 (t, NH), 5:81-5.96 (m, 2H), 330-4.05 (complex 8H) {066) CNM (asDMSO): 170.20, 149.52, 147.99, 135. 23, 116,60, 107-15, 80,60, $3.04, 45,64, 42.07, 36.24, 8.93, and 7.86 1.3-Dis(4-moepholinocarhony!)-2.4.6-siodb: ‘yanotabenzene [0067 QO : x [0068] “HNMR (CDCI,}:3.67-3.80 (m, 6H) and3.16-3.28 CNR (CDCI: 168.78, 168 05, 149.09, 147.64, 141.09, 128.64, 91.67, 8441, 66.92, 66.18, 65:90, 46.26 and 418, EXPERIMENTAL, Example 1 1 3:bis-[NIN-Bis-(23 - pound of formula (1) as defined in claim 1 together with 2 pharmaceutically acceptable carriers or excipient. 24. (canceled) 28. (canceled) 26, (canceled) 21. (canceled) 28. A method of imaging comprising administration of ‘compounds of formula (1) a defined in claim 1 0 the human ‘oranimal body, examining the body with diagnostic device ‘and compiling data from the examination and optionllyanal- ysing the dat,