Diastereoselective Synthesis of α-Aryl-Substituted LnDOTA Chelates from Achiral Starting Materials by Deracemization Under Mild Conditions.

Substituted derivatives of the DOTA framework are of general interest to alter chelate properties and facilitate the conjugation of chelates to other molecular structures. However, the scope of substituents that can be introduced into the α-position has traditionally been limited by the availability of a suitable enantiopure starting materials to facilitate a stereoselective synthesis. Tetra-substituted DOTA derivatives with phenyl and benzoate substituents in the α-position have been prepared. Initial syntheses used enantiopure starting materials but did not afford enantiopure products. This indicates that the integrity of the stereocenters was not preserved during synthesis, despite the homo-chiral diastereoisomer being the major reaction product. The homochiral diastereoisomer could be produced as the major or sole reaction product when starting from racemic or even achiral materials. Deracemization was found to occur during chelation through the formation of an enolate stabilized by the aryl substituent. This general ability of aryl groups to enable deracemization greatly increases the range of substituents that can be introduced into DOTA-type ligands with diastereochemical selectivity.

Analysis of the Relaxometric Properties of Extremely Rapidly Exchanging Gd3+ Chelates: Lessons from a Comparison of Four Isomeric Chelates.

Relaxometric analyses and in particular the use of fast-field cycling techniques have become routine in the study of paramagnetic metal complexes. The field dependence of the solvent proton relaxation properties (nuclear magnetic relaxation dispersion, NMRD) can provide unparalleled insights into the chemistry of these complexes. However, analyzing NMRD data is a multiparametric problem, and some sets of variables are mutually compensatory. Specifically, when fitting NMRD profiles, the metal-proton distance and the rotational correlation time constant have a push-pull relationship in which a change to one causes a predictable compensation in the other. A relaxometric analysis of four isomeric chelates highlights the pitfalls that await when fitting the NMRD profiles of chelates for which dissociative water exchange is extremely rapid. In the absence of independently verified values for one of these parameters, NMRD profiles can be fitted to multiple parameter sets. This means that NMRD fitting can inadvertently be used to buttress a preconceived notion of how the complex should behave when a different parameter set may more accurately describe the actual behavior. These findings explain why the effect of very rapid dissociative exchange on the hydration state of Gd3+ has remained obscured until only recently.

Differences in the Relaxometric Properties of Regioisomeric Benzyl-DOTA Bifunctional Chelators: Implications for Molecular Imaging.

The bifunctional chelator S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane- N, N', N″, N‴-1,4,7,10-tetraacetate (IB-DOTA) is on paper the most attractive of the commercially available bifunctional chelators for magnetic resonance imaging (MRI) applications. The preserved DOTA scaffold is known to produce extremely kinetically and thermodynamically robust chelates with the Gd3+ ion. Also, ligation through four acetate pendant arms should ensure that the rapid water exchange kinetics so, crucial to the function of an MRI contrast agent are retained. However, upon ligation of the Gd3+ ion, IB-DOTA differentiates into two distinct isomers defined by the positions of the benzylic substituent (corner or side). A relaxometric analysis of these two isomers revealed marked differences in the property and behavior of the two chelates. Most notably the side isomer is found to be substantially more likely to aggregate in aqueous solution than its corner counterpart. This aggregation results in higher relaxivity for the side isomer versus the corner isomer, an observation that potentially obscures the impact of differences in water exchange kinetics between the two isomers. The side isomer is composed of a significant fraction of a twisted square antiprismatic coordination geometry that exchanges water more rapidly than optimal (τM = 7 ns) for maximizing relaxivity. The impact of this excessively fast exchange is not observed in the relaxivity of the side isomer only because in isolation this chelate tumbles much more slowly than the corner isomer. However, this situation is not expected to persist when the chelate is employed in a typical bioconjugate. These results imply that the corner isomer of IB-DOTA may represent a better choice of bifunctional chelator for bioconjugation applications in which a large macromolecule is to be tagged for MRI applications.

Crystal Structures of DOTMA Chelates from Ce3+ to Yb3+ : Evidence for a Continuum of Metal Ion Hydration States.

