AMPHIPATIC POLYCARBOXYLIC CHELATES AND COMPLEXES WITH PARAMAGNETIC METALS AS MRI CONTRAST AGENTS

Abstract: Substituted polycarboxylic ligand molecules and corresponding metal complexes of said ligands, preferably paramagnetic metals complexes for generating responses in the field of magnetic resonance imaging (MRI). The paramagnetic complexes of the polycarboxylic ligands possess advantageous tensioactive properties and are useful as MRI contrast media in formulations for investigating the blood pool.

Description: AMPHIPATIC POLYCARBOXYLIC CHELATES AND COMPLEXES WITH PARAMAGNETIC METALS AS MRI CONTRAST AGENTS Field of the invention The present invention addresses novel polycarboxylic ligand molecules and chelated complexes of said ligands with metals; the metals are for instance transition metals, e.g. paramagnetic metals for generating responses in the field of magnetic resonance imaging (MRI) The present polycarboxylic ligands exhibit outstanding tensioactive properties which make them particularly useful in the form of paramagnetic chelates for making formulations and compositions useful as MRI contrast media of controllable and long lasting activity in the blood pool . Background art US-A-5, 466,438 (WO 92/231017) discloses compounds of formulae (I) di) in which formulae I-III Rl is independently a suDStituteα or unsubstituted C7-30 straight cnam or cyclic compound; R ? is independently a substituted or unsubstituted C]_-C 30 straight chain or cyclic compound wnicn may be nternal_ interrupted by O, NH, NR-, or S, where R 3 is a C..-C-, alkyl; n is 0-1 in formula I and 1-20 in formula III; m is 1-2 ; B is a substituted or unsubstituted C--C,„ straight chain or cyclic compound which may be internally interrupted by O, NH, NR.- or s. In formula IV: R, , R- are independently H or a substituted or unsuostituted C-- C,„ straight chain or cyclic compound; R-,, R. are independently H or a substituted or unsubstituted C-- C- n straight chain or cyclic compound which may oe internally interrupted by O, NH, R. or S, where R^ is a C,-C 3 alkyl; and in formula V: R- is independently a substituted or unsubstituted C-,-C, n straight chain or cyclic compound R„ is independently a substituted or unsubstituted C, -C ™ straight chain or cyclic compound which may be internally interrupted by 0, NH, NR 4 or S, where R. is a C.-C, alkyl; R, is independently a substituted or unsubstituted C,-C- n straight chain or cyclic compound which may be internally interrupted by O, NH, NR. or S, where R. is a C,-C- alkyl and m is 0-12. The reference also discloses contrast agents obtained with the compounds of the above formulae (I-V), the latter further comprising lipids; the lipids are in the form of emulsions, liposomes or micelles. US-A-5, 312, 617 dicloses a method of imaging comprising administering to patients a contrast agent comprising a complex of a paramagnetic metal and a ligand selected from formulae IV and V disclosed in the foregoing US-A-5, 466, 38. Liposomes incorporating the above chelates are also discloseα as well as tne possibility of having the compounds in the form of emulsions or micelles. The mi celles can fce prepared by a variet y c r convent ional xiposome preparatory techniques ; s ui table l ipids mcluαe , for example , τιono yrιstoyl-phospnatιc., --cnolιne , monopa l-pnoscnatiαylcholme , αibut yroyl -phosphat ol ine ana the l ike , I mole.c acid , oleic acid, palmitic acid, ana the like. Lipid emulsions car oe prepared by conventional techniques, for instance a typical methoc is as follows: 1. In a suitable flask, the lipids are dissolved in ethanol or chloroform or any other suitable organic solvent. 2. The solvent is evaporated leaving a thin layer cf lipid at the bottom of the flask. 3. The lipids are resuspended in an aqueous medium, such as phosphate buffered saline, this producing an emulsion 4. Somcation or microfluidization can then De applied to _mprove homogeneity. 5. The contrast agents can be added to the lipids during preparation of the emulsion, or they may be added to the emulsion afterwards . 6. Useful additives include, for example, soybean lecithin, glucose, Pluronic F-68 and D, -α-tocopherol ; these additives are particularly useful where mjectable intravenous formulations are desired. The foregoing contrast agents may further comprise suspension stabilizers such as polyethyleneglycol, lactose, mannitol, sorbitol, ethyl alcohol, glycerin, lecithin, polyoxyethylene sorbitan monoleate, sorbitan monoleate and albumin. Various sugars and other polymers may also be added, such as polyethylene glycol, polyvmylpyrrolidone, polypropylene glycol and polyoxyethylene. The contrast agents of this reference have high T and T„ relaxivity, especially when lipids are also present. Because of the high relaxivity, these contrast media are particularly useful for imaging the blood pool . Summary of the invention Despite the merit of the paramagnetic polycarboxylic chelates of the prior art as contrast agents for MRI, there was a need for a new range of chelating compounds of further improved properties designed to provide blood-pool contrast agents of outstanding long life in the circulation. In view of their structure including strongly hydrophobic and hyαropn ± iic moieties, the compounds of tne present _nvent on achieve a siqmficant step in the right direction. The novel compounds of tne present invention, either raceme or enantiomenc, have the following formulae t) ano (IV) (IV) (t) in which n and m are 1 or 0 but not simultaneously 1, and when n = m = 0, R' is H, and R* is a Ci2-25 linear or ramified, saturated or unsaturated, hydrocarbon radical; when n = 1 and m = 0, R* is H or a Cχ_3 alkyl or alkylene substituent ; and R' is selected from -NHR3, -NR 4 R5 and -ORg where the R3 to Rς are independently Cι_25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -O- and optionally terminated by -NR7R8 in which R 7 and R3 are independently H or Cχ2-25 hydrocarbon radicals; when n = 0 and m = 1, R* is H or a C]_-3 alkyl or alkylene substituent; and R' is selected from Rg and -CH2-O-CO-R9 m which Rg is a Cχo-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by -NH-, -NRin-, -CO- or -0-, R^Q being a lower aliphatic hydrocarbon; and Rl2 is H or a C^2-30 hydrocarbon radical optionally interrupted by -NH-, -NRirj-, -CO- or -0- and optionally terminated by a cholesteryl residue, and the R13 are -OH; or one or two R13 are a -NH- Rl4 group in which Rχ 4 is a C2-30 linear or ramified, saturateα or unsaturated, hydrocarbon radical optionally interrupted by -NH-, NR10-, -CO-, -0-, and/or -OPO(OH)0-, the remaining R13 being -OH. The compounds of formulae (t) and (IV) can be used as chelates of paramagnetic metals, preferably Gd(III), Mn(II), Cr(III), Cu(II), Fe(III), Pr(III), Nd(III), Sm(III), Tb(III), Yb(III), Dy(III), Ho(III) and Er(III) m the preparation of MRI contrast formulations and compositions of outstanding long life in the blood which makes tnem ideal agents for investigating the circulation in appended organs. Detailed description of the invention Preferred are the compounds encompassed by formula (t), m which n and m are 1 or 0 but not simultaneously 1, and when n = 1 and m = 0, R* is an alkylene group, and the other variable groups are the meanings defined above. Equally preferred are the compounds encompassed by formula (t), in which n and m are 1 or 0 but not simultaneously 1, and when n = 1 and m = 0, R* is H or a Cι_3 alkyl; and R' is selected from -NHR3, or -NR4R5, where the R3 to R5 groups are independently C_2-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals, optionally interrupted by -CO- and/or -0- and optionally terminated by -NR7R8 m which R7 and Rg are independently H or Ci2-25 hydrocarbon radicals with the same meaning just above defined. Equally preferred are the compounds encompassed by formula (t), in which n and m are 1 or 0 but not simultaneously 1, and when n = 0 and m = 1, R* is an alkylene group, and the other variable groups are the meaning defined above. Equally preferred are the compounds encompassed by formula (t), in which n and m are 1 or 0 but not simultaneously 1, and when n = 1 and m = 0, R* is H or a C1-3 alkyl; and R' is selected from R9 and -CH2-O-CO-R9 in which Rg is a Cχ2-25 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by -NH-, -NR]_o~f -CO- or -0-, Rio being a C ] __ 4 linear or ramified, saturated or unsaturated, hydrocarbon radical. Furthermore are prefered the compounds of general formula (IV) in which R]_2 is H, and two R13 are a -NH-Rχ 4 group in which R]_ 4 is a CI2- 25 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by -NH-, -NRin-, -CO-, -0-, and/or -OPO(OH)0-, the remaining R13 being -OH The compounds of formula (t) are preferably selected among compounds of the following formulae (I), (II) or (III) H wherein R* is as defined heretofore; R is H or a Cι_3 alkyl or alkylene substituent; Rl is selected from -NHR3, -NR4R5 and -ORβ where the R3 to R5 are independently Cι_25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -O- and optionally terminated by -NR7R8 in which R7 and Rs are independently H or Ci2-25 hydrocarbon radicals; R2 is selected from Rg and -CH2-O-CO-R9 in which Rg is a Cιo-60 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by one or more -NH-, -NRιo~, -CO- or -0-, R^n being a lower aliphatic hydrocarbon. For instance, the compounds of formula (II) can have formula (Ha) (Ma) in which R3 is a C12-25 linear or ramified, saturated or unsaturated, hydrocarbon radical. Particularly preferred are the compounds of formula (Ila) in which R3 is a C 6_20 linear or ramified, saturated or unsaturated, hydrocarbon radical. Or they can have formula (lib) (lib) in which R4 and R5 are independently C 2-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -0- . Particularly preferred are the compounds of formula (lib) in which R4 and R5 are independently Cχ6-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals interrupted by -CO- and -O- . Furthermore, they can have formula (lie) (lie) in which A is -NH- or -0-, Ai is a Cι_20 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -O- and R and R8 are defined as above. Particularly preferred are the compounds of formula (lie) in which R is an alkylene substituent. Equally preferred are the compounds of formula (lie) in which A is -NH-, Ai is a Ci-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals interrupted by -CO- and -0- and R and R8 are defined as above. Also the compounds of formula (lie) are preferred m which A is -O- and Ai is a Ci-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals interrupted by -CO- and -0- and R7 and R8 are defined as above. Compounds of formula (III) can have formula (Ilia) (Ilia) in wmcπ R is ^ and R? - s 1 S a c 10-30 linear cr ra^i r ieα, saturated cr unsaturateα, .ydrocarccn raαical optionally mterrupteα by one or more -NH- , - - , -CO- or -O . Otherwise , they can nave formula ( Il lb) below in which R is H and Rg is a Cio-25 lmear alkyl, or a C o-50 linear or ramified, saturated or unsaturated, hydrocarbon raαical optionally interrupted by one or more -N-, -CO- and/or -O- . Some preferred compounds of formula (IV) are those m whicn all the R13 are -OH and R 2 is defined as mentioned above. Otherwise, compounds of formula (IV) can be selected from the compounds of formulae (IVa) and (IVb) below. In Formula (IVa), OOH HOOC CONHR, ) R 14 HNOC COOH (IVa) the R14 are independently as defined above for formula (IV; . Particularly preferred are the compounds of formula (Iva) in which R 14 is CI2-25 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by -CO- and/or-O-, and/or - OPO(OH)0-. In formula (IVb) shown below, HOOC " COOH HOOC COOH (IVb) R 4 is a C 2-25 linear or ramified, saturated 02 unsaturated, hydrocarbon radical. The compounds of this invention of formulae (T) ana (IV) can De as represented in the formulae, or they can De in the form of complex chelates with paramagnetic metal ions (as indicated heretofore) and the salts thereof with pnysiologically acceptable bases selected from primary, secondary, tertiary amines and basic aminoacids, or inorganic hydroxides of sodium, potassium, magnesium, calcium or mixtures thereof; or with physiologically acceptable anions of organic acids selected from acetate, succinate, citrate, fumarate, maieate, oxalate, or inorganic acids selected from hydrogen halides, sulphates, phosphates, phosphonates and the like; or with cations or anions of aminoacids selected from lysine, arginme, ornithine, aspartic and glutamic acids, and the like; For preparing the compounds of formula (I) in the form of complexes with metals (ME) , one can proceed as in the following Scheme 1: Scheme 1 PgOOC - f ~ \ /- COOPg HOOC— \ / \ /- COOH " OOC- -COO 1 R*-X CO PLEXATION -N r ~ \N- ► M Mee nn++ 2 DEPROTEC TION ^~ N N SALIFICATION -NM NM"-— PgOOC HOOC — / \ / ^ R * OOC a1 b1 1A 1B 1C Where Pg is a protecting group; R* is as defined for formula (I); ME is a metal ion; n = 2 or 3. In step al the compound IA, i.e. 1, 4 , 7, 10-tetraazacyclodoαecane- 1, 4 , 7-trιacetιc acid, whose carboxylic groups are suitably protected by groups such as benzyl or t-butyl, is reacted with R*-X, where R* is a substituent residue and X is a leaving group such as Cl, Br, I. The reaction product is then deprotected by known methods (e.g. with CF3COOH) to give the free ligand IB. The ligand is then complexeo with a suitable metal ion oxide or salt (preferably paramagnetic), such as Gd oxide, chloride or acetate, in order to obtain the desired metal complex chelate IC. Depending on the value of n, IC may be salified with a suitable counter-ion. For the complexes of the compounds of formula (Ila), one may proceed according to the scheme 2 oelow: Scheme 2 XCHR-CO-X + R3NH2 - 2A 2B a2 2C in which Pg is a protecting group as in Scheme 1; R and R3 have been defined above, and ME and n are as in Scheme According to the method of Scheme 2, one prepare: compound 2C by the reaction of a halogenated halide (or equivalent) ith a primary amine R3NH2 in a suitable solvent, such as CH2CI2, CHCI3 or H2O/CH2CI2 mixtures, in the presnce of a base (e.g. K2CO3) . Then, Compound 2C is reacted with compound 2D and the product is deprotected (b2) to furnish the desired free ligand 2E. The latter is finally complexed according to the general procedure disclosed in Scheme 1. If required, i.e. depending on whether n has an appropriate value, compound 2F may be salified with a suitable counter-ion. For preparing the metal complexes of the compounαs of formula (lib), one may proceed according to the Scheme 3 below: Scheme 3 / (CH 2 ) n (OCH2CH2) p OH , (CH 2 ) n (OCH2CH2) p OOCAIk Alk-COY CIH HN CIH HN N (CH 2 ) n (OCH2CH2) p OH a3 ~ (CH 2 ).(OCH2CH2)_OOCAIk 3B 3A 3C PgOOC PgOOC (CH 2 ) n (OCH2CH2) p OOCAIk (CH 2 ) n (OCH2CH2) p OOCAIk 3F 3G in wnicn n = 1-6; p = 0-5; = 2 or 3; v = nalogen; Pg _s a crotectmg group and Alk is a lipophilic alkyl chain. In step a3 compound 3A is reacted with a suitable long-chain carboxylic acid halide 3B in a suitable aprotic dipolar solvent to obtain compound 3C. The latter is reacted (step b3) with compound 3D, i.e. 1, , 7, 10-tetraaza-cyclododecane-l, 4 , 7, 10-tetraacetιc aciα of which three acetic groups are protected with, for example, benzyl or t-butyl groups, in the presence of 1-propanephosphonιc acio cyclic anhydride (PPAA) and a base (e.g. Et3N) in a suitable solvent such as CH 2 Cl2. Compound 3E ODtamed in step c3 is deprotected by known methods (e.g. by catalytic hydrogenation) which provides the free ligand 3F, which is then complexed with a metal (step d3) , according to the procedure describeα earlier. This affords the desired complex cnelate 3G . Then, compound 3G may be salifieα with a suitable counter-ion if the value of m permits. For preparing the compounds of formula (lie) in which A is -NH-, one can proceed like in the previous scheme, the first step (condensation of triprotected 1, 4 , 7, 10-tetraazacyclododecane-l, 4 , 7 , 10- tetraacetic acid (4A) with an amine H2N-A1-NR7R8 (4B) being effected in the presence, as condensing a agent, of (benzotrιazo-1-yloxy) - tris (dimethylammo) -phosphonium hexafluorophosphate and a sterieally hindered tertiary amine such as diisopropylethylamine (DIEA) when 4B is an a-aminoacid derivative, or N. ' -bis (2-oxo-3-oxazolιdyl ) - phosphoro-diamidic chloride (BOP). This is illustrated in Scheme 4. Scheme 4 PgOOC — v r— L-_ PgOOC—/ 4A 4C 4 D 4E A similar methcα can be applied for coπpounαs (lie) in whicn A is -0-, i.e. the esterification of triprotected 1, 4, 7, 10- tetraazacyclododecane-l, 4 , 7, 10-tetraacetιc acid with a halogenated compound X-A1-NR7R8 m the presence of 1 , 8-d azabιcyclo [5.4.0] unαec- ene. Then tne resulting intermediate 5C is deprotected, complexed and salified as in the previous schemes (Scheme 5). Scheme 5 PgOOC— \ I \ / —COOPg PgOOC— \ I \ / —COOPg M DEPROTECTION • N N — - X X.-AA11--rN.RR, 7 RR 8 . I (.5.BR)I , N N - L. N N I_J ] DDBBUU ( (AA5S), C L_ N N J-J o b5 PgOOC — x \ / — COOH PgOOC — / \ / ^-"^ (4B) O-A,- 4A 4C 5D 5E The compounds of formula (Ilia) can be obtained as illustrated in Scheme 6. The protected 1, 4 , 7, 10-tetraazacyclododecane-l, 4 , 7-trιacetιc acid 6A is reacted with an alkyl epoxide / ^—R in a solvent such as ethanol and the resulting product is deprotected and treated as described in the previous schemes Scheme 6 PgOOC— \ / \ /—COOPg 0 - N N ^ ^_ (6B ) + Heat, then (H + > p 9 00 C-\ ri ^-COOPg C - N 3 N " ^ I J OH PgOOC -/ \ / ~ H a6 b6 / N N PgOOC — ^ \ / 6A 6C COMPLEXATION/SAUFICATION OOC — \ / \ / — COO » . I Me m+ I OH c6 N - OOC - 6D A possible technique for making the compounds (Illb) and the corresponding metal chelates and salts is illustrated in Scheme 7. Here the initial reactant to be condensed with the triprotected 1, 4 , 7, 10-tetraaza-cyclododecane-l, 4, 7-trιaacetιc acid is 2,3- epoxypropanol 7B which provides the vic-diol 7C, the primary -OH of which is thereafter esterified with an acid Rg-COOH, the remaining steps being as described previously. Scheme 7 7A 7C The following preparative methods are applicable regarding the compounds of formula (IV) in which R12 is H. For instance, for the compounds (IVa), one may operate as illustrated in Scheme 8, by reacting in DMF the DTPA cyclic dianhydride (N, N-bis [2- (2, 6-dιoxo-4- morpholmyl) ethyl] gly-cme) 8A with an amine H2NR14, the remaining step being that of co plexation with a metal and possible salification as discussed earlier. Scheme 8 0 r COOH O H 2 N-Chaιn r COOH → HOOC N' ~ N COOH a8 Cham-NH-CO CO-NH-Chain 8A 8C COMPLEXATION/SALIFICATION r COO OOC N ' N COO b8 Chain-NH-CO J n+ CO-NH-Chain Me' 8D Otherwise, one may first effect protection of up to four cf the - COOH's groups in DTPA, tne unprotected group being thereafter amiαated _.n DMF witn an amine H2 R 4 according to usual means (see Scheme ' Scneme 9 r COOH ,CONHR Condens with H 2 NR 14 ^ PgOOC N N COOPg PgOOC N' ' N COOPg PgOOC COOPg PgOOC COOPg One preparative route for the compounds of formula (IV) with a substituent R12 in α- to the central carboxylic function is to first attach in the said position, a carbon chain functionalized with, for example, a -NH2 or -COOH group (Scheme 10) . For example, compound 10A can be prepared, according to Rapoport et al. in J. Org. Chem. 58 (1993), 1151-1158, or using a method disclosed in WO 98/05626. The synthon is then reacted with, for example, a chloride of a carooxylic acid having the desired chain length, or with a suitable amine, depending on the nature of the said functional group. The ' -, the resulting compound 10B is deprotected and complexed as already shown in the previous Schemes. Scheme 10 Functionalized subst ^ .COOH R,, .COOH RCOCI OR NH 2 etc , N ^ /\ PgOOC N COOPg f PgOOC N ^ ^^ ~^ N COOPg PgOOC COOPg PgOOC ^" COOPg 10A 10B R 12 COO DEPROTECTION COMPLEXATION/SALIFICATION ' N^ ^ ^ COO 00c ^ Me n+ coo 10C Tnis tecnmαue _s exemplified m the syntnesis or -e compound of Example 16 involving reaction with cholesteryl cnlorofornate . The mjectable compositions and formulations according to the invention wnich are .saole as contrast agents ror MRI _nvestιgatιons will preferably contain further additives, in adoitior tc one or more of the afore discussed novel oaramagnetic chelates and a carrier liquid. The additives mcluae non-ionic and/or ionic surfactants and mixtures thereof, as well as other amphipatic compounds. Due to their physiological suitability, the non-ionic surfactants are preferred. The non-ionic surfactants are preferably block-copciymers having polyoxyethylene and polyoxypropylene sequences, poly ethyleneglycol- alkylethers such as, for example, polyethyleneglycol-cctadecylether, or polyoxyethylene fatty acid esters or polyoxyethylene sorbitan fatty acid esters, or n-alkyl glycopyranoside and n-alkyl maltotrioside . The non-ionic surfactant in the compositions of the invention is conveniently selected from the commercially available products, such as Pluronic ®, Poloxamer®, Poloxamine®, Synperonic®, BRIJ®, Myrj®, Tween ®s (polysorbates ) and their mixtures. The weight proportion of the surfactant relative to the amount of the paramagnetic imaging agent is from 1:50 to 50:1, preferacly 1:10 to 10:1, and even more preferably 1:1. The ionic surfactants preferably include biliary acid salts such as sodium deoxycholate . The amphipatic compounds suitable in the present compositions are phospholipids which may be selected from phosphatidic acid (PA), phosphat: dylcholme (PC), phosphatidylethanolami e (PE), phosphatioylsenne (PS), phosphatidylglyceroi (PG), phosphatidylmositol (PI), cardiolipin (CL) and sphyngomielin (SM) . The amphipatic compound may also consists of a monophospnate ester of a substituted or partially substituted glycerol, at least one functional group of said glycerol being esterified by saturated or unsaturated aliphatic fatty acid, or etherified by saturated or unsaturated alcohol, the other two acidic functions of tne phosphoric acid being either rree or salified with alkali or earth-alkali metals. Preferably the phosphate esters will include monopnosphates of fatty acid glyceriαes s lected from dimiristoylphosphat dic acid, dipalmitoylphosphatidic acid, or distearoylphosphatidic ac d. The phospholipids may also include diacyl and dialkyl glycerophospholipiαs _n nich the aliphatic chains have at least twel e carDon ators, as v.e_._. as one or ^ σ re compounds selected from ionic and .eu:ra_ pnosononpiαs, monoaikyl or alkenyl esters of pnospnoric aciσ ano/cr cholesterol, ergosterol, phytosterol, sitostero , lanosterol, tocoonerci . In the compositions containing phospholipids, tne weignt proportion of the phospholipiαs to the amphiphilic chelate seems not critical and it may vary, for example, from 1:50 to 50:1. The practical range will be between 10:1 and 1:10, preferably between 1:5 and 5:1 and even more preferably between 1:3 and 3:1. In the compositions in wnich phospholipids are used the weight ratio of the phospholipiα to the surfactant may vary as above, nowever the ranges from 1:10 to 10:1 and, preferably, between 1:2 and 2:1 are considered optimal. The compositions of the present invention may exist in micellar form, in which case they can De prepared using known techniques, namely as described in WO 97/00087; Poly . Prepr . 