Ln s Ab c





Roentgenography of gastrointestinal tract

191, 192

B = —(CH2CHCH20)2(CH2)4(0CH2CHCH2)2-, where R = H or glyceryl

3. Mixtures of iodobenzoic acid derivatives and cellulose derivatives

Z = H, halo, Ci-C2o alkyl, cycloalkyl, lower alkoxy, cyano; R = C2-C25 alkyl, cycloalkyl or halo-lower alkyl, fluoro-lower alkyl, aryl, lower alkoxy, hydroxy, carboxy, lower-alkyl carbonyl or lower alkoxy-carbonyloxy; or (CR1R2)p-(CR3=CR4)m Q or (CR^V C=C-Q; Rlf R2, R, R4 = lower alkyl or halo-alkyl; X = 1 3 ; y = 1-4; n = 1-5; m = 1-15; = l-15;p = 1-10; and Q = H, lower alkyl, alkenyl, alkynyl, lower alkylene, aryl or aryl-lower alkyl.

A mixture of the derivatives—used for oral or retrograde examination of GI tract

Table 10.7 Potential Radiopaques: Substituted 3,5-Dilodo-4( li/)-pyridones

-CH2C02R [R = Bu, CH2Ph, C4-C10 alkyl, CH2OAc, CH2OCOCMe3, CH2CCI3] -(CH2)raC02R [R = H, Me, Et, Bu, Am, octyl, CH2CH2NMe2, CH2CH2OH, NH2] -CH2CONH{CH2)nNR1R2 {n = 2,3; R1 = R2 = Me, Et, R!R2 = CH2CH2OCH2CH2] —CH2CH2R


Urography, lymphography

Comment Synthesis

Synthesis (18 compounds prepared) Synthesis (high toxicity)

Syn thesis (high toxicity)

Ref. 343,352,385

387 387

trast molecule can dissociate in solution into an iodine-containing anion and an iodine-free cation, thus reducing the ratio of three iodine atoms per molecule by a factor of 2 to a ratio of 1.5 iodine atoms on average per ion (177,180). All the ionic monomers are therefore known as iodine ratio 1.5 contrast agents. The mono-acidic bis compound ioxaglate with one car-

acid group and six iodine atoms in the molecule is a ratio 3.0 contrast agent. The nonionic monomers, which contain no ioniz-able groups and do not undergo dissociation in solution, are ratio 3.0 contrast agents, and their dimers or bis compounds ratio 6.0 agents. Higher ratio contrast agents with higher iodine content per particle will give bet-

Table 10.8 Potential Radiopaques: Monoiodophenyl Derivatives




-C02X02CR [X = (CH2)2, (CHa)*, CH2CHMe, or (CH2)4; R = Me, Et, Pr, i-Pr, Bu, (CH2)4Me, (CH2)5Me, or CH2OMe] -C02(CH2)„02CR in = 2 4 , R = Me, Et, Pr, i-Pr, (CH2)3Me, (CH2)4Me, (CH2)3Me, CH2CHMe, or CH2OMe] -X-0C02R [X = (CH2)2, (CH2)s, CHMeCH2CH2, CH2CHEtCH2, or CH2CHBuCH2; R = Et, i-Pr, Bu, i-Bu, pentyl, hexyl, octyl, decyl, CHMeC6H13, CH2CH(Et)Bu, CHMeCH2CH(CH3)2, CH(Et)Pr, or CH2CH20Me]



Myelography, lymphography, bronchography, salpingography

Synthesis Synthesis Synthesis

Table 10.9 Miscellaneous Potential Radiopaques










[R ■= OH, 0(CH2)20Me, 0(CH2)20Et, (0CH2CH2)0Me, (0CH2CH2)20Et, 0(CH2)3Me, 0(CH2)2CHMe2, NH(CH2)2OH, NHCH2CH(0H)Me, NHC(CH2OH)2Me, N(CH2CH2OH)2, NHCHC02H, or NMeCH2C02H] BuNHCONHR (R = 2,3,5,6-tetraiodo-p-tolylsulfonyl)


ch2c(ch3)c02h nh2

i so2r i

Radiography of pancreas and prostate gland




Synthesis, toxicity studies

185 395

Cholescystography Synthesis

Cholecystography Synthesis

[R1 = NH„ N - CHNMe2; R = NH„ OH, NMe2, NEt2f NBu2f morpholino, piperidino, NHCH2CH2OH, N(CH2CH20H)2, or NMeCH2(CHOH)4CH2OH]

Table 10.9 (Continued)





CONR2R3 [NRR1, NRZR3 = NHMe, NHCH2C02H, NHCH(Pr)C02H, morpholino, 2-carboxy-l-pyrrolidinyl, NHCHEtCH2C02H,

NMeCH2C02H, NEtCH2C02H] + +

R R1

[n = 2, 4, 6, or 10; R, R1 = H, ethylacetyl, 3-iodobenzyl, 2,4,5-triiodobenzyl, 5-amino-2,4-didiodobenzyl, 3-amino-2,4,6-triiodobenzyl; X = CI, I]


Binding to cartilage Synthesis

ter X-ray image and resolution. Radiopacity is a physical property, affected not only by the atomic number but also by the localization and concentration of contrast medium in the organ.