The crystal structures of chelates formed between each stable paramagnetic lanthanide ion and the octadentate polyamino carboxylate ligand DOTMA are described. A total of 23 individual chelates structures were obtained; in each chelate the coordination geometry around the metal ion is best described as a twisted square antiprism (torsion angle -25.0°--31.4°). Despite the uniformity of the general coordination geometry provided by the DOTMA ligand, there is a considerable variation in the hydration state of each chelate. The early Ln3+ chelates are associated with a single inner sphere water molecule; the Ln-OH2 interaction is remarkable for being very long. After a clear break at gadolinium, the number of chelates in the unit cell that have a water molecule interacting with the Ln3+ decreases linearly until at Tm3+ no water is found to interact with the metal ion. The Ln-OH2 distance observed in the chelates of the later Ln3+ ions are also extremely long and increase as the ions contract (2.550-2.732 Å). No clear break between hydrated and dehydrated chelates is observed; rather this series of chelates appear to represent a continuum of hydration states in which the ligand gradually closes around the metal ion as its ionic radius decreases (with decreased hydration) and the metal drops down into the coordination cage.

Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure.

Purpose To determine whether gadolinium remains in juvenile nonhuman primate tissue after maternal exposure to intravenous gadoteridol during pregnancy. Materials and Methods Gravid rhesus macaques and their offspring (n = 10) were maintained, as approved by the institutional animal care and utilization committee. They were prospectively studied as part of a pre-existing ongoing research protocol to evaluate the effects of maternal malnutrition on placental and fetal development. On gestational days 85 and 135, they underwent placental magnetic resonance imaging after intravenous gadoteridol administration. Amniocentesis was performed on day 135 prior to administration of the second dose of gadoteridol. After delivery, the offspring were followed for 7 months. Tissue samples from eight different organs and from blood were harvested from each juvenile macaque. Gadolinium levels were measured by using inductively coupled plasma mass spectrometry. Results Gadolinium concentration in the amniotic fluid was 0.028 × 10-5 %ID/g (percentage injected dose per gram of tissue) 50 days after administration of one gadoteridol dose. Gadolinium was most consistently detected in the femur (mean, 2.5 × 10-5 %ID/g; range, [0.81-4.1] × 10-5 %ID/g) and liver (mean, 0.15 × 10-5 %ID/g; range, [0-0.26] × 10-5 %ID/g). Levels were undetectable in the remaining sampled tissues, with the exception of one juvenile skin sample (0.07 × 10-5 %ID/g), one juvenile spleen sample (0.039 × 10-5 %ID/g), and one juvenile brain (0.095 × 10-5 %ID/g) and kidney (0.13 × 10-5 %ID/g) sample. Conclusion The presence of gadoteridol in the amniotic fluid after maternal injection enables confirmation that it crosses the placenta. Extremely low levels of gadolinium are found in juvenile macaque tissues after in utero exposure to two doses of gadoteridol, indicating that a very small amount of gadolinium persists after delivery. © RSNA, 2017.

Gadolinium Chelate Contrast Material in Pregnancy: Fetal Biodistribution in the Nonhuman Primate.

PURPOSE: To determine the extent to which gadolinium chelate is found in nonhuman primate fetal tissues and amniotic fluid at 19-45 hours after intravenous injection of a weight-appropriate maternal dose of the contrast agent gadoteridol. MATERIALS AND METHODS: Gravid Japanese macaques (n = 14) were maintained as approved by the institutional animal care and utilization committee. In the 3rd trimester of pregnancy, the macaques were injected with gadoteridol (0.1 mmol per kilogram of maternal weight). Fetuses were delivered by means of cesarean section within 24 hours of maternal injection (range, 19-21 hours; n = 11) or 45 hours after injection (n = 3). Gadolinium chelate levels in the placenta, fetal tissues, and amniotic fluid were obtained by using inductively coupled plasma mass spectrometry. The Wilcoxon rank sum test was used for quantitative comparisons. RESULTS: Gadoteridol was present in the fetoplacental circulation at much lower quantities than in the mother. At both time points, the distribution of gadolinium chelate in the fetus was comparable to that expected in an adult. The highest concentration of the injected dose (ID) was found in the fetal kidney (0.0161% ID per gram in the 19-21-hour group). The majority of the in utero gadolinium chelate was found in the amniotic fluid and the placenta (mean, 0.1361% ID per organ ± 0.076 [standard deviation] and 0.0939% ID per organ ± 0.0494, respectively). Data acquired 45 hours after injection showed a significant decrease in the gadolinium chelate concentration in amniotic fluid compared with that in the 19-21-hour group (from 0.0017% to 0.0007% ID per gram; P = .01). CONCLUSION: Amounts of gadolinium chelate in the fetal tissues and amniotic fluid were minimal compared with the maternal ID. This may impact future clinical studies on the safety of gadolinium contrast agent use in pregnancy.

