A nonaromatic, small-molecule, gadolinium(3+)-chelate code named MP-2269 was synthesized and evaluated in animals as a potential MR contrast agent for blood pool. The ligand of MP-2269 was prepared by conjugating a lipophilic, albumin-binding moiety, 4-pentylbicyclo[2.2.2]octane-1-carboxylic acid, to an amino-functionalized DTPA derivative by means of a diaspartic acid linker. Proton relaxometry studies in vitro yielded spin-lattice relaxivities (R1) for MP-2269 of 6.2, 20.0 and 26.1 mM(-1)sec(-1) in water, rabbit blood, and human blood, respectively. The enhanced relaxivities in blood indicate significant binding of the agent to blood proteins. At a dose of 45 micromol/kg, MP-2269 showed a biphasic rabbit blood clearance profile with half-lives of 4.7 and 142 minutes, respectively, for the fast and slow components. In rats, the agent is cleared predominantly through the hepatobiliary pathway (approximately 70% in 24 h by this mode). The LD50 value of MP-2269 is approximately 3.0 mmol/kg in mice. Preliminary MR angiograms obtained in the rabbit showed excellent enhancement of blood vessels. Hence, MP-2269 has potential for future exploitation as a contrast agent for MR angiography.

A new series of gadolinium chelates designed as blood pool contrast enhancing agents for magnetic resonance imaging applications is described. Complexes having four Gd(III) chelate units display a significant increase in molecular relaxivity per gadolinium ion in water (9-13 L x mmol(-1) x (s-1) compared to Gd(III)-DTPA (5 L x mmol(-1) x s(-1). A further jump in relaxivity (25 L x mmol(-1) x sec(-1) in 4% BSA solution was observed in the case of a fatty acid-containing tetrachelate and is attributed to noncovalent binding of the tetrachelate to serum albumin. This agent was successfully used for imaging the rat circulatory system.

Administration of gadoversetamide or gadodiamide caused no significant effect on serum calcium concentration. Neither gadoversetamide nor gadodiamide interfered with measurement of serum calcium with the arsenazo III or ICP-MS method. However, the orthocresolphthalein method of measuring serum calcium produced a transient hypocalcemia artifact in the presence of gadoversetamide or gadodiamide.

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When isolated from the hamster cheek pouch, cannulated, and perfused, 60- to 90-microns arterioles spontaneously contracted to 67 +/- 4% of maximum diameter. Vessel sensitivity to variations in extracellular Ca2+ was then evaluated. Tone, regardless of its source, was highly dependent on the concentration of Ca2+ in the bathing solution. The magnitude of responses to changing Ca2+ depended upon which vessel surface (luminal or abluminal) the change was made. For K(+)-induced tone the Ca2+ concentration-response curve was right shifted 60-fold for luminal vs. abluminal changes. These results suggest that restricted diffusion of Ca2+ from lumen to smooth muscle dramatically reduces smooth muscle Ca2+ concentration and that under standard in vitro conditions the smooth muscle layer is effectively isolated from luminal contents. Both the cytosolic and stored Ca2+ in these microvessels were dependent on the Ca2+ concentration in the bathing solution. Abrupt removal of Ca2+ from bath produced a rapid maximal dilation with a mean time to half-maximal response (t1/2 max) of 14 +/- 4 s. Ca2+ replacement induced a return to the previous level of tone with a mean t1/2 max of 8 +/- 3 s. The magnitude of transient responses to caffeine (10 mM) was inversely related to the time of exposure to zero Ca2+ with a rapid decay in magnitude (t1/2 max = 2.7 +/- 0.8 min). These data suggest that the smooth muscle cells of arterioles have a particularly rapid transmembrane Ca2+ flux that is tightly controlled by an intracellular regulatory mechanism, which may explain the generally increased dependence of smaller vessels on extracellular Ca2+.