Gadolinium chelates provide contrast enhancement in CT and also in MRI. Gadolinium has a higher atomic number than that of iodine and can attenuate X-rays more efficiently than iodine at equivalent mass concentration, although iodinated contrast media yield better resolution at higher concentrations (91).

6.3.3 Acidity. The inductive effect of the iodine atoms in the molecule makes the substituted 2,4,6-triiodobenzoic acids stronger acids than the substituted 2,4,6-triiodophenyl or triiodophenoxy alkanoic acids. The pKa values of many ionic contrast agents were measured by Felder et al. (263). The nonionic contrast agent ioparnidol has a pKa value of 10.7 for the nitrogen proton next to the triiodiophenyl ring, but the molecule is practically undissoci-ated at the physiologic pH 7.0-7.5 (194).

6.3.4 Electron Density. Substituent groups attached to the triiodinated phenyl ring can donate electrons to the ring or withdraw elec trons from it. Substituent groups attached to the ring through oxygen and nitrogen atoms will donate electrons to the ring and those attached through the carbonyl carbon atoms will withdraw a-electrons from the ring. So-vak (203) related the decrease in toxicity of a series of model compounds to the decrease in a-electrons in the ring. The following groups are listed in the order according to their increasing ability to withdraw a-electrons from the ring: methyleneoxy (t#>-CH2-0-) < methyl-eneamino (<£-CH2-N-) < reversed amido (<£>-NH-CO-) < alkyloxy (<£-0-CH2-) < carbamoyl ((¿>-CO-NH-) group. Among the nonionic contrast media, listed in Table 10.3, iosimide (7g) and iotriside (7h) are derivatives of trimesic acid, which belong to the CCC subclass and have the lowest a-electron density in the ring.

Gries and Mtitzel (205) gave the number of a-electrons in the benzene ring, in addition to the six benzene electrons, for a series of model compounds ranging from subclass NNN to subclass CCC. These a-electron values are given for each subclass in parentheses as follows:

"NNN" (a: 0.1088) > "CNN" (a: 0.1077) > "CCN" (a:0.0947) > "CCC" (a: 0.0815).

This means that the model compound derived from triiodotrimesic acid (subclass CCC) contains fewer Tr-electrons than the model compound derived from isophthalic acid (subclass CCN) and thus has a greater biosafety and a higher intravenous median lethal dose (LDS0) than that of the latter. Average values of neural tolerance, expressed in mg iodine per kg body weight, for these model compounds are given in parentheses below:

These values support the hypothesis that associates the least toxicity of an iodinated contrast molecule with the smallest 7r-electron density in the benzene ring.

6.3.5 Hydrophilicity and Solubility. Contrast agents for angiography are by necessity administered intravascularly in large doses and, for this, high water solubility is required. Agents for oral cholecystography need an optimum oil-and-water solubility so that upon ingestion, the molecule can be absorbed and transported across the intestinal cell membrane, from blood to the liver, and concentrated in the gall bladder. Agents for myelog-raphy may be oil-soluble or water-soluble compounds. The molecular requirements for different contrast agents differ and do not necessarily focus on the same substituent groups.

Solubility of contrast agents is determined mainly by the presence of hydrophilic groups (180, 209). In an ionic contrast molecule the carboxyl group in the R group in (1) confers a high water solubility to the molecule; and an acylamino, alkylcarbamoyl, or hydroxylated alkylamino group in the X or Y group in (1) modifies such properties as its hydrophilicity, toxicity, distribution, and excretion. Thus, substituted triiodobenzoates and triiodo-isophthalamates are highly water soluble compounds. Solutions with concentrations as high as 90%can be achieved with iothalamates and metrizoates. These highly soluble contrast agents are also strong acids with pl£a values less than 3. In nonionic contrast molecules the hydroxyl groups, hydrogen bonding, and hydrophobic associations determine the water solubility (171, 182, 202), which may be further enhanced by introducing more hydrophilic groups (199).

Asymmetry in the substitution of contrast molecules also influences the solubility (9). The sodium salt of diatrizoic acid with a symmetrical 3,5-diacetamido substitution has relatively low water solubility and concentrations greater than 50% cannot be obtained. The solubility is enhanced when one of the acetamido groups is replaced with a N-meth-ylcarbamoyl, N-methylacetamido, or acet-amidomethyl group, as in iothalamate, me-trizoate, or iodamide. N-Methyl substitution can substantially increase the water solubility of nonionic contrast agents (199), but the hy-droxyl groups have to be evenly distributed to mask the lateral and facial lipophilic regions in the molecule, distinguished conceptually as lateral hydrophilicity and facial hydrophilicity (204).