Isomerism in benzyl-DOTA derived bifunctional chelators: implications for molecular imaging.

The bifunctional chelator IB-DOTA has found use in a range of biomedical applications given its ability to chelate many metal ions, but in particular the lanthanide(III) ions. Gd(3+) in particular is of interest in the development of new molecular imaging agents for MRI and is highly suitable for chelation by IB-DOTA. Given the long-term instability of the aryl isothiocyanate functional group we have used the more stable nitro derivative (NB-DOTA) to conduct a follow-up study of some of our previous work on the coordination chemistry of chelates of these BFCs. Using a combination of NMR and HPLC to study the Eu(3+) and Yb(3+) chelates of NB-DOTA, we have demonstrated that this ligand will produce two discrete regioisomeric chelates at the point at which the metal ion is introduced into the BFC. These regioisomers are defined by the position of the benzylic substituent on the macrocyclic ring: adopting an equatorial position either at the corner or the side of the [3333] ring conformation. These regioisomers are incapable of interconversion and are distinct, separate structures with different SAP/TSAP ratios. The side isomer exhibits an increased population of the TSAP isomer, pointing to more rapid water exchange kinetics in this regioisomer. This has potential ramifications for the use of these two regioisomers of Gd(3+)-BFC chelates in MRI applications. We have also found that, remarkably, there is little or no freedom of rotation about the first single bond extending from the macrocyclic ring to the benzylic substituent. Since this is the linkage through which the chelate is conjugated to the remainder of the molecular imaging probe, this result implies that there may be reduced local rotation of the Gd(3+) chelate within a molecular imaging probe. This implies that this type of BFC could exhibit higher relaxivities than other types of BFC.

Aggregation in amphiphilic macrocycle-substituted Gd(3+) DOTA-type chelates is affected by the regiochemistry of substitution.

Gd(3+) chelates of macrocyclic bifunctional chelators (BFCs) can differentiate into two regioisomers: corner and side. These isomers afford different orientations of chelate relative to conjugate. These differences alter the self-assembly, tumbling, and effectiveness as magnetic resonance imaging contrast agents of the two biphenyl conjugate isomers.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: In patients presenting with an exacerbation of COPD can a normal venous blood gas pCO2 rule out arterial hypercarbia?

A shortcut review was carried out to establish whether a normal partial pressure of carbon dioxide (pCO2) on a venous blood sample could be used to rule out hypercarbia. Eleven studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that a normal venous pCO2 effectively rules out arterial hypercarbia.

Human whole-blood (1)H2O longitudinal relaxation with normal and high-relaxivity contrast reagents: influence of trans-cell-membrane water exchange.

PURPOSE: Accurate characterization of contrast reagent (CR) longitudinal relaxivity in whole blood is required to predict arterial signal intensity in contrast-enhanced MR angiography (CE-MRA). This study measured the longitudinal relaxation rate constants (R1 ) over a concentration range for non-protein-binding and protein-binding CRs in ex vivo whole blood and plasma at 1.5 and 3.0 Tesla (T) under physiologic arterial conditions. METHODS: Relaxivities of gadoteridol, gadobutrol, gadobenate, and gadofosveset were measured for [CR] from 0 to 18 mM [mmol(CR)/L(blood)]: the latter being the upper limit of what may be expected in CE-MRA. RESULTS: In plasma, the (1) H2 O R1 [CR]-dependence was nonlinear for gadobenate and gadofosveset secondary to CR interactions with the serum macromolecule albumin, and was well described by an analytical expression for effective 1:1 binding stoichiometry. In whole blood, the (1) H2 O R1 [CR]-dependence was markedly non-linear for all CRs, and was well-predicted by an expression for equilibrium exchange of water molecules between plasma and intracellular spaces using a priori parameter values only. CONCLUSION: In whole blood, (1) H2 O R1 exhibits a nonlinear relationship with [CR] over 0 to 18 mM CR. The nonlinearity is well described by exchange of water between erythrocyte and plasma compartments, and is particularly evident for high relaxivity CRs.

The effect of regioisomerism on the coordination chemistry and CEST properties of lanthanide(III) NB-DOTA-tetraamide chelates.

