ABSTRACT:We report the synthesis of DO3A derivatives of 2, 2′-diaminobiphenyl (1a,b) and their Gd complexes of the type [Gd(1)(H 2 O)]·xH 2 O (2a,b) for use as new MRI blood-pool contrast agents (BPCAs) that provide strong and prolonged vascular enhancement. Pharmacokinetic inertness of 2 compares well with that of structurally related Dotarem, a DOTA-based MRI CA currently in use. The R 1 relaxivity in water reaches 7.3 mM −1 s −1 , which is approximately twice as high as that of Dotarem (R 1 = 3.9 mM −1 s −1 ). They show interaction with HSA to give association constants (K a ) in the order of two (∼10 2 ), revealing the existence of the blood-pool effect. The in vivo MR images of mice obtained with 2 are coherent, showing strong signal enhancement in both heart, abdominal aorta, and small vessels. Furthermore, the brain tumor is vividly enhanced for an extended period of time. KEYWORDS: Gd chelates, DO3A, biphenyl, MRI BPCA, brain tumor M agnetic resonance imaging (MRI) is a powerful technique for noninvasive diagnosis of the human anatomy, physiology, and pathophysiology on the basis of superior spatial resolution and contrast useful in providing anatomical and functional images of the human body.1 At the clinical level, MRI techniques are mostly performed employing Gd(III) chelates (GdL) to enhance the image contrast by increasing the water proton relaxation rate in the body. 2Despite their wide and successful applications in clinics, however, conventional Gd(III)-based low-molecular weight CAs are mostly extracellular fluid (ECF) agents exhibiting rapid extravasation from the vascular space. As a result, the time window for imaging is considerably reduced, thus limiting acquisition of high-resolution images. 3−5To overcome such limitations inherent to ECF CAs, the necessity for the development of blood-pool contrast agents (BPCAs) has risen in the expectation that they reside in the blood vessel for an extended period of time and thus are eliminated much more slowly from the circulation than their ECF counterparts. The BPCAs provide strong and prolonged vascular enhancement. The BPCAs thus far developed may be divided into three classes according to their mechanism of action: (i) the noncovalent binding of low-molecular GdL to HSA to prevent immediate leakage into the interstitial space, 6−8 (ii) systems incorporating polymers or liposomes based on an increase in the size of CAs, which slows down leakage through endothelial pores, 9−12 and (iii) systems based on nanoparticles, involving a change in the route of elimination.13−15 The most successful approach so far is the class (i) represented by MS-325, a Gd−DTPA derivative containing a cholic acid moiety. These complexes bind strongly and reversibly to HSA, leading to not only high R 1 relaxivity at clinical field strengths but also much longer residence times in the blood as compared to ECF agents. The lipophilic component represented by aromatic

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We present the synthesis and characterization of DTPA-bis(histidylamide) (1a), DTPA-bis(aspartamide) (1b), and their gadolinium complexes of the type [Gd(L)(H 2 O)] (2a: L = 1a; 2b: L = 1b). Thermodynamic stabilities and R 1 relaxivities of 2a-b compare well with Omniscan ® , a well-known commercial, extracellular (ECF) MRI CA which adopts the DTPA-bis(amide) framework for the chelate: R 1 = 5.5 and 5.1 mM −1 for 2a and 2b, respectively. Addition of the Cu(II) ion to a solution containing 2b triggers relaxivity enhancement to raise R 1 as high as 15.3 mM , which corresponds to a 300% enhancement. Such an increase levels off at the concentration beyond two equiv. of Cu(II), suggesting the formation of a trimetallic (Gd/Cu 2 ) complex in situ. Such a relaxivity increase is almost negligible with Zn(II) and other endogenous ions such as Na(I), K(I), Mg(II), and Ca(II). In vivo MR images and the signal-to-noise ratio (SNR) obtained with an aqueous mixture of 2b and Cu(II) ion in an 1:2 ratio demonstrate the potentiality of 2 as a copper responsive MRI CA.