1997, 38(1), 545- 546; Acad. Radiol. 1996, 3, 232-238. These documents describe micelles of amphiphilic Gd chelates useful in percutaneous lymphography . The micelles have particle size between 10 and 500 nm, preferably between 50 and 200 nm. The micelles can be prepared in any physiologically acceptable aqueous liquid carrier, such as water or saline, neat or bufferd, according to usual practice. Depending upon the choice of the components, the dispersion can be achieved by gentle mixing or by more energetic means, such as homogenisation, microfluidization or sonication. In an advantageous mode of preparing the micelles of the invention, one part by weight of tne paramagnetic chelate contrast component is admixed with one to two parts each of surfactants and of lipids, and with 100 to 200 parts of liquid carrier, for example Tris/Glycerol buffer. The compositions can be stored and used as such, or may be lyophilized dry, according to known methods, e.g. by freeze-αrying. This dry form (porous lumps or free flowing powder) is particularly convenient for long-term storage. The formulations can be reconstituted before usage by dispersion of the lyophilizate m a physiologically acceptable liquid carrier, tnus obtaining a suspension corresponding to the eaπy formulation and directly usable cs NMR imaging contrast agent. For prac t ically applying the compositions of the invention in tne medical field, tne lyophilized components and the carrier liquid can be marketed separately m a kit form. The lyophilizeα components may be stored under a dry, ^ nert atmosphere ana the carrier liquid may further contain isotomc additives ana other physiologically acceptable ingredients, such as various mineral salts, vitamins, etc. The compositions of the invention are particularly useful as magnetic resonance contrast agents for the imaging of the blood pool. They have shown to possess a sufficiently high relaxivity effect on the blood after injection m the rat and an exceptionally favourable elimination kinetic profile from the blood circulation, as demonstrated by pharmacokinetic and biodistribution data. These two combined characteristics make them very suitable for angiographic magnetic resonance imaging m general. The compositions of the invention can therefore facilitate MR angicgraphy and help to assess myocardial and cerebral ischemia, pulmonary embolism, vascularization of tumours and tumour perfusion. The following examples further illustrate the invention in more detail . Example 1 [10-Hexadecyl-l, 4,7, 10-tetraazacyclododecane-l, 4,7-trιacetato(3- ) Iqadolinium 10-Hexadecyl-1,4,7, 10-tetraazacyclododecane-l, 4, 7-trιacetιc acid A mixture of 1 , 4 , 7, 10-tetraazacyclodooecane-l, 4 , 7-trιacetιc acid tris (1, 1-dιmethyiethyl) ester (prepared according to EP-A-299795) (20.6 g; 40 mmol) and i-bromohexadecane (12.4 g; 40.6 mmol) in CH3CN (500 mL) was heated to reflux for 2 h. Then, the reaction mixture was evaporated and the residue was flash chromatographed (CH2Cl2/MeOH = 9/1 (v/v) to give a solid. This product was dissolved in CHCI3 and an excess CF3COOH was addeo. After 2 h the reaction mixture was evaporated and tne oily residue redissolved m CF3COOH. After 16 h at room temperature the solution was evaporated and the residue was ourified by flash chromatograpny (CH2CI2 /MeOH/UH OH 25 (w/w) = 12/4/1 (v / v/v)). Tne product was α_sso veα m ri2θ ano acιc_f_eα w± z i -z HCI, the solution was loadeα onto an Amberlite"- XAD-8 resin co__.™n and eluted with a CH3CN/H2O gradient. The fractions containing tne product were evaporated ana oneo under reduced pressure to give the desired product (6.1 g; 1- mmol . Yield 35%. HPLC: 98% (area . ). Karl Fisher (K.F.)- 4.05 . The " -NMP, MS and IR spectra were consistent with t e structure. Elementa1 analysis ( s ) : anhydrous i ) flO-Hexadecyl-1, 4,7, 10-tetraazacyclooodecane-l , 4,7- tπacetato (3-) Iqadolinium A solution of GdCl3"6H2θ (3.9 g; 10.5 mmol) in H2O (40 L) was added to a solution of the product from the previous preparation (6 g; 10.5 mmol) in H O; the pH was maintained at 6.8 by addition of a solution of NaOH IN (30 mL) . The solution was treated with n-BuOH and the organic phase was evaporated to give a solid that was extracted at reflux with CHCI3 in a Soxhlet apparatus. The solution was evaporated to give a solid. The product was dissolved in H2O and i-PrOH, loaded onto a mixed bed of Amberlιte D IRA 400 (250 mL) and Duolite 0 C20 MB resin (250 mL) ; then, it was and eluted with H2θ/ι-PrOH 1:_. The fractions containing the product were evaporated to give the title compound (2 g; 2.7 mmol). Yield 26%. HPLC : 99% (area % ) ; K.F. : 2.49%; Weight loss: (120°C): 10.45%. The MS and IR spectra were consistent with the structure postulated. EXAMPLE 2 [ 10-Oct aoecyl - l , 4 , ~ > , 10 -tet raa zacyclooooecane- l , 4 , 7 - t nacetato ( 3- ) ] gadol inium A ) 10-Octadecvl- l , 4 , 7 , 10-tetraa zacyclododecane- l , 4 , 7 -t rιacet ιc acid A mixture of 1 , 4 , 7 , 10-tetraazacyclododecane-l , 4 , 7-trιacetιc acid trιs(l, 1-dιmethylethyl) ester (37.5 g; 72.8 mmol) and 1- bromooctadecane (24.5 g; 73.5 mmol) in CH3CN (500 mL) was heated to reflux. After 2 h the reaction mixture was evaporated and the residue was dissolved in CHCI3 and a portion of CF3COOH was added. After 16 h at room temperature the reaction mixture was evaporateα and the oily residue dissolved in CF3COOH. After 3 days at room temperature, the solution was evaporated, the residue taken up in CHCI3 and the solution evaporated. This operation was repeated three times. The oily residue was purified by flash chromatography as follows: Eluents: (a) CH2Cl2/MeOH = 3/1 (v/v) 3 litres (b) CH2Cl2/MeOH/NH 4 OH 25% (w/w) = 12/4/1 (v/v/v) 12 litres (c) CH2Cl2/MeOH/NH4θH 25% (w/w) = 6/3/1 (v/v/v) 2 litres The product was dissolved in H2O and acidified with 6N HCI; then, the solution was loaded onto an Amberlite^ XAD-8 resin column and eluted with a CH3CN/H2O gradient. The product started eluting with 20% CH3CN. The fractions containing the product were evaporated and dried under reduced pressure to give the desired product (24.2 g; 40 4 mmol) . Yield 55% . HPLC : 91% (area %); K.F. : 8.01%; the 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): anhydrous B) [10-Octaoecyl-l, 4, 7, 10-tetraazacyclododecane-l, 4,7- triacetato (3-) ] gadolinium (CH3COO)3Go (7.05 g; 1 ~ .3 mmol) was added to a suspension of the free ligand issued from tne orevious preparation (10.4 g; 17.3 mmol) m MeOH (400 mL) at 50°C. T e reaction mixture was kept at 50°C for 1 h, after which the clear solution was evaporated and dried under reduced pressure to give the title compound (11 g; 14.6 mmol). Yield 84%. HPLC : 100% (area %); K.F. : 1.83%; Weignt loss (120°C) : 5.04%. The MS and IR spectra were consistent with the structure. Elemental anal sis (%) EXAMPLE 3 [ 10- ( 2-Hydroxyoctadecyl ) - 1 , 4 , 7 , 10-tetraazacyclo-dodecane- l , 4 , 7 - triacetato- ( 3- ) ] qadolinium ) 10- (2-Hydroxyc tadecyi ) -1 , 4 , 7 , 10-tetraazacyclodode-cane- 1 , , 7-trιacetιc acid A solution of 1, 2-epoxyoctadecane (17.4 g; 65 mmol) in abs. EtOH (100 mL) was added dropwise to a solution of 1,4, 7, 10- tetraazacyclododecane-l, 4,7-trιacetιc acid tris- (1, 1-dιmethylethyl ) ester (33.3 g; 65 mmol) in abs. EtOH and the mixture was heated to reflux. After 3 h, the reaction mixture was evaporated and the residue was dissolved m EtOAc and wasned with brine. The organic pnase was separated, dried over a2SOa and evaporated under reduced pressure. The residue was flasn-chromatographeo, (Eluent: CH2Cl2/ eOH = 9/1 (v/v) ) The obtained product was dissolved m 5N HCI (500 mL) and the solution was heated to reflux. After 1.5 h, the mixture was evaoorated ano t ne residue purified oy flash cnromatography CH2Cl2 MeOH NH 4 OH 25% (w/w) = 12/4/1 (v/v/v) ) Tne product was dissolved in H2O and 6N HCI, the solution was loaoed onto an Amberlite ® XAD-8 resin column (800 mL) and eluteo witn a CH3CN/H2O gradient. The fractions containing the product were evaporated and dried under reduced pressure to give the desired product (18 g; 29 mmol) . Yield 45 %. Acidic titer (0.1 N NaOH): 95 % HPLC: 94% (area %); K.F.: 7.10%. The 13 C-NMR, MS and IR spectra were consistent with the structure . Elemental analysis (%): anhydrous BJ [10- (2-Hydroxyoctadecyl) -1,4,7, 10-tetraazacyclodode-cane- 1, 4, 7-trιacetato-(3-)] gadolinium Gd2θ3 (3.62 g . ; 10 mmol) was added to a solution of the free ligand issued from the previous preparation (12.3 g; 20 mmol) in H2O (150 mL) and the resulting suspension was heated at 50°C for 40 h. The. reaction mixture was filtered through a Millipore'-' apparatus (HA 0.45 μm filter); the filtrate (pH 6.7) was evaporated under reduced pressure and dried to give the title compound (14.2 g.; 18 mmol). Yield 92%. Free ligand : 0.7%; HPLC : 95 % (area %); K.F. : 7.94 %. The MS and IR spectra were consistent with the structure. Elemental analysis (%): nhydrous EXAMPLE 4 [10- [2- (Octadecylamino) -2-oxoethyl] -1, 4, 7, 10-tetraazacyclododecane-l, 4 , 7-trιacetato (3-) ] gadolinium A) 2 -Bromo-Λ/-octadecylacetamιde ' C . A . S . regist ry numoer 154 91 - 4 3- 7 ) A solution of ororroacet _ oromide (44.4 g; 0.22 r-ol) _.n CH2CI2 (50 mL) was added dropwise _n 2.5 h at 20°C to a mixture of octadecylamine (59.3 g; 0.22 clj and K2CO3 (30.4 g; 0.22 mol) in CH2CI2 (600 mL) and H2O (600 rrl, After 16 h at room temperature the organic layer was separated, asned with H2O, dried o"er Na2Sθ4 and evaporated. The crude product was purified by f asn chromatography (CH2Cl2/MeOH = 100/1 ( v/v ) ) to give the desired product (60 g; 0.154 mol). Yield 70%. GC : 96% (area .), K.F. <0.1^ H-NMR, 13 C-NMR and MS spectra were consistent with the postulated structure. Elemental anal sis (%) B) 10- [2- (Octaoecylamino) -2-oxoethyl] -1,4, 7, 10-tetraazacyclododecane-l, 4, 7-trιacetιc acid A mixture of 1, 4, 7, 10-tetraazacyclododecane-l, 4 , 7-trιacetιc acid tris (1, 1-dιmethylethyl) ester (24 g; 46.6 mmol) and 2-bromo-N- octadecylacetamide (18.2 g; 46.6 mmol) in EtOH (500 mL) was heated to reflux. After 2.5 h, the reaction mixture was evaporated, the residue was dissolved in CH2CI2 and CF3COOH was added. After 15 min, the solvent was evaporated and the oily residue dissolved in CF3COOH. After 16 h at room temperature the solution was evaporated and the oily residue was purified by flash chromatography (CH2Cl2/MeOH = 3/1 (v/v); then CH2Cl2/MeOH/NH 4 OH 25% (w/w) = 12/4/1 (v/v/v)). The product was dissolved m H2O and 6N HCI, the solution was loaded onto an Amberlite® XAD-8 resin column and eluted with a CH3CN/H2O gradient. The product elutes with 50% CH3CN. The fractions containing the product were evaporated and dried under reduced pressure to give the desired product (12 g; 18 mmol). Yield 39%. Acidic titer (0.1 N NaOH): 91%; HPLC: 95% (area %); K.F.: 8.82%. The C-NMR, MS and IP spectra were consistent with the structure . Elemental analysis (% ) : anhydrous C ) [10- [2- (Octadecyiammo) -2-oxoethyl] -1,4, 7, 10-tetraazacyclododecane-l , 4, 7-tr acetato'3~) ] gadolinium Gd2θ3 1.97 g; 5.4 mmol) was added to a solu o n of tne free ligand from the previous preparation (7.12 g; 9.7 mmcl) in H2O (310 mL) and the resulting suspension was heated to 50°C for 9.5 h. The reaction mixture was filtered through a Millipore rercrane { HA 0.45 μm filter) and the solution was evaporated to give tne title compound (8.6 g; 9.5 mmol). Yield 98%. HPLC: 98% (area %); K.F. : 9.98%; MS and IR spectra were consistent with the structure. Elemental analysis (%): EXAMPLE 5 [ 10- [2- (Dioctadecylamino) -2-oxoethyl] -1,4,7, 