Kofi Adzamli

Blood pool agent strongly improves 3D magnetic resonance coronary angiography using an inversion pre-pulse.

The ability of a blood pool contrast agent to enhance MR coronary angiography was defined. The proximal coronary vessels of pigs were imaged before and after administration of Gd‐DTPA bound covalently to bovine serum albumin (0.2 mmol/kg). The contrast agent resulted in a reduction of the blood T1 value to 33 ± 5 msec, as determined in vivo with a Look‐Locker technique. Both 2D and 3D imaging techniques were performed. An inversion pulse suppressed the signal of nonblood tissue postcontrast. After contrast agent administration, in the 3D data set the signal‐to‐noise ratio (SNR) of blood and contrast‐to‐noise ratio (CNR) of blood to myocardium were improved by factors of 2.0 ± 0.2 and 15 ± 8, respectively (P < 0.05). Postcontrast, the 3D acquisition was superior to the 2D technique in terms of spatial resolution, SNR of blood, and CNR of blood to myocardium. The high contrast of the 3D data set allowed for direct and rapid display of coronary arteries using a “closest vessel projection.”Magn Reson Med 41:360–367, 1999.

Direct assessment of water exchange on a Gd(III) chelate bound to a protein

Abstract The Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-l-aspartyl-lysine-derived DTPA, [GdL(H2O)]2–, binds to serum albumin in vivo, through hydrophobic interaction. A variable temperature 17O NMR, EPR, and Nuclear Magnetic Relaxation Dispersion (NMRD) study resulted in a water exchange rate of k298ex=4.2×106 s–1, and let us conclude that the GdL complex is identical to [Gd(DTPA)(H2O)]2– in respect to water exchange and electronic relaxation. The effect of albumin binding on the water exchange rate has been directly evaluated by 17O NMR. Contrary to expectations, the water exchange rate on GdL does not decrease considerably when bound to bovine serum albumin (BSA); the lowest limit can be given as kex, GdL-BSA=kex, GdL / 2. In the knowledge of the water exchange rate for the BSA-bound GdL complex, the analysis of its NMRD profile at 35  °C yielded a rotational correlation time of 1.0 ns, one order of magnitude shorter than that of the whole protein. This value is supported by the longitudinal 17O relaxation rates. This indicates a remarkable internal flexibility, probably due to the relatively large distance between the protein- and metal-binding moieties of the ligand.

MRI contrast enhancement of necrosis by MP-2269 and gadophrin-2 in a rat model of liver infarction

Ni Y, Adzamli K, Miao Y, et al. MRI contrast enhancement of necrosis by MP-2269 and gadophrin-2 in a rat model of liver infarction. Invest Radiol 2001;36:97–103. rationale and objectives. The mechanisms of action leading to specific localization of necrosis-avid contrast agents (NACAs) such as gadophrin-2 are not well defined. It has been suggested recently that agents with a high degree of serum albumin binding may also serve as NACAs by virtue of nonspecific hydrophobic interactions. The present MRI-histomorphology correlation study was conducted to verify the likelihood of the proposed albumin-binding mechanism by comparing an albumin-binding blood pool agent, MP-2269, with gadophrin-2 in a rat model of reperfused liver infarction. methods.Reperfused infarction in the right liver lobe was surgically induced in six rats. Serial T1-weighted MRI was performed before and after intravenous injection of MP-2269 at 0.05 mmol/kg and repeated in the same rats 24 hours later after intravenous injection of gadophrin-2 at the same dosage (0.05 mmol/kg). The MR images were matched with corresponding histomorphological findings. The signal intensity and contrast ratio of infarcted and normal hepatic lobes were quantified and compared between the two agents during the postcontrast course. results.Before contrast, the infarcted lobe was indiscernible from normal liver on T1-weighted MRI. Shortly after injection of both MP-2269 and gadophrin-2, a negative contrast occurred between infarcted and normal liver because of a strong liver signal intensity enhancement and an inferior uptake in the necrotic liver. On delayed phase (>60 minutes), a necrosis-specific contrast enhancement (contrast ratio 1.6) developed with gadophrin-2 but not with MP-2269. The MR images matched well with corresponding histomorphological findings. conclusions.Although both MP-2269 and gadophrin-2 feature an albumin-binding capacity, only gadophrin-2 displayed a persistent necrosis-specific contrast enhancement in the rat model of reperfused liver infarction. Therefore, the role of albumin binding in the mechanisms of NACAs should be reevaluated.