Chemical exchange saturation transfer (CEST) offers many advantages as a method of generating contrast in magnetic resonance images. However, many of the exogenous agents currently under investigation suffer from detection limits that are still somewhat short of what can be achieved with more traditional Gd(3+) agents. To remedy this limitation we have undertaken an investigation of Ln(3+) DOTA-tetraamide chelates (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) that have unusually rigid ligand structures: the nitrobenzyl derivatives of DOTA-tetraamides with (2-phenylethyl)amide substituents. In this report we examine the effect of incorporating hydrophobic amide substituents on water exchange and CEST. The ligand systems chosen afforded a total of three CEST-active isomeric square antiprismatic chelates; each of these chelates was found to have different water exchange and CEST characteristics. The position of a nitrobenzyl substituent on the macrocyclic ring strongly influenced the way in which the chelate and Ln(3+) coordination cage distorted. These differential distortions were found to affect the rate of water proton exchange in the chelates. But, by far the greatest effect arose from altering the position of the hydrophobic amide substituent, which, when forced upwards around the water binding site, caused a substantial reduction in the rate of water proton exchange. Such slow water proton exchange afforded a chelate that was 4.5 times more effective as a CEST agent than its isomeric counterparts in dry acetonitrile and at low temperatures and very low presaturation powers.

The presence of fast-exchanging proton species in aqueous solutions of paraCEST agents can impact rate constants measured for slower exchanging species when fitting CEST spectra to the Bloch equations.

LnDOTA-tetraamide complexes typically exist in solution as a mixture of square-antiprismatic (SAP) and twisted square-antiprismatic (TSAP) coordination isomers. In most cases, the SAP isomer, which is preferred for CEST imaging, predominates, and the presence of the minor TSAP isomer is assumed to have little influence on quantitative measures of the water-exchange rate constant for the SAP isomer. Here, we sought to confirm the validity of this assumption by mixing two chelates with different SAP and TSAP isomer populations while measuring the water-exchange rate constant of the SAP isomer. The results show that an increase in the population of the TSAP isomer in solution results in as much as a 30% overestimation of the water-exchange rate constant for the SAP isomer when CEST spectra are fit to the Bloch equations. This effect was shown to be significant only when the TSAP isomer population exceeded 50%.

α-Aryl substituted GdDOTA derivatives, the perfect contrast agents for MRI?

Enhancing the performance of Gd3+ chelates as relaxation agents for MRI has the potential to lower doses, improving safety and mitigating the environmental impact on our surface waters. More than three decades of research into manipulating the properties of Gd3+ have failed to develop a chelate that simultaneously optimizes all relevant parameters and affords maximal relaxivity. Introducing aryl substituents into the α-position of the pendant arms of a GdDOTA chelate affords chelates that, for the first time, simultaneously optimize all physico-chemical properties. Slowing tumbling by binding to human serum albumin affords a relaxivity of 110 ± 5 mM-1 s-1, close to the maximum possible. As discrete chelates, these α-aryl substituted GdDOTA chelates exhibit relaxivities that are 2-3 times higher than those of currently used agents, even at the higher fields (1.5 & 3.0 T) used in modern clinical MRI.

Coupling fast water exchange to slow molecular tumbling in Gd3+ chelates: why faster is not always better.

The influence of dynamics on solution state structure is a widely overlooked consideration in chemistry. Variations in Gd(3+) chelate hydration with changing coordination geometry and dissociative water exchange kinetics substantially impact the effectiveness (or relaxivity) of monohydrated Gd(3+) chelates as T1-shortening contrast agents for MRI. Theory shows that relaxivity is highly dependent upon the Gd(3+)-water proton distance (rGdH), and yet this distance is almost never considered as a variable in assessing the relaxivity of a Gd(3+) chelate as a potential contrast agent. The consequence of this omission can be seen when considering the relaxivity of isomeric Gd(3+) chelates that exhibit different dissociative water exchange kinetics. The results described herein show that the relaxivity of a chelate with "optimal" dissociative water exchange kinetics is actually lower than that of an isomeric chelate with "suboptimal" dissociative water exchange. When the rate of molecular tumbling of these chelates is slowed, an approach that has long been understood to increase relaxivity, the observed difference in relaxivity is increased with the more rapidly exchanging ("optimal") chelate exhibiting lower relaxivity than the "suboptimally" exchanging isomer. The difference between the chelates arises from a non-field-dependent parameter: either the hydration number (q) or rGdH. For solution state Gd(3+) chelates, changes in the values of q and rGdH are indistinguishable. These parametric expressions simply describe the hydration state of the chelate--i.e., the number and position of closely associating water molecules. The hydration state (q/rGdH(6)) of a chelate is intrinsically linked to its dissociative water exchange rate kex, and the interrelation of these parameters must be considered when examining the relaxivity of Gd(3+) chelates. The data presented herein indicate that the changes in the hydration parameter (q/rGdH(6)) associated with changing dissociative water exchange kinetics has a profound effect on relaxivity and suggest that achieving the highest relaxivities in monohydrated Gd(3+) chelates is more complicated than simply "optimizing" dissociative water exchange kinetics.