10-tetraazacyclododecane-l, 4 , 7-trιacetato (3-) ] adolinium A) 2-Bromo-N, N-dioctadecylacetamide This novel compound was prepared as follows: Brorroacetyl bromide (4.25 g; 21 mmol) was added dropwise to a solution of oicctadecylamine (10 g; 19 mmol) and Et3N (2.13 g; 21 mmol) in CHCI3 (4C0 mL) . After 4 h at room temperature the reaction solution was washed -with H„0, dried over Na2S0 4 and evaporated. The residue was purified by flash chromatography (n-hexane/Et2θ = 8/2 (v/v) to give the αesired product (7.5 g; 11.5 mmol) . Yield 61%. K.F.: <0.1%; The 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the postulated structure Elemental analysis (% B) 10- [2- (Dioctadecylamino) -2-oxoethyl] -1,4, 7, 10-tetraazacyclododecane-l , 4, 7-trιacetιc acid tr hvdrochloride A mixture of 1 , 4 , 7 , 10-tetraazacyclooodecane- 1 , 4 , " '-triacetic acid tris (1, 1-dιmethylethyl ) ester (14.4 g; 28 mmol) and 2-bromo-Λ/. Λ7- dioctadecylamide (18.1 g; 28 mmol) m EtOH (800 mL) was heated to reflux. After 3 h the reaction mixture was evaporateα and tne residue was dissolved in CH2C12- The solution was washed with brine, dried over Na2Sθ4 ana evaporated to give the crude alkylated ester. This product was suspended in 5N HCI and refluxeo. After 2 h the suspension was filtered, the solid was washed with 5N HCI and dried under reduced pressure to give the desired compound (21.5 g; 21 mmol) . _ιeld 75%. HPLC: 95.7 % (area %). Argentometric titer (0.1 N AgNθ3): 98.5%; K.F.: 4.79%. The 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the desired structure. Elementa1 analysis (% ) : CJ [10- [2- (Dioctadecylamino) -2-oxoethyl] -1,4,7, 10-tetraazacyclododecane-l, 4 , 7-trιacetato (3-) ] gadolinium A solution of GdCl3-6H2θ (5.8 g; 15.7 mmol) in H2O (50 mL) was added dropwise to a refluxmg solution of the product from the previous preparation (16 g; 15.7 mmol) and 1 N NaOH (94.3 mL; 94.3 mmol) in abs. EtOH (1 L) . After 1.5 h the mixture was cooled to room temperature, filtered and concentrated to half its volume, thus causing the precipitation of a solid which was filtered, washed with H~0 and dried under reduced pressure. The solid was purified by flash chromatography (CH2Cl2/MeOH/Et3N = 16/4/1 (v/v/v) ) and then suspended in H2O at 50°C for 3 h. The suspension was drained and the solid was washed with H„0 and dried under reduced pressure to give the title compound (11.5 g; 10.8 mmol). Yield 69%. HPLC: 96% (area %); K.F.: 3.93%. The MS and IR spectra were consistent with the structure. Elemental anal sis (%) anhydrous EXAMPLE 6 [10- [2-Hydroxy-3- [ ( l-oxooctadec_/l ) oxy] propyl] -1, 4 , , 10-tetraazacyclododecane-l, 4, 7-trιacetato(3-) ] gadolinium A) 10- (2, 3-Dιhydroxypropyl) -1,4,7, 10-tetraazac clodo-decane- 1, 4, 7-trιacet c acid tris ( 1 , 1-dιmethylethyI ) ester adduct with NaCl A solution of 2, 3-epoxypropanol (3.7 g; 50 mmol) in aos . EtOH (80 mL) was added dropwise in 30 min to a refluxing solution of 1,4, 7, 10- tetraazacyclododecane-l, 4,7-trιacetιc acid tris ( 1, 1-dimethylethyl ) ester (25.7 g; 50 mmol) in abs. EtOH (250 mL) . After 2.5 h the solution was evaporated, the residue taken up with EtOAc and washed with brine. The organic phase was separated, dried (Na2S0 4 ) and evaporated. The crude was purified by flash cnromatography (CH2Cl2/MeOH = 9/1 (v/v) ) to give the desired compound (24 g; 37 13 mmol). Yield 74%. K.F.: 1.30%; The C-NMR, MS and IR spectra were consistent with the desired structure. Elemental anal sis (%): anhydrous B) 10- [2-Hydroxy-3- [ ( 1-oxooctadecyl ) oxy] propyl] -1, , 7, 10-tetraazacyclododecane-l, 4 , 7-trιacetιc acid tris- (1, 1-dimethylethyl) ester adduct with NaCl A solution of dicyclohexylcarbodnmide (0.43 g; 2.1 mmol) in CHCI3 (10 mL) was added dropwise in 10 min to a solution of stearic acid (0.44 g; 1.5 mmol) (commercial product), 10-(2,3- dihydroxypropyl) -l,4,7,10-tetraazacyclo-dodecane-l,4,7-tπacetιc acid tris (1, 1-dimethylethyl) ester adduct with NaCl (1 g; 1.5 mmol) and 4- (dimethylammo) pyridine (0.06 g; 0.5 mmol) (commercial oroduct) m CHCI3 (40 mL) at 0°C. The temperature of the reactio- mixture was allowed to come back to normal. After 16 h, the mixture was concentrated to half its volume, the precipitate was filtered off and the solution evaporated. The crude was purified by flash chromatograpny (CH2Cl2 MeOH = 10/1 'v/v* ) tc give tne αesireα co-pouno (0.95 g; 1.04 mmol). Yield 67%. The 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the structure. C) [10- [2-Hydroxy-3- [ ( 1-oxooctaoecy- ) oxy] propyl] -l^ ^lG- etra- azacyclo-dodecane-1, 4, 7-trιacetato ( 3-) ] gadolinium CF3COOH (20 mL) was added to a solution of the product from the previous preparation (13.9 g; 15.2 mmol) in CH2CI2 (5 ml). After 24 n the solution was evaporated and the residue taken up witr. more CF3COOH (15 mL) . After 6 h the mixture was evaporated and the crude oesa teα by dialysis (Spectra/Por® CE (Cellulose Ester) membrane MWCO 5 0/ tc afford a white solid (4 g) . A portion of this solid (2.9 z , was dissolved in 2-propanol (100 L) and H2O (25 mL) at 80°C then (CH3COO)3Gd (1.7 g) was added and the solution kept at 80°C for 3 h. The reaction mixture was evaporated and the residue was purified by flash chromatography (CH2Cl2/MeOH/H2θ = 5/5/1 (v/v/v) ) to gi-e tne title compound (1.53 g; 1.8 mmol). Yield 12%. HPLC : 100% (area % ) ; Weight loss (120°C) : 4.96%. The MS and IR spectra were consistent with the postulated structure. Elemental analysis (% ) : EXAMPLE 7 [ 10- [2-Hydroxy-3- [ [ [2- (Octadecyloxy) -1- [ (octadecyloxy ) methy_ - ethoxy] -acetyl]oxy] propyl] -1, 4,7, 10-tetraazacyclododecane-i , 4 , 7-trι- acetato ( 3- gadolm um A) 1, 3-Bιs (octadecyloxy) -2-propanol (C.A.S. Registry No. 18794- 74-6) Epichlorohydrin (4.6 g; 50 mmol) was added in 5 mm to excess stearyl alcohol (117 g;433 mmol) at 70°C in the presence of 8__ NaH mineral oil dispersion (1.65 g; 55 mmol) (commercial product . Tne mixture was stirred for 6 h, then cooled to room teπroerature ana treated with Et2θ (2 L . The mixture was filtered and tne solution evaporated. The cruoe product was crystallized four times from acetone to give the desired compound ( 16.5 g; 27.6 mmol). Yield 55%. K.F. : 1 ι 3 _0.1%. The H-NMR, C-N f 'R, MS ano IR spectra were consistent with the aoove structure. Elemental analysis (%): B) [2- (Octadecyloxy) -1- [ (octadecyloxy) methyl ] ethoxy] -acetic acid (C.A.S. Registry No. 79979-56-9) 80% NaH mineral on dispersion (2.65 g; 88 mmol) was added under nitrogen atmosphere to a solution of 1, 3-bιs (octadecyloxy) -2-propanol (6.92 g; 11.6 mmol) in THF (200 mL) . The mixture was heated to reflux and a solution of BrCH2COOH (8.1 g; 58 mmol) in THF (50 mL) was added dropwise in 30 mm. After another 30 min, MeOH was added, then the solvent was evaporated. The residue was dissolved in Et2θ, washed with 0.1 N HCI, dried and evaporated. The crude product was crystallized twice from EtOAc to give the desired compound (5.7 g; 8.7 mmol) . Yield 75%. K.F.: 0.47 the 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the foregoing structure. Elemental analysis (%] anhydrous C) The title compound was then prepared, starting from [2- (octadecyloxy) -1- [ (octadecyloxy)methyl] ethoxy] acetic acid and the intermediate (A) of Example 6, according to the synthetic method reported in Example 6. EXAMPLE 8 [6, 9-Bιs (carboxymethyl) -3- \2- (octaαecyi amino) -2-oxoet-hyl ] -11- oxo-3, 6, 9, 12-tetraazatrιacontanoato (3-) ] gadolinium A) 6, 9-Bιs (carboxymethyl) -3- [2- (octadecylammo) -2-oxoethyl] -11- oxo-3, 6, 9, 12-tetraazatrιacontanoιc acid (C.A.S. Registry Number 135546-68-8) The product was synthesized following the procedure F. Jasanada and F. Nepveu in Tetrahedron Lett. 33 (1992), 5745-5748. KF: 0,54%. 1 13 The H-NMR, C-NMR, MS and IR spectra were consistent with the foregoing structure. Elemental analysis (%) anhydrous B) [6, 9-Bιs (carboxymethyl) -3- [2- (octadecylammo) -2-oxoethyl] -11- oxo-3, 6, 9, 12-tetraazatrιacontanoato (3-) ] gadolinium This product was synthetized according to G.W. Kabalka et al. Magn. Reson . Med. 19 (1991), 406-415. Yield 82%. Weight loss (130°C): 5.95% The MS and IR spectra were consistent with the desired structure . Elemental analysis ( EXAMPLE 9 6, 9-Bιs (carboxymethyl) -3- ι2-oxo-6, 9, 12, 15, 18, 21, 24-hep-taoxa-3- azapentacosyi)-ll-oxo-15, 18, 21, 24, 27, 30, 33-heptaoxa-3, 6,9, 12-tetraaza tetratriacontanoato (3-) ] gadolinium A) 6, 9-Bιs (carboxymethyl) -3- (2-oxo-6, 9, 12, 15, 18,21, 24-heptaoxa-3- azapentacosyl) -ll-oxo-15, 18, 21, 24, 27, 30, 33-heptaoxa-3, 6, 9, 12-tetraaza tetratriacontanoic acid N, N-Bi s [2- (2, 6-dιoxo-4-morpholmyl ) ethyl] glycine (commercial product) (8.93 g; 25 mmol) was added to a solution of 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-amιne (prepared according to WO 95/17380) (16.97 g; 50 mmol) in DMF (250 mL) at room temperature. After 2 h, the reaction mixture was evaporated and the residue was dissolved in H2O and 6N HCI. The solution (pH 2) was loaded onto an A berlite XAD-1600 resin column and eluted with a CH3CN/H2O gradient. The product starts elutmg with 10% CH3CN. The fractions containing the product were evaporated and dried under reduced pressure to give the desired product (14 g; 13.5 mmol). Yield 54%. HPLC: 96% (area %). K.F.: 1.22%. The 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the above structure. Elemental analysis (%) anhydrous B) 6, 9-Bιs (carboxymethyl) -3- ( 2-0x0-6, 9, 12, 15, 18, 21 , 24-heptaoxa-3- azapentacosyl) -ll-oxo-15, 18,21,24,27,30, 33-hepta-oxa-3, 6,9, 12-tetraaza tetratriacontanoato (3-)] gadolinium Gd2θ3 (1.86 g; 5.1 mmol) was added to a solution of the free _ιgand from the previous preparation (10.62 g; 10.2 mmol) in H2O (200 L) and the resulting suspension was heated at 50 °C for 7 h. The reaction mixture was filtered tnroagh a Millipore® apparatus '^ 0.45 μm filter) ; the filtrate was evaporated and dried ander reduced pressure to give the title compound (11.9 g; 10 mmol). Yield 98%. Free ligand (C.OOl M GdCl3>: 0.05% (w/wj . HPLC: 98% (area % . K.F.: 1.69 %. Weight loss (120°C): 1.58%. The MS and IR spectra were consistent with the structure. Elemental anal sis (%) anhydrous EXAMPLE 10 [6, 9-Bιs (carboxymethyl) -3- (2, 16-dιoxo-6, 9, 12-trιoxa-3, 15-oιaza- ririacontanyl) -11, 25-dιoxo-15, 18, 21-tπoxa-3, 6, 9, 12, 24-pentaazado- etraontanoato (3-) ] gadolinium A) 1- [ (1-Oxooctadecyl ) oxy] -2, 5-pyrrol dmedione : . A . S . Registry Number 14464-32-5) This compound was synthetized according to M. Shinitzky and R. Haimovitz in J. Am . Chem . Soc . 115 (1993), 12545-12549, and Y. Lapidot, S. Rappoport and Y. Wolman in J. Lipid Res . 