Calcium/oxyanion-containing particles with a polymerical alkoxy coating for use in medical diagnostic imaging

The present invention provides new and structurally diverse particulates for use in magnetic resonance imaging and X-ray contrast imaging of body organs and tissues having the following general formula: Can Mm Xr Ys wherein M is a paramagnetic ion or stoichiometric mixture of metal ions having a valence of 2+ or 3+; X is a simple anion; Y is a tetrahedral oxyanion, or mixtures thereof; m is an integer greater than or equal to 1; n is an integer greater than or equal to 1; r and s are integers and are adjusted as needed to provide charge neutrality; and further comprising a polyalkoxy compound. Methods for using and making particles of the invention are also disclosed.

17O-NMR, EPR, and NMRD characterization of [Gd(DTPA-BMEA)(H2O)]. A neutral MRI contrast agent

A study including variable-temperature and -pressure, multiple-field 17O NMR, EPR and NMRD has been performed on the MRI contrast agent, [Gd(DTPA-BMEA)(H2O)]. The water exchange rate [kex298 = (0.39 ± 0.02) × 106 s−1] and the activation volume (ΔV≠ = +7.4 ± 0.4 cm3 mol−1), hence the mechanism, are identical to those for [Gd(DTPA-BMA)(H2O)]. The longer rotational correlation time of [Gd(DTPA-BMEA)(H2O)], as obtained from a global analysis of 17O-NMR, EPR and NMRD data, and compared to that of [Gd(DTPA-BMA)(H2O)], can be explained by water molecules hydrogen-bonded to the ether oxygen atoms of the ligand side chain.

NMRD ASSESSMENT OF GD-DTPA-BIS(METHOXYETHYLAMIDE) (GD-DTPA-BMEA), A NONIONIC MRI AGENT

RATIONALE AND OBJECTIVES Gd-DTPA-BMEA, a nonionic bis(methoxyethylamide) derivative of Gd-DTPA, is the active ingredient of OptiMARK, now awaiting FDA approval. In this study, we compare the relaxivities of Gd-DTPA-BMEA (OptiMARK) with those of the commercially available DTPA-based agents Gd-DTPA2- (Magnevist) and Gd-DTPA-BMA (Omniscan) at different field strengths (1/T1 nuclear magnetic relaxation dispersion (NMRD) profiles). In addition, we study how changes in structural attributes of small paramagnetic chelate complexes of Gd3+ ions influence 1/T1 NMRD profiles. METHODS 1/T1 NMRD profiles of Gd-DTPA-BMEA (OptiMARK) were measured at 5 degrees and 35 degrees C and a set of values for the parameters that describe relaxation by Gd(3+)-proton magnetic dipolar interactions was obtained. The rotational (tau R) and the diffusional (tau D) correlation times for Gd-DTPA-BMA were adjusted for the 15% greater molecular weight of Gd-DTPA-BMEA. tau M (the resident lifetime of Gd(3+)-bound water) was obtained from available 17O NMR relaxation data. For tau S0 and tau V (the low-field relaxation time of the Gd3+ moment and its correlation time), Gd-DTPA-BMA values were taken as initial values and tau S0 refined as needed. RESULTS Although, at 35 degrees C, tau M is comparable for the two neutral agents and an order of magnitude longer than that for Gd-DTPA2-, the 1/T1 NMRD profiles of Gd-DTPA-BMEA are indistinguishable from those of Gd-DTPA2- and Gd-DTPA-BMA. A 40% increase in the value of tau S0 from Gd-DTPA2- is required for agreement of data and theory for Gd-DTPA-BMEA. CONCLUSIONS Based on their 1/T1 NMRD profiles, the efficacy of the three agents should be identical in typical clinical MRI applications. The data can be fit reliably to theory, and differences in the fit parameters (and structure) have no effect on the three profiles at 35 degrees C. The relatively long values of tau M for the two neutral agents would only be of importance at low temperatures.