Structural analysis of isomeric europium(III) chelates of NB-DOTMA.

Water exchange in lanthanide(III) chelates is a key parameter in developing more effective MRI contrast agents. Our own efforts to optimize water exchange have focused on isolating single coordination geometries of LnDOTA-type chelates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate.) This isolation may be achieved by appropriately substituting the ligand framework to freeze-out the conformational exchange processes that interconvert coordination geometries. When a single nitrobenzyl substituent is used to "lock" the conformation of the macrocyclic ring, two regioisomeric chelates may be produced; the substituent may be alternatively located on the corner or the side of the ring. Here, we unambiguously demonstrate this regioisomerism by examining the COSY spectra of some conformationally locked Eu(3+) chelates. This exercise also demonstrated that diastereoisomeric chelates arising from racemization of chiral centers during the ligand synthesis, recently discounted as the origin of multiple isomeric chelates, can be produced and isolated. Furthermore, these COSY data revealed several through space NOE correlations that afford a great deal of information about the conformation of the nitrobenzyl substituent. In those isomers in which the substituent is located on the corner of the ring, the nitrobenzyl group is oriented approximately perpendicular to the plane of the macrocycle pointing upward and away from the chelate. In contrast, when the substituent is located on the side of the ring, the nitrobenzyl group is oriented approximately in plane with the macrocycle, pointing along the side of the chelate. Because the main purpose of the nitro group is to facilitate chemical modification and conjugation to biologically relevant molecules, these differences may have important consequences. Specifically, it seems likely that the same chelate may interact very differently with biological systems and molecules depending upon the regioisomer and therefore the orientation of the chelate relative to the biomolecule.

Chemical Exchange Saturation Transfer is Unaffected by Modest Changes in Pressure.

ParaCEST (paramagnetic Chemical Exchange Saturation Transfer) agents offer an unparalleled opportunity to perform quantitative molecular imaging by MRI. Agents that can alter the image contrast they generate in response to changes in local environmental parameters such as pH, glucose concentration or lactate concentration can be used ratiometrically to quantitatively describe the local tissue environment. However, when performing such quantitative measurements it is important that the results are not confounded by changes in a second environmental parameter. In vivo pressure varies quite considerably, both through the respiratory cycle and from tissue to tissue (tumors in particular have high interstitial pressures). Since paraCEST agents have positive activation volumes, their exchange kinetics and therefore the CEST effect that they generate are necessarily related to pressure. The purpose of this investigation was to examine whether the relatively small changes in pressure exhibited in vivo could affect CEST sufficiently to confound attempts to quantify other local environmental parameters. The CEST properties of a rigid EuDOTA-tetraamide was examined at temperatures ranging from 288 to 319 K, at applied pressures ranging from 0 to 414 kPa and pre-saturation (B1) powers ranging from 524 to 935 Hz. At no point was pressure found to affect the CEST generated by this chelate, indicating that changes in in vivo pressure is unlikely to confound the quantitative measurement of physiologically relevant parameters by paraCEST MRI.

Identifying risk factors and implications for beach drowning prevention amongst an Australian multicultural community.

Multicultural communities in Australia are recognised as a priority area for drowning prevention, but no evidence-based study has addressed their knowledge of beach safety. This study used an online survey tool to identify and examine risk factors relating to swimming ability, beach visitation characteristics and behaviour, and beach safety knowledge of the Australian Southern Asian community to assist in the development of future beach safety interventions. Data was obtained through 249 online and in-person surveys of people aged > 18 years. Most respondents reported poor swimming ability (80%), often swam in in the absence of lifeguards (77%), did not understand the rip current hazard (58%), but reported that they entered the water (76%) when visiting beaches. Close to one-quarter (28%) had not heard, or didn't know the purpose, of the red and yellow beach flags, which identify lifeguard supervised areas on Australian beaches. Length of time living in Australia is an important beach safety consideration for this community, with minimal differences in terms of gender and age. Those who have lived < 10 years in Australia visit beaches more frequently and are less likely to have participated in swimming lessons, be able to swim, heard of the flags or swim between them, understand rip currents, or have participated in a beach safety program. Very few (3%) respondents received beach safety information from within their own community. The importance of beach safety education and swimming lessons within the Southern Asian community should be prioritised for new and recent migrants to Australia.

Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents.

The extracellular pH (pH(e) ) of solid tumors is acidic, and there is evidence that an acidic pH(e) is related to invasiveness. Herein, we describe an MRI single-infusion method to measure pH(e) in gliomas using a cocktail of contrast agents (CAs). The cocktail contained gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (GdDOTA-4AmP) and dysprosium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetrakis(methylenephosphonic acid) (DyDOTP), whose effects on relaxation are sensitive and insensitive to pH, respectively. The Gd-CA dominated the spin-lattice relaxivity ΔR(1) , whereas the Dy-CA dominated the spin-spin relaxivity ΔR(2)*. The ΔR(2)* effects were used to determine the pixel-wise concentration of [Dy] which, in turn, was used to calculate a value for [Gd] concentration. This value was used to convert ΔR(1) values to the molar relaxivity Δr(1) and, hence, pH(e) maps. The development of the method involved in vivo calibration and measurements in a rat brain glioma model. The calibration phase consisted of determining a quantitative relationship between ΔR(1) and ΔR(2)* induced by the two pH-independent CAs, gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) and DyDOTP, using echo planar spectroscopic imaging (EPSI) and T(1) -weighted images. The intensities and linewidths of the water peaks in EPSI images were affected by CA and were used to follow the pharmacokinetics. These data showed a linear relationship between inner- and outer-sphere relaxation rate constants that were used for CA concentration determination. Nonlinearity in the slope of the relationship was observed and ascribed to variations in vascular permeability. In the pH(e) measurement phase, GdDOTA-4AmP was infused instead of GdDTPA, and relaxivities were obtained through the combination of interleaved T(1) -weighted images (R(1) ) and EPSI for ΔR(2)*. The resulting r(1) values yielded pH(e) maps with high spatial resolution.

Towards the rational design of MRI contrast agents: δ-substitution of lanthanide(III) NB-DOTA-tetraamide chelates influences but does not control coordination geometry.

LnDOTA-tetraamide chelates (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) have received considerable recent attention as a result of their potential to act as PARACEST contrast agents for magnetic resonance imaging (MRI). Although PARACEST agents afford several advantages over conventional contrast agents they suffer from substantially higher detection limits; thus, improving the effectiveness of LnDOTA-tetraamide chelates is an important goal. In this study we investigate the potential to extend conformational control of LnDOTA-type ligands to those applicable to PARACEST. Furthermore, the question of whether δ- rather than α-substitution of the pendant arms could be used to control the chelate coordination geometry is addressed. Although δ-substitution does influence coordination geometry it does not afford control. However, it can play an important role in governing the conformation of the amide substituent relative to the chelate in such as way that suggests a PARACEST agent could be designed that has detection limits at least as low as a conventional MRI contrast agent.

Analysis of the conformational behavior and stability of the SAP and TSAP isomers of lanthanide(III) NB-DOTA-type chelates.

Controlling the water exchange kinetics of macrocyclic Gd(3+) chelates, a key parameter in the design of improved magnetic resonance imaging (MRI) contrast media, may be facilitated by selecting the coordination geometry of the chelate. The water exchange kinetics of the mono- capped twisted square antiprism (TSAP) being much closer to optimal than those of the mono capped square antiprism (SAP) render the TSAP isomer more desirable for high relaxivity applications. Two systems have been developed that allow for selection of the TSAP coordination geometry in 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd(3+) chelates, both based upon the macrocycle nitrobenzyl cyclen. In this paper we report investigations into the stability and formation of these chelates. Particular focus is given to the production of two regioisomeric chelates during the chelation reaction. These regioisomers are distinguished by having the nitrobenzyl substituent either on a corner or on the side of the macrocyclic ring. The origin of these two regioisomers appears to stem from a conformation of the ligand in solution in which it is hypothesized that pendant arms lie both above and below the plane of the macrocycle. The conformational changes that then result during the formation of the intermediate H(2)GdL(+) chelate give rise to differing positions of the nitrobenzyl substituent depending upon from which face of the macrocycle the Ln(3+) approaches the ligand.