8 (1967), 142- 145. Yield: 86%. K.F.: <0.1 %. The 1 H-NMR, 13 C-NMR and IP spectra were consistent with the structure. Elemental analysis (%): B) 3, 6, 9-Trιoxaundecane-l, 11-dιamιne (C.A.S. Registry No. 929-75-9) This compound was prepared according to the method discloseα in Liebigs Ann. Chem. 2 (1990), 129-143. Elemental anal sis C) 13-OXO-3, 6, 9-trιoxa-12-azatrιaconτanyiamιne H 35 c 17-CONH-[ (CH2)2~0) 3-(CH2>2-N H 2 1- [ (1-Oxooctadecyl) oxy] -2, 5-pyrrolιdmedιone (3.87 g; 10.1 mmol) in CHCI3 (600 mL) was added dropwise in 6 h to a solution of 3,6,9- trιoxaundecane-1, 11-dιamιne (19.8 g; 103 mmol) in CKCI3 (100 mL) at 20°C. The reaction mixture was evaporated, the residue treated with CH2CI2 (50 mL) and the suspended solid filtered off. Tne solution was evaporated, the residue treated with H2O and extracted with EtOAc. The organic phases were combined and dried. Concentration to small volume led to the precipitation of the desired compound (4.04 g; 8.8 mmol) which was collected by filtration. Yield 87%. The H-NMR, 13 C-NMR, MS and IR spectra were consistent with the proposed structure. Elemental anal sis (%): anhydrous J 6, 9-Bιs (carboxymethyl) -3- (2, 16-dιoxo-6, 9, 12-trιoxa-3, 15- diazatritπacontanyl) -11, 25-dιoxo-15, 18, 21-trιoxa-3, 6, 9, 12,24- pentaazadotetracontanoic acid N, W-Bis [2- (2, 6-dιoxo-4-morpholιnyl ) ethyl] glycine (commercial product) (6.45 g; 18 mmol) was added to a solution of 12-aza-13-oxo- 3, 6, 9-trιoxatrιacontanylamιne (16.57 g; 36 mmol) in DMF (300 mL) at 70 °C. After 2 h the mixture was cooled to room temperature to give a precipitate that was filtered and washed with acetone. The crude was crystallized twice from acetone. The solid was filtered, washed with acetone and dried under reduced pressure to give the desired compound (17.35 g; 13.6 mmol). Yield 75%. HPLC : 98 % (area %); K.F. : 0.99 %. Weigth loss (120 °C) : 0.95 %. The 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the above structure. Elemental anal sis (%): O 00/30688 32 annvdrous Ej [6, 9-Bis (carpoxyme hyl ) -3- 1 2 , 16-dιoxo-6, 9, 12-trιoxa-3, 15- diazatπtriacontanyl) -11, 25-dιoxo-15, 18, 21-trιoxa-3, 6,9,12,24- pentaazadotetracontanoato ( 3- ) ] gadolinium (CH^COO) 3 Gα- H ? 0 (4.06 g; 10 mmol) was added to a solution of the product from the previous preparation (12.75 g; 10 mmol) in MeOH (600 mL) at 50°C. After 2 h the clear solution was evaporated and dried under reduced pressure to give the title compound (12.3 g; 8.6 mmol) . Yield 86%. Free ligand (0.001 M GdCl 3 ) : 0.02 (w/w). HPLC: 100 % (area %); K.F.: 1.90 %. Weight loss (120°C) : 3.02 %. The MS and IR spectra were consistent with the structure. Elemental analysis (%): anhydrous EXAMPLE 11 [6, 9-Bιs (carboxymethyl) -3- (2, 1 -dιoxo-18 , 21, 24 , 27 , 30,33,36- heptaoxa-3, 15-dιazaheptatrιacontanyl ) -11, 23-dιoxo-27, 30, 33, 36, 39, - 42, 5-heptaoxa-3, 6,9,12, 24-pentaazahexatetracontanoato (3-) ] adolinium A) 11- [ [ (1, 1-Dιmethylethoxy) carbonyl ] amino] undecanoic acid (C.A.S. Registry No. 10436-25-6) 11-Amιnoundecanoιc acid (3 g; 14.9 mmol) was suspended in a 10% solution of Et 3 N in MeOH (200 nL) ; dicarbomc acid bis (1,1- αimethylethyl ) ester (B0C2O) (3.58 g; 16.4 mmol) was added and the mixture was heated to 50°C for 15 run. ~.s soon as the ammoacid dissolved, reaction was complete. After evaporation of the solvent under reduced pressure, the trietrylamror.iurn salt cf tne product was treated witn a 20. solution cf citric acid ιr ~, 0 a d the tree acid was extracted witn EtOAc. The organic phase was separated, dried over Na2S0 and then evaporated under reduced pressure to give the desired compound (4.45 g; 14.1 mmol). Yield 95%. HPLC : 97% (area %); K. F. : <0.1%. Weight loss (60 °Cj : 0.83%. The 13 C-NMR, MS and IR spectra were consistent with the proposed structure. Elemental analysis (%): B) 11 -Amino -A- (3, 6, 9, 12, 15, 18, 21-heptaoxadocosyl ) - undecanam de To a stirred mixture of 11- [ [ ( 1, 1-dιmethyl- ethoxy) carbonyl] ammo] undecanoic acid (8.8 g; 29.2 mmol), 2, 5, 8, 11, 14 , 17, 20-heptaoxadocosan-22-amme (prepared accor-ding to WO 95/17380) (10.9 g; 32.1 mmol) and diethyl cyanophosphonate (DEPC) (5.2 g; 32.1 mmol; 4.9 mL) in DMF (200 mL) , maintained at 0°C, Et_.N (3.3 g; 32.1 mmol; 4.5 mL) was added over 1 h. The reaction mixture was stirred at 0°C for 30 min and then at room temperature for 1 h. The solvent was evaporated under reduced pressure, the crude was dissolved in 1.2 N HCI in MeOH and the resulting solution was stirred overnight. (In an analogous preparation the above-mentioned crude was purified by washing the solution of the product in EtOAc with 5% aq. NaHCOβ and identified as 11- [[( 1, 1-dιmethylethoxy) carbonyl ] amino] -N- ( 3, 6, 9, 12, 15, 18 , 21-heptaoxadocosyl ) undecanamide : HPLC: 91% (area %) . Weight loss (120 °C) : 0.71%; K.F.: 0.64% Elemental anal sis (%) : Anhydrous 13, The " C-NMR, MS and IR spectra were consistent with the structure) . After evaporation of the solvent under reduced pressure, the residue was dissolved in a saturated solution of NaHC03 and then washed with EtOAc. The aqueous phase was separatee and acidified with IN HCI until precipitation of the product occurred, the latter was filtered to give ll-ammo-W- (3, 6, 9, 12, 15, 18, 21-heptaoxa docosyl) undecanamide salified with 1/3 HCI (11.9 g; 22.3 mmol). Yield 76%. HPLC : 95% (area %). K.F. : 0.30%. The C-NMR, ['.S and IR spectra were consistent with the foregoing structure. Elemental anal sis (%): anhydrous C) 6, 9-Bιs (carboxymethyl) -3- (2, 14-dιoxo-18, 21, 24, 27, 30, 33, 36-heptaoxa- 3,15-dιazaneptatrιacontanyl)-ll, 23-dιoxo-27, 30, 33, 36, 39, 42, 45- heptaoxa-3, 6, 9, 12, 24-pentaazahexatetracontanoιc acid N, W-Bis [2- (2, 6-dιoxo-4-morpholmyl) ethyl] glycine (3.8 g; 10.6 mmol) (commercial product) was added to a suspension of ll-amino-N- (3, 6, 9, 12, 15, 18, 21-heptaoxadocosyl) undecan-amide (11.1 g; 21.1 mmol) in DMF (200 mL) . After 15 mm the reaction mixture oecame clear and the conversion was complete. The solvent was evaporated under reduced pressure, the residue was dissolved in CHC1_. and washed w th H„0. The organic phase was separated, dried over Na~SO. and then evaporated under reduced pressure. The solid was dissolved in H„0 and loaded onto an Amberlite® XAD-7 HP resin column (700 mL) and eluted with a CH-,CN/H_0 gradient. The fraction containing the product was evaporated to give the desired compound (11 g; 7.8 mmol). Yield 74%. HPLC : 85% (area %); K.F. : 0.49%. Weight loss (120 °C) : 0.45%. The 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): D) [6 9- -Bis car -boxymethyl) -3 -(2, 14- -dioxo- -18, 21 24, 27 30, 33 36- heptaoxa-3, 15-diazah< _ptatrιacontanyl) -11 23 -dioxo -27 ,30 ,33, 36 ,39 r ~ 42 ,45 -heptaoxa -3 6,9 12 24-pentaazahexatetracontanoato ( 3-)] qa dol inium Gd2θ3 (0.9 g; 2.5 mmol) was added to a solution of the free ligand from the previous preparation (7 g; 5 mmol) in EtOH (100 mL) and H_0 (150 mL) , the resulting suspension was heateo at 65°C for 1 h. The reaction mixture was filtered througn a Millipore 3 apparatus (HVLP type; 0.45 μm filter); the filtrate was evaporated under reduced pressure to give the title compound p.5 g; 4.74 mmol). Yield 95%. Free gadolinium (0.001 M Na-EDTA) : <0.01°. (w/w). HPLC : 96% (area %); K.F. : 1.691. The MS and IR spectra were consistent with the structure . Elemental analysis (%): anhydrous EXAMPLE 12 [ [6, 9-Bis (carboxymethyl) -16-nyαroxy-3- ( 7-hydroxy-2 , 7-dιoxo-e, 8- dιoxa-3-aza-7-phosphatetracosanyl> -11, 16-dιoxo-15, 17-dιoxa-3, 6, 9, 12- tetraaza- 16-phosphatrιtrιacontanoato (5-) ] gadolmate (2- ) η disodium salt Na A) Phosphoric acid mono (2-amιnoethyl) monohexadecyl ester [C.A.S. Registry Number 57303-02-3] A solution of hexadecyl alcohol (26.2 g; 108 mmol) in THF (100 mL) was added dropwise in 30 min to a solution of POCI3 (16.56 g; 108 mmol) and Et 3 N (12.35 g; 122 mmol) in THF (200 mL) at 0°C. After 5 min a solution of ethanolamme (7.2 g; 118 mmol) and Et-,N (43.51 g, 430 mmol) in THF (60 mL) was added dropwise in 60 mm. at 0°C. The reaction mixture was allowed to reach room temperature m 3 h; then it was heated at 40 °C and HCI 10 _ (100 mL) was added. After 2 r. the mixture was cooled to room temperature and addition of H ? 0 (200 mL) afforded a precipitate that was filtered, washed with H„0 and αried under reduced pressure to give the desired product (33.4 g; 91 mrol). Yield 85 %. K.F. : 0.53 .. The ^Η-NMR, 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental anal sis ("): anhydrous B) 6, 9-Bis (carooxymethyl) -16-hydroxy-3- ' 7-hydroxy -2, -dιoxo-6, 8- dιoxa-3-aza-7-phosphatetracosanyl' -11, 16-dιoxo-15, l "7 -d oxa-3, 6, 9, 12- tetraaza- 16-phosphatritriacontanoic acid W,W-Bιs [2- (2, 6-dιoxo-4-morpnolmyl) ethyl] glycme '7.15 g; 20 mmol) (commercial product) was added to a suspension of phosphoric ac d mono ι 2-amιnoethyl ) monohexadecyl ester (14.62 g; 40 mmol) in DMF (700 mL) at 75 °C to afford a solution after 15 min. After 5 h the reaction mixture was evaporated and the crude was treated with H~0 and 2N HCI to give a solid that was filtered, washed with H O and acetone. The solid was purified by flash chromatography (CH-Cl-ZMeOH/NH.OH 25% (w/w) = 6/3/1 (v/v/v) ) The fractions containing the product were combined and concentrated to 200 mL. Acidification with 2N HCI down to pH 1 led to the formation of a precipitate that was filtered, washed with H-,0 and acetone ana dried under reduced pressure to give the desired compound (17 g; 15.6 mmol) . Yield 78 Ϊ. Acidic titer (0.1 N NaOH): 95 %. HPLC: 99 % (area %). Weight loss (120°C) : 3.45 % ; K.F. : 3.06 The 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%) anhydrous C] [ [6, 9-Bιs (carboxymethyl) -16-hydroxy-3- (7 -hydroxy-2 , 7-dιoxo- 6, 8-dιoxa-3-aza-7-phosphatetracosanyl ) -11, 16-dιoxo-15, 17-dιoxa- 3, 6, 9, 12-tetraaza-16-phosphatrιtrιacontanoato (5-) ]gadolmate(2-) ] disodium salt (CH- j COO) 3 Gd- H 2 0 (4.06 g; 10 mmol) was added to a solution of the free liganα from the previous preparation (10.88 g; 10 mmol) in MeOH (500 mL) a a 1 N NaOH (20 mL; 20 mmol) . After 24 h the clear solution was evaporated, the residue dissolved n H~0 (200 mL) and the solution nanofiltered for 16 h : The retentate was evaporated and dried under reduced pressure to give the title compound (11 g; 8.6 mmol). Yield 86 _. HPLC : 99 % (area .). Weight loss (120°C) : 4.33 * K.F.: 4.23 i . The MS ana IR spectra were consistent with the structure . Elemental analysis ( * : anhydrous EXAMPLE 13 l 6, 9-B s (carboxymethyl) -11, 19-dιoxo-3- [ 2- r { 2- [ 2- [ (1-oxoocta- decyl' oxy] ethoxy] ethyl] ammo] -2-oxoetnyl] -15, 18-dιoxa-3, 6, 9, 12-tetra- azahexatriacontanoato ( 3-) ] gadolinium A) Octadecano c acid 2- (2-ammoethoxy) ethyl ester hydrochloride 1.2 M HCI in CH3OH (30 mL) was added to a solution of 2- (2- ammoetnoxy) ethanol (2.1 g; 20 mmol) (commercial product) in CH3OH (30 mL) ; after 30 min the solution was evaporated and dried under reduced pressure to give 2- (2-amιnoethoxy) ethanol hydrochloride (2.9 g; 20 mmol) . Stearoyl chloride (6.4 g; 21 mmol) (commercial product) was added dropwise in to solution 2- 2-amιnoethoxy) etnanol hydrocnloride (2.9 g; 20 mmol) in DMF (50 mL) at room temperature to afford a suspension. After 16 h, the suspension was diluted with acetone and the precipitated solid filtered and wasned with acetone. The crude was crystallized from EtOAc; the solid was filtered, washed with EtOAc ana dried under reduced pressure to give ^e desired compound (3.3 g; 8 mmol). Yield 40%. Acidic titer (0.1 N NaOH): 93 %. K.F. : 1.06-. The lu -NMR, 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (°): anhydrous B) 6, 9-Bis (carooxymethyl) -11, 19-dιoxo-3- [2- f 2— [2— [ ( 1-oxo- octadecyl) oxy] ethoxy] ethyl 1 ammo 1 -2-oxoethyl] -15, 18-d oxa-3, 6, 9, 12- tetraaza-nexatπacontanoic aciα W,W-Bιs [2- (2, 6-dιoxo-4-morpnolmyl) ethyl] glycine (1.9 g; 5.5 mmol) (commercial product) was added to a solution of octadecanoic acid 2- (2-amιnoethoxy) ethyl ester nydrochloride (4.5 g; 11 mmol) and Et3N (1.5 g; 14 mmol) in DMF (150 mL) at 60°C. After 5 mm the temperature was decreased to 45°C. After 2.5 h the mixture was cooled to room temperature to give a precipitate that was filtered, washed with acetone/H2θ 15/5, then with acetone. The crude was dissolved m acetone and 0.1 N HCI and the solution heated at 50°C. After 10 mm the solution was cooled to room temperature to afford a precipitate which was filtered, wasned with acetone/H2θ 15/5 then with acetone and dried under reduced pressure to give the desired compound (1.7 g; 1.5 mmol) . Yield 27 %. HPLC : 100 % (area %) . HPCE : 100 % (area) . K.F.: 3.11 Weight loss (120 °C) 4.49 The H-NMR, 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%) C) [6, 9-B s (carboxymethyl) -11, 19-dιoxo-3- [ 2- [ [2-[2-[ (1- oxooctadecy 1) oxy] ethoxy] ethyl] ammo "1 -2-oxoethyl] -15, 18-dιoxa-3, 6, 9, 12- tetraazahexatriacontanoato ( 3- ) ] gadolinium (CH 3 COO) 3 Gd-4H 2 0 (1.11 g; 2.7 mmol) was added to a solution of the free ligand from the previous preparation (3 g; 2.7 mmol) in MeOH (150 mL) at 40°C. After 1 h the clear solution was evaporated and dried under reduced pressure. The crude was purified by flash chromatography (CH.