Water-proton relaxation by a noncovalent albumin-binding gadolinium chelate: an NMRD study of a potential blood pool agent.

Magnetic dipolar interactions between solvent water protons and paramagnetic solutes, such as chelated Gd3 ions, provide an efficient means for increasing both the longitudinal (1/T1) and transverse (1/T2) relaxation rates of solvent protons. For small paramagnetic chelate complexes, interactions by direct water coordination to the metal ion (inner sphere) and diffusion in the outer sphere environment of the metal complexes are the two main contributors to relaxation enhancement. At magnetic resonance imaging (MRI) fields and physiologic conditions, these contributions are additive and generally comparable in magnitude, whereas for macromolecular complexes, inner sphere contributions tend to dominate relaxation. The inner sphere contribution to 1/T1 is given by: 1/T1p q[Gd3 ]/55.5(T1M M). Here, q is the number of coordinated inner sphere water molecules, T1M is the longitudinal relaxation time of the coordinated water protons, and M is their lifetime on the metal ion. For coordinated Gd3 ions with q 1, both T1M and M are of the order of microseconds. 1/T1 is a complicated function of the strength of the interaction, the magnitude of the applied MRI field B0, and an overall correlation time, C. C is given by C 1 R 1 S 1 M 1, the inverse of the sums of the reciprocals of the orientational relaxation time of the complex R, the electronic relaxation time of the paramagnetic metal ion S, and M, respectively. For Gd3 ions, S can also be a function of B0, often characterizable by another correlation time V. In any event, the enhancement is maximized for kinetically labile complexes, when exchange of the inner sphere water is rapid (but not too rapid), such that C M T1M (1–3). Attachment of Gd3 chelates to macromolecules generally leads to a peak in 1/T1 in the MRI field range (2,3). This phenomenon is well understood and is associated with the long R of macromolecular complexes and related to the fact that S becomes very long at MRI fields. Hence, formation of a rigid macromolecular paramagnetic complex is a design goal for obtaining high-relaxivity contrast agents. To date, several covalently bonded Gd3 macromolecular complexes have been explored, but the peak relaxivity has been limited either by lack of rigidity or by a long value of M (4–8). Relatively rigid paramagnetic macromolecular complexes have been generated in vivo, in the blood pool, through reversible noncovalent hydrophobic interactions of small lipophilic Gd3 chelates with serum (9,10). Depending on the specifics of the docking interaction at the known hydrophobic patches on albumin, highly efficient intravascular contrast agents can be produced. In addition, the reversibility of the noncovalent interactions ensures increased circulation lifetime of the agent and ease of elimination by the kidneys as small molecules, thereby reducing toxicity problems. A monomeric nonaromatic MR agent (code-named MP-2269) that binds to serum albumin has been synthesized. MP-2269 is the Gd3 complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-L-aspartyl-lysine-derived-DTPA (see Fig 1 for MP-2269 structure). The lysine-DTPA derivative is -(N,N-bis-[2-[N ,N -bis(carboxy-methyl-amino)]]ethyl)-L-lysine (11). The hydrophobic pentylbicyclo[2.2.2]octane side chains associate with albumin, and negAcad Radiol 2002; 9(suppl 1):S11–S16

POLYETHYLENEGLYCOL-STABILIZED MANGANESE-SUBSTITUTED HYDROXYLAPATITE AS A POTENTIAL CONTRAST AGENT FOR MAGNETIC RESONANCE IMAGING : PARTICLE STABILITY IN BIOLOGIC FLUIDS