Oral cholescystographic agents must possess an optimum oil-and-water solubility for duodenal absorption. Substituents, such as carboxyl, alkyl, or aralkyl groups, can impart both hydrophilicity and lipophilicity to the molecule. Iopanoate, ipodate, and tyropano-ate, for example, are substituted triiodophenyl alkanoic acids and will meet this requirement. The chain length of the substituent can affect the quality of the image. Epstein et al. (406) observed that in a series of iodinated p-hy-droxyphenylalkanoicacids, optimal visualization of dog bladder was achieved with five to eight carbon atoms in the alkanoic acid chain. Felder et al, (291) reported that the insertion of a methyl group between the oxygen and the a-carbon in the series of substituted triiodo-phenoxyalkoxyalkanoic acids can improve oral absorption, biliary excretion, and gall bladder visualization.

6.3.6 Chemotoxicity. The development of modern contrast agents began with the observation by Wallingford et al. (219) that iodo-benzoic acids have very low toxicity. lodina-tion, substitution, and acetylation can modify the acute toxicity of substituted benzoic acids (209,210). For example, amination of sodium benzoate decreases toxicity, and the intrave nous median lethal dose (LD50) values of 3-aminobenzoate and 3,5-diaminobenzoate (i.e., 3270 and 2600 mg/kg, respectively) in mice are higher than that of benzoate (1440 mg/kg). Acetylation decreases toxicity, as is shown by the even higher LD50 values of 3-ac-etamidobenzoate and 3,5-diacetamidobenzo-ate (3400 and 5580 mg/ kg) than of the corresponding amines given above. In the series of S-acylamino^^^-triiodobenzoates, the detoxifying effect of substitution by acylation reaches a maximum of two carbon atoms in the acetyl group and further lengthening of the acyl chain causes an increase in toxicity (219).

Iodination may either decrease or increase the toxicity, depending on whether the parent compound is acetylated or unacetylated. Both 3-acetamido-2,4,6-triiodobenzoate and 3,5-di-acetamido-2,4,6-triiodobenzoate (LD50: 8300 and 14,000 mg/kg) have lower toxicities than their corresponding noniodinated parent compounds. A fully substituted benzene ring further decreases the toxicity. 3,5-Diacetamido-

is the least toxic of the series and is available commercially as diatrizoate sodium and meglumine salts for clinical use in angiography, pyelography, urography, and other related roentgeno-graphic procedures.

Although contrast media are remarkably safe, when injected intravascularly in high concentrations as a bolus, the blood is replaced for a very brief period with the contrast medium. Such high concentrations can produce a myriad of dose-dependent pharmacological effects, often manifested as undesirable side effects. Rosati and de Haen (407) classified these toxic effects as (l)chemotoxicity in distinction to molecular toxicity, arising from unique structural features that show affinity to binding with biomacromolecules; and (2) osmotic toxicity, attributed to many side effects caused by the considerably higher osmolality of ionic contrast media relative to that of body fluids. These authors correlated the LD50 values of ionic and nonionic iodinated contrast media for uroangiography directly with their osmolality. Nonionic contrast agents, because of their lower osmolality, high water solubility, and a fully substituted benzene ring, do not combine with proteins or macromolecules and are considerably less toxic than ionic contrast media. Contrast agents, regardless of their ionic and osmolality differences, in the presence of X-ray irradation, may cause chromosome aberrations (408-411). Iodinated contrast agents in combination with X-ray radiation can develop synergistic cytotoxicity, possibly mediated by energetic photoelec-trons, and this cytotoxicity increases with iodine concentration (410). Norman et al. (413) showed that iniodine dose-enhancement therapy for brain tumors, the iodine contrast media help localize the tumor and increase the absorbed radiation dose.

The contrast bis compounds, in general, have lower toxicity than that of the corresponding monomers (258). The toxicity of hexaiodinated ionic bis compounds increases with increasing length of the alkylene bridge and also with increasing length of the substituent group at position 5 of the triiodophe-nyl ring (224,414). Bis compounds with open positions in the triiodophenyl rings linked by a polyoxymethylene bridge have a higher intravenous toxicity in mice than those with the fully substituted benzene rings. Replacement of the substituent n-butyramido group with a butyrolactamyl group decreases the toxicity of the bis compounds linked by a short alkylene bridge but increases the toxicity of those linked by a long alkylene bridge. Introduction of one or more oxygen atoms into the alkylene bridge greatly reduces the toxicity. For this series of bis compounds, optimum tolerability was achieved in the compound formed by joining two molecules of 3-amino-5-acetylamino-methyl-2,4,6-triiodo-benzoic acid with tetra-oxahexadecane-dicarboxylic acid dichloride (224). Ioxaglate is an asymmetric bis compound, consisting of a dipeptide bridge linked to two dissimilar monomers, one ionic and the other nonionic (189). Ioxaglate is a ratio 3.0 contrast agent and has lower osmolality and lower toxicity than that of the ratio 1.5 symmetric ionic bis compounds.

Hexaiodinated nonionic bis compounds are ratio 6.0 contrast agents and owe their low osmolality, high hydrophilicity, and high biological tolerance to 8-12 hydroxyl groups in the molecule. Iotrolan containing 12 hydroxyl groups has an osmolality isotonic to blood. In concentrated solutions nonionic contrast me dia may undergo molecular association (i.e., hydrophobic interaction), to form relatively small aggregates (quasi-dimers or quasi-oligomers), thus giving a lower osmolality than that in dilute solutions (202,415).

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