-OH) to give tne title compound (3.2 g; 2.5 mmol). Yield 94 _. HPCE : 100 % (area %) . K.F.: 4.07%. Weight loss (120°C) : 4.08%. the MS and IR spectra were consistent with the structure. Elemental anal sis (%) : anhydrous EXAMPLE 14 [ [ N, I! ' - ' [ [2- (Octaoecylamino) -2-oxoethyl , imino 1 d -2 , 1-etnaneoιyl bis [ .'.- (carboxymetnyl) glycmato(4-) ] ] gadolm-ate ( 1-' 1 soαium salt OOC N N COO .. ♦ " OOC J o_ » COO A N, A/-bιs[2-[bιs[2-(l, 1 -dimethylethoxy) -2-oxoethyl I amino 1 - ethyl] glyc ne The compound was prepared according to the methca discioseα patent application WO-A-95/32741. B) N, N ' - [ [ [ 2 - (Octadecylam o) -2-oxoethyl] imino αι-2, 1-etnane- diyl] bis [N- [2- (1, 1-dιmethylethoxy) -2-oxoethyl] glycine 1, 1-dιmethyl- ethyl ester] Isobutyl chloroformate (205 mg; 1.65 mmol; 215 μL) was added dropwise to a solution of the product from the previous preparation (950 mg; 1.54 mmol) and Et N (165 mg; 1.65 mmol; 230 μL) in THF (50 mL) at -5°C and under nitrogen. After 15 mm a suspension of octadecylamme (450 mg; 1.65 mmol) in THF (50 mL) was added tc the reaction mixture at -5 C C. After 20 mm the reaction mixture was allowed tc rise to room temperature and stirred cvernignt . Tne suspension was filtered to remove the residual octadecyia ine arc tne solution was evaporated under reduced pressure. Tne residue was dissolved m Et2θ and the solution washed with 5% aq. NaHC03. The organic pnase was dried over Na2S0 4 and then evaporated under reduced pressure. The crude product was purified by flash chromatograpny (CH2Cl2/Me0H = 100/2 (v/v)) to give the desired compound (1.1 g; 1.26 mmol) . Yield 80%. HPLC : 94% (area ~> . The 13 C-NMR, MS and IP spectra were consistent with the structure. CJ N, N ' - [ { [ 2 - (Octadecylammo' -2-oxoethyl] imino 1 dι-2, 1-e nane- dιyl]bιs [ K- ( carboxymethyl) glycine] 0.5 M H2SO4 (100 mL; 50 mmol) was added dropwise to a solution of the tetraester from the previous preparation (21 g; 24.3 mmo_.) m αioxane (150 mL) and the resulting mixture was neated at 90°C for 4 n. The pri of tr.e solution was ac.stea tc 5 witr 2 II NaOH 10 rl arc t-e solvent ..as evaporateα unαer reduceα pressure Tne residue .as dissolved in CHCl3/MeOH (4:1) and the resulting suspension was filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2/MeOH/NH 4 OH 25% (w/w) = 6/3/1 (v/v/v)). The product was dissolved in H2O (150 mL) and 12 N HCI (7 mL) and desalted by elution through an Amberlιte J XAD 7-HP resin column with a CH3CN/H2O gradient. The fractions containing tne product were evaporated to give the desired compound (4 g; 6.2 mmol). Yield 25%. HPLC 99% (area %). K.F.: 3.77%. The 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%) anhydrous D) [ [ N, N '- [ [ [ 2- (Octadecylammo) -2-oxoethyl] ιmιno]dι-2, 1- ethanedιyl]bιs [ N- (carboxymethyl) glycmato (4-) ] ] gadoli-nate ( 1-) ] sodium salt 1 N NaOH (4.5 mL) was added to a suspension of the free ligand from the previous preparation (2.9 g; 4.5 mmol) in 1:1 H2O/CH3CN (600 mL) . A solution of GdCl3'6H2θ (1.66 g; 4.48 mmol) in H2O (50 mL) was added dropwise to the reaction mixture mantamed at pH 6.8 by the addition of 1 N NaOH (13.5 mL) . After 2 h the solution was evaporated; the residue was dissolved in H2O and desalted by elution through an Amberlite® XAD 7-HP resin column (250 mL) with a H2O/CH3CN gradient. The fractions containing the product were evaporated. The solid residue was dissolved in H2O and the solution eluted througn a Dowex® CCR 3LB weak cation exchange resin column (Na form, 20 mL) . The eluate was evaporated and dried under reduced pressure to give the title compound (1.35 g; 1.64 mmol). Yield 35%. HPLC : 100% (area %). K.F.: 8.85%. Weight loss (120 °C) : 8.15%. The MS and IR spectra were consistent with the structure. Elemental analysis (%) EXAMPLE 15 [AT , AT-B s [ 2- [PIS (carboxymeth l) amino] ethyl 1 - U - ( 1-oxooctadecyl ) L-lysmato ( 5-) ] gadolinate (2-) ] disodium salt A) 2 , A^-Bis [2- [b s [2- (1, 1-dιmethylethoxy) -2-oxoethyl ] -amino] - ethyl] -L-lysine 1 , 1-dimethylethyl ester This product was prepared accordmg to Example 2 of WO 98/05626. 13 1 The C-NMR, H-NMR, MS and IR spectra were consistent with the disclosed structure. Elemental analysis (%): BJ N 2 -A^-Bis [2- [b s [2-(l, 1-dιmethylethoxy) -2-oxoethyl] ammo] ■ ethyl] -N - (1-oxooctadecyl) -L-lysine- (1, 1-dimethylethyl) -ester Stearoyl chloride (5.45 g; 18 mmol) dissolved CHCI3 (60 mL) was added dropwise in 1 h to a solution of AT , T-bis [ 2- [bis [2- ( 1 , 1- dimetn lethoxy) -2-oxoethyl] amino] etnyl] -L-lysine 1, 1-dimethylethyl ester (13.5 g; 18 mmol) in CHCI3 (300 mL) at 0°C. After 10 min the reaction mixture was allowed to rise to room temperature and TLC analysis showed the complete conversion of the starting materials. The solution was washed with 5% aq. NaHCθ3, the organic phase was separated, dried over Na2S0 4 and then evaporated under reduced pressure. The crude product was purified Dy flash chromatography (;ι- hexane/EtOAc = 6/4 (v/v)) to give the desired product (11.3 g; 11.2 mmol). Yield 62%. HPLC: 95% (area _). the 1 C-NMR, MS and IR spectra were consistent with the structure. CJ Ar . AT -Bι s [ 2- [ bιs ( carboxymethyl ) amino 1 ethyl ] -M - ( 1 -oxoocta- decyl ) -L-lysine o 9 ϊf ~ , AT-Bis [ 2- [bis [ 2- ( 1 , 1-dιmetr vl ethoxy ) -2-oxoethyl j -ammo ] ethyl ] - ( i -oxooctadecyl ) -L-lysine 1 , 1-d metnylethvl ester τmol ) was dissolved _r 6 N HC_ (200 mL) and the solution was stirred for 3 days. The reaction mixture was directly loaded onto an Amberlite'-' XAD 7-riP resin column and desalted oy eiution with a CH3CN/H2O gradient. The solid obtained from the column was completely converted into tne expected acid by treatment witn neat CF3COOH for 2 n. CF3COOH was eliminated oy repeated dilution with CH2CI2 and Et2θ followed each time by evaporation under reduced pressure. The residue was dried to give the desired product (3.1 g; 4.06 mmol). Yield 45%. HPLC: 94.4% (area %). Weight loss (120°C): 4.22%. The 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): D ) [AT .AT-Bis [2- [bis (carboxymethyl) ammo] ethyl] -N - (1-oxooctadecyl) -L-lysmato (5-) ] gadolinate (2- ) ] disodium salt The free ligand from the previous preparation (2.16 g; 2.96 mmol) was suspended in H2O (50 mL) and dissolved by addition of 1 N NaOH (5.9 mL) . Dropwise addition of a 1 M aq. solution of (CH3COO) 3Gd (2.96 mL) led to the precipitation of a solid, which was dissolved by addition of EtOH (150 mL) . The solvent was evaporated under reduced pressure to give the title compound (2.57 g; 2.66 mmol). Yield 90%. HPLC: 99% (area %). K.F. : 3.81%. Weight loss (120 °C) : 3.84%. The MS and IR spectra were consistent with tne structure. Elemental analysis EXAMPLE 16 ? 6 [ [ N 2 Ar -Bis [ 2 - [ b s ca rpoxymet h /I ) amino ] ethyl ] - ιV - [ ( 3 7)-cho es t - 5- en-3-yl ] oxy ] caroonyl ] -L- ys inato ( 5- ) ] gadol ate ( 2 - ) | di sodium salt A) ^'N 2 - Bιs[2-[bιs[2-(l, 1-dιmethylethoxy) -2-oxoethyl] -amino] ethyl] -A7°- [ [ [ (3/7) -cholest-5-en-3-yl] oxy] carbonyl] -L-lysme 1, 1-dι- methylethyl ester A solution cnolesteryl chloroformate fll mmol ) (commercial product) in CHCI3 (60 mL) was added in 1 h to a solution of A/ 2 , A7 2 -bιs[2- [bis [2- (1, 1-dιmethylethoxy) -2-oxoethyl] amino] ethyl] -L- lysme 1,1-dimethyl ethyl ester (14.9 g; 20 mmol) (prepared according to Example 2 of WO 98/05626) in CHCI3 (150 mL) . The reaction mixture was stirred overnight. The solution was then washed with 5% aq. NaHC03, the organic phase was separated, dried over Na2S0 4 and then evaporated under reduced pressure The crude product was purified by flash chromatography (n-Hexane/EtOAc = 85/15 (v/v) ) to give the desired compound (18.2 g; 15.7 mmol). Yield 7! HPLC : 94% (area %) . 13- Weight loss (100 °C) : 1.23%. The "C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): B) AT 2 , A/ 2 -Bιs [2- [bis (carboxymethyl ) amino] ethyl ] -A/ 6 - [ [ [ ( 3/7) cholest-5-en-3-yl] oxy] carbonyl] -L-lys e 12.6 g of the product from the previous preparation (10.88 mmol) were dissolved in formic acid (250 mL) and refluxed for 1.5 n. The solution was evaporated under reduced pressure, tne crude was suspended water, stirred for 30 min and filtered to give the desired compound (7.8 g; 8.5 mmol). Yield 79%. HPLC: >91% (area %). K.F. : 3.73%. The "C-NMR, MS and IR spectra were consistent with this structure . Elemental anal sis (%): anhydrous C) [ [N 2 , 2 -Bιs [2- [bis (carpoxymethyl) amino] ethyl] -N 6 - [ [ [ (3β) ■ cholest-5-en-3-yl] oxy]carbonyl]-L-lysιnato(5-) ] qadolinate (2-) ] disodium salt 5.3 g of the free ligand from the previous preparation (5.8 mmol) were suspended in H2O (300 mL) and dissolved by the addition of 2 N NaOH (5.8 mL) . A solution of GdCl3-6H2θ (2.16 g; 5.8 mmol) in H2O (10 mL) was added dropwise to the reaction mixture mantained at pH 6.8 by the addition of 2 N NaOH (8.7 mL). After 1 h the solution was concentrated to 50 mL, the addition of CH3CN led to the precipitation of the title compound, which was filtered and dried (4.94 g; 4.60 mmol). Yield 79%. HPLC: >89% (area %). K.F.: 10.12%. Weight loss (120 °C) : 11.89%. The MS and IR spectra were consistent with the structure. EXAMPLE 17 [ 10- [ [ 2- [ 2- [ 2- ( Dioctadecylamino ) -2-oxoethoxy] -2-oxoethyl ] ammo] 2-oxoethyl ] -1 , 4 , 7 , 10-tetraazacyclododecane-l , 4 , 7-tπacetato ( 3- ) ] gadolinium A) A/-Octadecyl-l-octadecanam ne ( dioctadecyl amine ) I.A.S. Registry No. 112-99-2. Al) Dioctadecylcyanamide (C.A.S. Registry No. 113576-09-3) Cyanamide (5 g; 119 mmol) was added to stirred 50% aq. NaOH (100 g) . The mixture was cooled to 25°C, then a solution of Aliquat 1 - 336 (trioctylmethylammonium cnloride) (2.42 g; 6 mmol (commercial product) and 1-bromooctadecane (40.37 g; 121 mmol) in tcmene (50 mL) was added. The mixture was vigorously stirred at 55°C for 6 h. The organic phase was separated and evaporated to give the desired compound (38 g) . The crude product was used in the hydrolysis step 1 13 without any further purification. K.F.: < 0.1%. The H-NMR, C-NMR, MS and IR spectra were consistent witn the structure. Elemental analysis (' A2) -Octadecyl-1-octadecanamme (dioctadecylamine) The crude dioctadecylcyanamide (38 g) was suspended in 2.75 M H2SO4 (150 mL) and the mixture was refluxed for 2.5 h. After cooling to room temperature H2O (100 mL) , 30% NaOH (100 mL) and CHCI3 (300 mL) were added. The organic phase was separated, dried and evaporated. The solid residue was suspended in Et2θ and stirred for 1 h. The solid was filtered and washed with to give the desired compound (15.3 g; 29.3 mmol). Yield 48%. K.F. : 0.20%. The 1 H-NMR, 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%) anhydrous B) 2-Hydroxy-Af, A-dιoctadecylacetamιde (Acetyloxy) acetyl chloride (3.8 g; 28.1 mmol) (commercial product) dissolved in CHCI3 (150 mL) was added dropwise to a solution of dioctadecylamine (13.3 g; 25.5 mmol) and Et3N (3.9 mL; 28.1 mmol) in CHCI3 (350 mL) and the solution was stirred at room temperature overnight. MeOH (250 mL) and 2 N NaOH (50 mL) were added to tne solution. H2O was added to the reaction mixture and a two phase system was obtained. Tne lower organic layer was separated ana evaporated. The solid residue was suspended n-hexane and filtered to give the desireo compound (12.1 g;20.9 mmol). Yield 82%. HPLC: 96% (area %). 