RATIONALE AND OBJECTIVES Polymer-stabilized manganese(II)-substituted hydroxylapatite (MnHA) has been investigated as a particulate contrast agent for magnetic resonance imaging. The MnHA core requires a polymer coating to retard opsonization, thereby prolonging its systemic persistence. Therefore, the aim of this study was to assess the stability of various formulations in biologic media in vitro. METHODS Polyethyleneglycol-coated manganese(II)-substituted hydroxylapatite particles were studied in bovine plasma as a function of the concentration of polymer in the formulation. Particle sizing techniques and nuclear magnetic resonance proton relaxometry were used to evaluate both in vitro and in vivo stability. RESULTS A small-sized particle (approximately 10 nm diameter) that is stable in bovine plasma and rabbit whole blood was formed in formulations with high amounts of polymer concentration. In formulations with low amounts of polymer concentration, larger-sized particles (approximately 100 nm diameter) were present along with the small-sized population. The larger particles de-aggregated into the small-size particle distribution on dispersion in bovine plasma and rabbit whole blood. CONCLUSIONS Ultrasmall particles with high surface coat were stable in plasma, whereas larger aggregates de-aggregated. Unlike Mn2+, the interaction of polyethyleneglycol-stabilized manganese(II)-substituted hydroxylapatite with plasma proteins was weak.

1H-NMRD and 17O-NMR assessment of water exchange and rotational dynamics of two potential MRI agents: MP-1177 (an extracellular agent) and MP-2269 (a blood pool agent)

The parameters that govern water proton magnetic relaxation (e.g. water exchange rates, and rotational and electronic correlation times) of representatives of two classes of Gd(III) complexes have been estimated, using two different approaches and the results compared with those derived for known analogs. The complexes studied are: (i) the non-ionic GdDTPA-bis(methoxyethyl-amide) [Gd(DTPA-BMEA)], a typical small-molecule extracellular MR agent, and (ii) the ionic Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-l-aspartyl-lysine-derived-DTPA [GdL]4−, a prototype MR blood pool agent, which binds to serum albumin in vivo through non-covalent hydrophobic interactions. An17O-NMR study of [Gd(DTPA-BMEA)] gives a water exchange rate constant ofkex298=(0.39±0.02)×106 s−1, identical to that for the bismethylamide analog [Gd(DTPA-BMA)]. Both approaches yield longer rotational correlation times for [Gd(DTPA-BMEA)], consistent with its higher molecular weight. An17O-NMR study of [GdL]4− gives a water exchange rate constant ofkex298=(4.2±0.1)×106 s−1, identical to that for [Gd(DTPA)]2−. The water exchange rate on [GdL]4− did not decrease considerably when bound to albumin, the lowest limit iskex,GdL-BSA=kex,GdL/2. Both approaches yield identical rotational correlation times for [GdL]4−, however, it was difficult to derive a consistent rotational constant for the albumin-bound [GdL]4− using the different approaches (values ranged between 1.0 and 23.0 ns).

Development of a novel nonaromatic small-molecule MR contrast agent for the blood pool

The ideal contrast agent for MR angiography should be safe, efficacious, blood-persistent, and easily excreted. The binding of small Gd chelates to macromolecules has been shown to provide a mechanism of proton relaxation enhancement in MR images through longer rotational correlation times of the macromolecule-bound Gd-chelate complexes (1,2). Several effective macromolecules bearing such covalently attached Gd chelates have been synthesized and evaluated previously for MRA applications. These, however, either proved unsafe (protein precipitants) or had undesirably long blood retention, ie, were not easily excreted (3-6). Reversible noncovalent binding of small Gd chelates to serum albumin (via hydrophobic interactions) produces an efficacious, blood persistent alternative to macromoleculebased MR blood-pool agents without attendant clearance problems (7,8). A prime requirement for this approach is the presence of a lipophilic component on the Gd chelate that can undergo reversible protein binding. An MR blood-pool agent, MS-325, which takes advantage of the binding of aromatic side chains on a Gd-chelate compound to albumin, is under development (2,7,8). We now report the results of our attempt to develop a nonaromatic small Gd 3+ chelate as a contrast agent for MR angiography (ie, MP-2269, a water-soluble MR agent that binds blood proteins reversibly to yield an efficacious blood-pool agent).