David Lee Ladd

A targeted contrast agent for magnetic resonance imaging of thrombus: Implications of spatial resolution

A preparation of ultra‐small superparamagnetic iron oxide (USPIO) particles coupled to an RGD peptide (RGD‐USPIO) was investigated as an MR contrast agent, targeted to activated platelets, in both ex vivo and in vivo thrombus models. Thrombus visualization ex vivo was compared using RGD‐USPIO and a non‐targeted UPSIO. The influence of thrombus visualization on thrombus exposure time to RGD‐USPIO (ex vivo) and on the spatial resolution of the MR image (ex vivo and in vivo) was assessed. RGD‐USPIO resulted in better thrombus visualization than non‐targeted USPIO ex vivo, and maximum enhancement was achieved after approximately one hour exposure time of the thrombus to RGD‐USPIO. The ability to visualize the clots was highly dependent on the spatial resolution of the image. In vivo, an in‐plane resolution of less than 0.2 × 0.2 mm2 was required for good clot visualization after contrast enhancement. It is concluded that the achievable resolution and sensitivity is a potential limitation to the usefulness of active vascular targeting in MRI. J. Magn. Reson. Imaging 2001;13:615–618.

Polymeric gadolinium chelate magnetic resonance imaging contrast agents: design, synthesis, and properties.

We have synthesized and evaluated five series of polymeric gadolinium chelates which are of interest as potential MRI blood pool contrast agents. The polymers were designed so that important physical properties including molecular weight, relaxivity, metal content, viscosity, and chelate stability could be varied. We have shown that, by selecting polymers of the appropriate MW, extended blood pool retention can be achieved. In addition, relaxivity can be manipulated by changing the polymer rigidity, metal content affected by monomer selection, viscosity by polymer shape, and chelate stability by chelator selection.

Gadolinium-based linear polymer with temperature-independent proton relaxivities: a unique interplay between the water exchange and rotational contributions†‡

Macromolecular complexes of Gd(III) chelates are widely investigated as MRI contrast agents. In addition to the potential increase in relaxivity, they have a further advantage over the Gd(III) chelates of an extended lifetime in the blood pool, which is necessary for magnetic resonance angiography applications. When designing macromolecular complexes of Gd(III) chelates, it is important to know how the parameters that determine relaxivity are affected in comparison with those of the chelate. This paper reports variable‐temperature EPR, variable‐temperature and ‐pressure, multiple field 17O NMR and variable‐temperature NMRD studies on a linear Gd(DTPA–bisamide)–poly(ethylene glycol) copolymer. The rate [kex298=(4.8±0.1)×105 s‐1] and mechanism (dissociatively activated) of the water exchange are identical with those on the corresponding chelate. The rotational correlation time (τR=232 ps) is not much longer than that of the monomer unit restricted to rotate around a single axis, indicating large flexibility of the ethylene glycol chain. The proton relaxivities of the linear polymer complex are virtually independent of temperature, a result of an offset between the opposite dependences of the outer‐ and inner‐sphere contributions with temperature. ©1998 John Wiley & Sons, Ltd.

Time-of-flight MR angiography with Gd-DTPA hexamethylene diamine co-polymer blood pool contrast agent: comparison of enhanced MRA and conventional angiography for arterial stenosis induced in rabbits.

Vascular stenoses were induced in the external iliac arteries of New Zealand white rabbits by a combination of hypercholesterolemic diet and repeat balloon injury. Two‐dimensional (2D) and three‐dimensional (3D) time‐of‐flight (TOF) magnetic resonance angiography (MRA) was performed with a specifically designed phased array coil in a 1.5 T system. Enhancement with gadolinium‐diethylene triamine pentaacetic acid (Gd‐DTPA) hexamethylene diamine co‐polymer (Nycomed: NC 22181), a blood pool MR contrast agent, was measured after contrast administration and compared with pre‐contrast images at the same levels. Vessel diameter measurements were obtained at multiple levels and compared with comparable levels on conventional angiograms of the same animals. Stable enhancement, averaging 227% above baseline, was observed with the 3D TOF MRA over the 40 minutes of this study. Enhancement was not observed with the 2D TOF technique. Measurement of the smallest vessels in this study with 3D TOF MRA was slightly improved following contrast enhancement, although both pre‐ and post‐contrast diameter measurements tended to underestimate the assumed true vessel diameter. Thus, Gd‐DTPA hexamethylene diamine co‐polymer (Nycomed: NC 22181), a blood pool MR contrast agent, produces significant, stable enhancement with the 3D TOF technique and may improve MRA measurement of small vessels. J. Magn. Reson. Imaging 2000;11:638–646.

Binding constant determination of WIN 22169, a novel polymeric ligand

WIN 22169 is a co-polymer containing approximately 11 repeating units of polyoxyethylene and diethylenetriamine pentaacetic acid (DTPA). WIN 66368, a magnetic resonance imaging (MRI) contrast agent, is the gadolinium III complex of WIN 22169. WIN 22169 has been characterized with respect to its equivalent weight, acidity constants and excess acid or base, as well as its metal ion binding constants. The logs of the equilibrium binding constants of the ligand to Gd3+, Ca2+, Zn2+ and Cu2+ were found to be 16.6, 7.47, 12.2 and 14.0. The Gd selectivity constant, a measure of the preferential binding of the ligand toward Gd3+ versus the three in vivo ions: Ca2+, Zn2+ and Cu2+, of WIN 66368 was calculated to be 7.9. This value compares favourably to that for Gd DTPA which has a Gd selectivity constant of 7.04.

Synthesis and NMR Characterization of Monomethoxypoly(Ethylene Glycol) Aldehydes from Monomethoxypoly(Ethylene Glycol) Tosylates

Abstract A procedure for the synthesis of monomethoxypoly(ethylene glycol) aldehydes from monomethoxypoly(ethylene glycol) tosylates is described. The tosylates are converted to aldehydes in high yield via treatment with disodium hydrogen phosphate and DMSO; minimal oligomeric by-products are formed.