13 K.F.: <0.1%. The C-NMR, MS and IR spectra were consistent with the structure . C) N- [ (Phenylmethoxy) carbonyl] glycine f 2- (dioctadecylamino) -2- oxoethyl] ester A solution of DCC (2.1 g; 10.3 mmol) in CHCI3 (50 mL) was added αropwise to a solution of 2-hydroxy-N, A/-dιoctadecylacetamιde (5 g; 8.6 mmol) and Z-glycine (2 g; 9.5 mmol) in CHCI3 (250 mL) . DMAP (0.1 g; 0.9 mmol) was added to the resulting solution. After 1 h the reaction mixture was filtered and the solvent was evaporated. The crude was purified by flash chromatography (n-Hexane/EtOAc = 7/3 (v/v) ) to give the desired compound (5.6 g; 7.3 mmol). Yield 84%. HPLC : 99% (area %) . K.F.: <0.1% The C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): D) Glycine [2- (dioctadecylamino) -2-oxoethyl] ester hydrochloride 10% Pd/C (150 mg) was added to a solution of A7- [ (phenylmethoxy) - carbonyl] glycine [2- (dioctadecylamino) -2-oxoethyl ] ester (1.2 g; 1.4 mmol) in EtOAc (100 mL) and the suspension was stirred for 3 h under nydrogen atmospnere at room temperature. After filtration (through a Millipore® filter FT 0.45 μm) 1.2 M HCI in MeOH (1.3 mL; 1.6 mmol) was added dropwise to the resulting solution obtaining the precipitation of a white solid that was filtered to give the desired compound (830 mg; 1.2 mmol). Yield 86%. HPLC: 100% (area %). K.F. : 0.22%. The MS and IR spectra were consistent with the structure. Elemental analysis (%): anhydrous E) 1,4,7, 10-tetraazacycιododecane-l, , 7, 10-tetraacetιc acid is (phenylmethyl ) ester El) 1 , 4 , 7 , 10-Tetraazacycioαodecane-l-acetιc acid (1,1- α metnyleth 11 ester A solution of t-butyl bromoacetate (25.3 g; 130 mmol) in CHCI3 (500 mL) (commercial product) was added dropwise in 7 n to a solution of 1, , 7, 10-tetraazacyclododecane '112.3 g; 650 mmol) icommercial product) in CHCI3 (2 L) maintained under nitrogen at room temperature. After 14 h the solution was concentrated to 800 mL, washed with H2O, dried and evaporated to give the desired compound (39 g; 129 mmol) . Yield 99%. GC: 92 % (area %). K.F.: 0.42 The 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental anal sis (%): anhydrous E2) 1, 4 , 7, 10-Tetraazacyclododecane-l , 4 , 7-tetraacetιc acid (1,1- dimethyl-ethyl ) tris (pheny methyl ) ester A solution of 1, 4 , 7, 10-tetraazacyclodooecane-l-acetιc acid (1,1- dimethylethyl) ester (36 g; 126 mmol) in DMF (200 mL) was added dropwise in 7 h to a suspension of benzyl bromoacetate (94.96 g; 414 mmol) and K2CO3 (86.8 g; 628 mmol) in DMF (250 mL) maintained under nitrogen at room temperature. After 14 h the suspension was filtered and the solution evaporated to dryness. The residue was dissolved in EtOAc, washed with H2O, then with brine. The organic phase was separated, dried over Na2S0 4 and evaporated. The residue was purified by flash chromatography (CH2Cl2/ e0H = 15/1 (v/v) ) to give the desired compound (51 g; 65 mmol). Yield 51 %. HPLC : 90 % (area %). K.F.: 0.48 Thee 1 1 3 3CC--NNMMRR,, MMSS aanndd IIRR spectra were consistent with the structure. Elemental analysis (' anhydrous E3) 1,4,7, 10-Tetraazacyclodoαecane-l, 4, 7-tetraacetιc acid tris (phenyl-methyl) ester 1, 4 , 7, 10-Tetraazacyclododecane-I, 4 , 7, 10-tetraacetιc acid (1,1- dimethyl-ethyl) tris (phenyimethyl ) ester adduct with NaCl (47.11 g; 60 mmol) was dissolved in dioxane (500 L) . Tne solution was treated with 12 N HCI (500 mL) under nitrogen at room temperature, obtaining a precipitate. After 16 h the suspension was evaporated and the residue dissolved in H2O by ultrasound somcation. The solution (pH 2 was loaded onto an Amberlite® XAD-1600 resin co urrn (900 m ' and eluteo with a CH3CN/F2O gradient The fractions containing the product were concentrated to remove CH3CN, then extracted with EtOAc. The organic phase was oried over Na2S0 4 and evaporated. The residue was triturated with EtOAc to give the desired compound (21 g; 31 mmol) . Yield 52 %. HPLC: 99 % (area %) . K.F.: < 0.1 %. The 13 C-NMR, MS and IR spectra were consistent with the structure Elemental analysis (' F] 10- [ [2- [2- [2- (Dioctadecylamino) -2-oxoethoxy] -2-oxoethyl] - ammo] -2-oxoethyl] -1, 4, 7, 10-tetraazacyclododecane-l, 4,7-trιacetιc acid tris (phenyimethyl ) ester To a suspension of 1, 4 , 7, 10-tetraazacyclododecane-l , , 7, 10- tetraacetic acid tris (phenyimethyl) ester (2.7 g; 4 mmol) and glycine [2- (dioctadecylamino) -2-oxoethyl] ester hydrochloride (3 g; 4.4 mmol) in CHCI3 (250 mL) was added DIEA (dnsopropylethylamme ) (1.5 mL; 8.8 mmol). BOP ( (benzotrιazol-1-yloxy) tris (dimethylam o) phosphonium hexafluorophosphate, commercial product) (2.2 g; 4.8 mmol) was added to the resulting solution, which was stirred at room temperature for 2 h. The solvent was evaporated and the solid residue was suspended in 9:1 ι-PrOH/H2θ and filtered to obtain the desired compound (4.9 g; 3.8 13 mmol). Yield 95%. The C-NMR, MS and IR spectra were consistent with the given structure. Elemental analysis (%): Gj 10- [[2- [2- [2- ( Dioctadecylamino ) -2-oxoethoxy] -2-oxoethyl ] - amino] -2-oxoetnyl] -1, 4, 7, 10-tetraazacyclododecane-l ,4,7-trιacetιc acid 10% Pd/C (150 mg) was added to a solution of 10- [ [2- [2- [2- (dioctadecylamino) -2-oxoethoxy] -2-oxoethyl] ammo] -2-oxoethyl ]— 1,4,7,— 10-tetraazacyc-ododecane-l, 4, 7-trιacetιc acid tris (phenyimethyl ) ester (1.5 g; 1.2 mmol) in CH3COOH (150 mL) and the suspension was stirred for 8 h unαer hydrogen atmosphere at room temperature. After filtration (through a Millipore® filter FT 0.45 μm) the solvent was evaporated ana the residue was dried unαer reduced pressure to give the αesired compound (3 g; 1 mmoi) . Yield 83%. HPLC : 97", (area 13. The C- -NNMMRR,, MMSS aanndd IIRR ssppeeccttrra were consistent with tne structure. Elemental analysis (%): HJ [10- [[2- [2- [2- (Dioctaαecylamiπo) -2-oxoethoxy] -2-oxoethyl ] - amino] -2-oxoethyl] -1,4,7, 10-tetraazacyclododecane-l, , 7-trιacetato(3- ) ] adolinium The free ligand from the previous preparation (2.2 g; 2.2 mmol) was dissolved in 3:1 EtOH/H2θ (120 mL) ; a 0.5 M aq. solution of (CH3COO) 3Gd (4.4 mL) was added dropwise. The resulting solution was heated at 50°C for 4 h. The solvent was evaporated to give the title compound (2.2 g; 1.9 mmol). Yield 86%. HPLC: 95% (area %). The MS and IR spectra were consistent with the structure. Elemental analysis (%) EXAMPLE 18 [ 10- [ l-Methylene- 14 -octadecyl-2 , 10 , 13-trιoxo-6 , 9-dιoxa-3 , 14 - d azadotr acontanyl ] -1 , 4 , 7 , 10-tetraazacyclododecane-l , 4 , 7- triacetato ( 3- ) ] gadolinium A) 4- (Dioctadecylamino) -4-oxobutanoιc acid (C.A.S. Registry No. 37519-63-4) A suspension of dioctadecylamine (24.5 g; 47 nmol) (prepared according to Example 17, Step A) and succimc anhydride (4.7 g; 47 mmol) in THF (100 mL) was stirred at room temperature for 18 h. Solvent was removed by evaporation and the residue was dissolved in CH2C12- The solution was washed with 1 N HCI, αrieα and evaporated. The crude was crystallized from CH3CN to give tne αesireα compound (21.8 g; 35 mmol). Yield 75%. .F.: 0.37%. The -NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): anhydrous B) [10- [l-Methylene-14-octadecyl-2, 10, 13-tπoxo-6, 9-dιoxa-3, 14- diazadotriacontanyl]-!, , 7, 10-tetraazacyclo-dodecane-l , 4,7- triacetato (3- ) ] gadolinium 4- (Dioctadecylamino) -4-oxobutano c acid (7.6 g; 12.3 mmol) in CHCI3 (100 L) was added to a solution of 10- [2- [ [2- (2- hydroxyethoxy) ethyl] ammo] -1- (methylene) -2-oxoethyl] -1, 4, 7, 10- tetraazacyclododecane-1, 4 , 7-trιacetato (3-) ] gadolinium (8.1 g; 12.3 m o ) (prepared according to Example 2 of WO 96/04259) in DMSO (100 mL) , then 1- (3-dιmethylammopropyl) -3-ethylcarbodιιmmιde nydrochloride (EDCI) (2.6 g; 13.4 mmol) and 4-dιmethylamιnopyrιdιne (DMAP) (0.75 g; 6.1 mmol) were added and the clear solution was stirred at room temperature. After 24 h more EDCI (2.6 g; 13.4 mmol) was added. After another 24 h CH3CN and H2O were added to obtain the precipitation of a solid, which was filtered with a paper filter. The solid was dissolved in 1/1 CH2Cl2/MeOH and the solution loaded onto a silica gel flash column (CH2Cl2/MeOH = 1/1 (v/v) (5 L) ; CH 2 Cl 2 /MeOH/H 2 0 = 5/5/1 (v/v/v) (4 L) ) . The fractions containing the product were evaporated to give the title compound (6 g; 4.7 mmo ) Yield 38%. HPLC . 98% (area %). K.F.. 3.02 I . The MS and IF spectra were consistent w th the structure . Elemental anal sis (%): anhydrous EXAMPLE 19 [10- [2- f 2- (Dioctadecylamino) -2-oxoethoxy] -2-oxoethyl] -1, 4, 7, 10- tetraazacyclododecane-l, 4,7-trιacetato(3-) ] gadolinium A) 10- [2- [2- (Dioctadecylamino) -2-oxoetnoxy] -2-oxoethyl]-!,'., 7, 10- tetraazacycιododecane-1, 4, 7-trιacetιc acid tris- (phenyimethyl ) ester DBU (820 μL; 5.5 mmol) was added to a suspension of 1,4,7,10- tetraazacyc_.ododecane-l, 4,7,10-tetraacetιc acid tris (phenyimethyl) ester (prepared accordmg to Step E3 of Example 17) (3.71 g; 5.5 mmol) in toluene (350 mL) obtaining a clear solution, then 2-bromo-N,N- dioctadecylacetamide (prepared according to Example 5, Step A) (3.9 g; 6.05 mmol) αissolved in toluene (50 mL) was added dropwise. After 2 h the reaction mixture was filtered and the solvent was evaporated. The crude was suspended in CH3CN (50 L) and the insoluble was filtered off with a paper filter. The solution was evaporated obtaining the desired product (4.63 g; 3.74 mmol). Yield 68%. The 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (% ) : anhydrous B) 10- [2- [2- (Dioctadecylamino) -2-oxoethoxy] -2-oxoethyl] - 1,4,7, 10-tetraazacyclododecane-l, 4,7-trιacetιc ac d 10% Pd/C (0.4 g) was added to a solution of the product from the previous preparation (4.9 g; 4 mmol) in CH3COOH (400 mL) and the suspension was stirred for 6 h under hydrogen atmosphere (consumed H2 : 270 mL; 12 mmol) at room temperature. After filtration through a Millipore® filter FT 0.45 μm the solvent was evaporated under reduced pressure ana the residue was dried (1.3 kPa; NaOH pellets; 35°C) to give the desired compound (3.1 g; 3.2 mmol). Yield 80%. The 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): anhydrous C) [10- [2- [2- (Dioctadecylamino) -2-oxoethoxy] -2-oxoethyl] -1, 4,7, 10- tetraazacycloαodecane-1 , 4, 7-trιacetato (3-) ] gadolinium The free ligand from the previous preparation (3.6 g; 3.7 mmol) was αissolved in 2:1 ι-PrOH/H2θ (250 mL) and a 0.5 M aq. solution of (CH3COO)3Gd (".4 mL) was added dropwise. The resulting solution was heated at 5C°C for 6 h. The solvent was evaporated to give tne title compound (3.6 g; 3.2 mmol) . Yield 87%. MS and IR spectra were consistent with the structure. Elemental anal sis (%): anhydrous EXAMPLE 20 [10-[2-[Bιs[2-[ (l-oxonexadecyl) oxy] ethyl j amino] -2-oxoethyl] -1, 4, 7, 10- tetraazacyclododecane-l , 4,7-trιacetato(3-) ] gadolinium A) Hexadecanoic acid ιmιnodι-2, 1-ethanedιyl ester hydrochloride (C.A.S. Registry No. 84454-85-3) Palmitoyl chloride (29.8 g; 108.4 mmol) (commercial product) was added dropwise in 30 mm to a solution of diethanolamine hydrochloride (7 g; 49.4 mmol) (commercial product) in DMF (100 mL) . After standing for 1.5 h a white solid crystallized. MeOH (350 mL) was added and the reaction mixture heated to reflux. After cooling to room temperature the recrystallized product was filtered to give as a white solid hexadecanoic acid ιmιnodι-2, 1-ethanedιyl ester hydrochloride (15 g; 24.2 mmol). Yield 49%. K.F.: 0.4%. The 13 C--NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): anhydrous BJ 10-[2-[Bιs[2-[ (1-oxohexadecyl) oxy] ethyl] ammo] -2-oxoethyl] - 1,4,7, 10-tetraazacyclododecane-l, 4, 7-trιacetιcacιdtrιs( phenyimethyl )- ester A 50% solution of 1-propanephosphonιc acid cyclic anhydride (14.4 g; 22.6 mmol) in EtOAc (commercial product) was added to a solution of 1,4,7, 10-tetraazacyclododecane-l, 4,7,10-tetraacetιc acid tris (phenyimethyl) ester (15 g; 22.2 mmol) (prepared according to Step E3 of Example 17), nexadecanoic acid ιnmoαι-2 , 1-ethaneαiv i ester hyαrochloriαe (14 g; 22.6 mmo ) and Et3N (6.5 L; 46.6 mmoi) in CH2CI2 (200 mL) . The reaction mixture was stirred at room temperature for 24 h, then more 1-propanepnosphonιc acid cyclic anhydride (14.4 g; 22.6 mmol) was added. After another 24 h the mixture was washed with brine, dried and evaporated. The residue was purified by flash cnromatography (CH2Cl2/MeOH = 9/1 (v/v)) to give the desired compound (17 g; 13.7 mmol). Yield 62%. HPLC: 96% (area %). The C-NMR, MS ana IR spectra were consistent with the proposed structure. Elemental analysis (%) : anhydrous CJ 10- [ 2- [Bιs [ 2 - [ ( 1-oxohexadecyl ) oxy] ethyl ] amino] -2-oxoethyl ] - 1,4,7, 10-tetraazacyclododecane-l, , 7-trιacetic acid 10% Pd/C (1.6 g) was added to a solution of 10- [2- [bis [2- [ ( 1- oxohexadecyl) oxy] ethyl] ammo] -2-oxoethyl] -1,4,7, 10-tetraazacyclo-dodecane- 1, 4, 7-trιacetιc acid tris (phenyimethyl ) ester (16 g; 12.9 mmol) m EtOH (500 mL) and the suspension was stirred for 12 h under hydrogen atmosphere at room temperature. After filtration through a Millipore® filter FT 0.45 μm the solution was evaporated under reduced pressure to give the desired compound. Yield 93%. HPLC : 98% (area %). The 13 C-NMR, MS and IR spectra were consistent with the structure. Elemental analysis (%): anhydrous D) [10-[2-[Bis[2-[ (1-oxohexadecyl) oxy] ethyl] ammo] -2-oxoethyl] - 1,4,7, 10-tetraazacyclododecane-l, 4,7-trιacetato-(3) ] gadolinium (CH3COO) 3Gd-4H2θ (4.63 g; 11.4 mmol) was added to a solution of the free ligand from the previous preparation (11 g; 11.4 mmol) in EtOH (500 mL) at 50°C. After 6 h the solution was evaporated and dried under reduced pressure tc give the title compound (12.3 g; 11 mmol). Yield 96%. HPLC : 99% (area The MS ana IR spectra were consistent with the structure. Elemental analysis (%)

Claims: Claims 1. Compounds either racemic or enantiomeπc of the formulae ( t ) and (IV) and corresponding metal chelates in which n and m (IV) (t) are 1 or 0 but not simultaneously 1, and when n = m = 0, R 1 is H, and R* is a C]_2-25 linear or ramified, saturated or unsaturated, hydrocarbon radical; when n = 1 and m = 0, R* is H or a C1-3 alkyl or alkylene substituent; and R 1 is selected from -NHR3, -NR4R5 and -ORg where the R3 to Rβ are independently C]_-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -O- and optionally terminated by -NR Rg in which R and RQ are independently H or C]_2-25 hydrocarbon radicals; when n = 0 and m = 1, R* is H or a Cχ-3 alkyl or alkylene substituent; and R' is selected from Rg and CH2-O-CO-R9 in which R9 is a Cχo-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by -NH-, _ CO- or -0-, Rm being a lower aliphatic hydrocarbon; and Rχ2 is H or a C]_2-50 hydrocarbon radical optionally interrupted by -NH-, -NRin-, -CO- or -0- and optionally terminated by a cholesteryl residue, and the R 3 are -OH; or one or two R13 are a -NH- Rχ4 group in which R]_ 4 is a C2-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by -NH-, NRin-, -CO-, -0-, and/or -OPO(OH)0-, the remaining R13 being -OH. 2. Compounds encompassed by formula T according to claim 1, having formulae (I), (II) or (III) HOOC —\ / \ /—COOH HOOC —\ / \ / — COOH ■N N- o N N HOOC— \ / R * HOOC- (I) (li) wherein R* is defined as in claim 1; R s H or a Cχ-3 alkyl or alkylene substituent; Rl is selected from -NHR3, -NR 4 R5 and -ORg where the R3 to Rg are independently Ci-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -O- and optionally terminated by -NR Rg in which R and Rg are independently H or C 2-25 hydrocarbon radicals; R2 is selected from Rg and -CH2-O-CO-R9 in which Rg is a C10-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by one or more -NH-, -NR10-, -CO- or -0-, R Q being a lower aliphatic hydrocarbon. 3. Compounds according to claim 2 of formula (Ila) (Ila) in which R3 is a Ci2-25 linear or ramified, saturated or unsaturated, hydrocarbon radical. 4. Compounds according to claim 2 of formula (lib) (lib) in which R 4 and R5 are independently Cχ2-25 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -O- . 5. Compounds according to claim 2 of formula (lie) (lie) in which A is -NH- or -0-, Ai is a Ci-20 linear or ramified, saturated or unsaturated, hydrocarbon radicals optionally interrupted by -CO- and/or -O- . and R and Rg are defined in claim 1. 6. Compounds according to claim 2 of formula (Ilia) (Ilia) in which R is H and R2 is is a Cιo-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by one or more -NH-, -N-, -CO- or -0- . 7. Compounds according to claim 2 of formula (Illb) in which R is H and Rg is a Cio-25 linear alkyl, or a C Q-30 linear or ramified, saturated or unsaturated, hydrocarbon radical optionally interrupted by one or more -N-, -CO- or -0- . 8. Compounds encompassed by formula (IV) m claim 1, having formula ( IVa ) HOOC CONHR, ) R 14 HNOC COOH (IVa) in which the Rι_ 4 are independently as defined claim 1. 9. Compounds encompassed by formula (IV) in claim 1, having formula (IVb) .CONR,„ ( HOOC Iι COOH HOOC COOH (IVb) in which Rχ 4 is a Ci2-25 linear or ramified, saturated or unsaturated, hydrocarbon radical. 10. Compounds according to claim 1 of formula (IV) m which all the Rχ3 are -OH and R 2 is defined as in claim 1. 11. Compounds according to claims 1 to 10, in the form of complex chelates with paramagnetic metal ions and the salts thereof with physiologically acceptable bases selected from primary, secondary, tertiary amines and basic aminoacids, or inorganic hydroxides of sodium, potassium, magnesium, calcium or mixtures thereof; or with physiologically acceptable anions of organic acids selected from acetate, succmate, citrate, fumarate, maleate, oxalate, or inorganic acids selected from hydrogen halides, sulphates, phosphates, phosphonates and the like; or with cations or anions of aminoacids selected from lysme, arginine, ornithine, aspartic and glutamic acids, and the like. 12. NMR imaging compositions comprising one or more of the compounds of claims 1 to 11, and one or more physiologically acceptable non-ionic surfactants and carriers. 13. The compositions of claim 12, wherein the paramagnetic metal ion is selected from Gd(III), Mn(II), Cr(III), Cu(II), Fe(III), Pr(III), Nd(III), Sm(III), Tb(III), Yb(III), Dy(III), Ho(III) and Er (III) . 14. The compositions of claims 12-13, wherein the physiologically acceptable base is selected from ethanolam e, diethanolamine, morpholine, glucam e, N-methylglucamme, N,N- dimethylglucamme, lys e, arginme, ornithine. 15. The compositions of claims 12-14, further comprising one or more amphipatic compounds. 16. The compositions of claims 12-14, wherein the non-ionic surfactant is selected from block-copoly ers having polyoxyethylene and polyoxypropylene segments, polyethylene-glycolalkylethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and n-alkylglucopyranosides, or n-alkyl maltotπosides . 17. The compositions of claim 16, wherein the surfactant is BRIJ , Myr , Pluronic , Poloxamer , Poloxam e , Synperonic , Tween", or mixtures thereof. 18. The compositions of claims 15-17, wherein the amphipatic compound is a phosphorus compound, for instance a dialkyl glycerophospholipid in which the alkyl group has at least twelve carbon atoms. 19. The compositions of claim 18, wherein the glycerophospholipid is selected from phosphatidic acid, phosphatidylchol e, phosphatidylethanolamine, phosphatidy-lserine, phosphatidyl-glycerol, phosphatidylinositol, cardiolip and sph gomyelm. 20. The compositions of claim 18, wherein the phospholipid consists of a mono-phosphate ester of a substituted or partially substituted glycerol, at least one functional group of said glycerol being esterified by saturated or unsaturated aliphatic fatty acid, or etherified by saturated or unsaturated alcohol, the other two acidic functions of the phosphoric acid being either free or salified with alkali or earth-alkali metals. 21. The compositions of claim 20, wherein the pnospholipid is a monophospnate of a fatty acid glyceride selected from dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid or distearoylphosphatidic acid. 22. The compositions of claims 15, wherein the amphipatic compound comprises two or more compounds selected from ionic and neutral phospnolipids, mono alkyl or alkenyl esters of phosphoric acid and/or cholesterol, ergosterol, phytosterol, sitosterol, lanosterol and tocopherol. 23. The compositions of claims 12-22, wherein the weight ratio of paramagnetic chelate to surfactant in the composition is between 1:10 and 10.1, preferably between 1:3 and 3:1. 24. The compositions of claims 12-23, wherein the weight ratio of phospholipids to surfactant in the composition is between 1:10 and 10:1, preferably between 1:2 and 2:1. 25. A pulverulent formulation comprising the ingredients of any of the compositions of claims 12-24 in dry form, said formulation forming, upon dispersion in a physiologically acceptable liquid carrier, a dispersion useful as contrast medium for MRI. 26. An mηectable aqueous suspension comprising the compositions of claims 12-25 suspended in a physiologically acceptable liquid carrier, useful as NMR imaging contrast medium. 27. A method for making the compositions of claims 12-24, characterized by the steps of: a) selecting and suspending a complex of a paramagnetic metal ion with any one of the chelating agents of formulas (t) to (IVb) claimed in claims 1-10, one or more non-ionic surfactants, and optionally one or more amphipatic compounds in an aqueous phase to form a mixture, and b) energising the mixture by sonicating or microfluidizing to produce an homogeneous dispersion of the components in micellar form. 28. The method of claim 27, wherein the dispersion of the components in micellar form is sterilized and/or lyophilised. 29. The method of claims 27-28, wherein the surfactant is added to the mixture after said energising and optionally repeating the sonication or microfluidization. 30. The compositions of claims 12-24 for use in NMR blood pool imaging of organs in the human or animal body 31. Use of the compositions of claims 12-24 for the manufacture of an MRI contrast medium. 32. A two component kit comprising, as the first component, a dry formulation of claim 25 storeα under an inert atmospnere and, as the second component, a physiologically acceptable carrier liquid which, when admixed with the first component, provides, as a suspension of the two components, an miectable NMR contrast composition of claims 1-24. 33. The compositions of claims 12-24, wherein the MRI responsive components are in micellar form. 34. The compositions of claim 33, wherein the micelles have particle size between 10 and 500 nm, preferably between 50 and 200 nm.

Inventors: ANELLI PIER LUCIO, GABELLINI MILENA, LATTUADA LUCIANO, LUX GIOVANNA, SERLETI MICHELE, TOURNIER HERVE, UGGERI FULVIO, ANELLI, PIER, LUCIO, GABELLINI, MILENA, LATTUADA, LUCIANO, Lux, Giovanna, SERLETI, MICHELE, TOURNIER, HERVE, UGGERI, FULVIO
Applicants: BRACCO INT BV, BRACCO INTERNATIONAL B.V.
Application year: 1999
Main classification: A61K49
IPC codes: A61K49, C07C229, C07C233, C07C237, C07F9, C07J41