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Gd Complexes of DO3A-(Biphenyl-2,2'-bisamides) Conjugates as MRI Blood-Pool Contrast Agents.

ABSTRACT: We report the synthesis of DO3A derivatives of 2,2'-diaminobiphenyl (1a,b) and their Gd complexes of the type [Gd(1)(H2O)]·xH2O (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.

SUBMITTER: Jung KH

PROVIDER: S-EPMC4025651 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Gd Complexes of DO3A-(Biphenyl-2,2'-bisamides) Conjugates as MRI Blood-Pool Contrast Agents.

Jung Ki-Hye KH Kim Hee-Kyung HK Park Ji-Ae JA Nam Ki Soo KS Lee Gang Ho GH Chang Yongmin Y Kim Tae-Jeong TJ

ACS medicinal chemistry letters 20121023 12

We report the synthesis of DO3A derivatives of 2,2'-diaminobiphenyl (1a,b) and their Gd complexes of the type [Gd(1)(H2O)]·xH2O (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 ...[more]

PMID: 24900422

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Project description:We hypothesized that chelating Gd(III) to 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetylamide (DO3A) on peptide nucleic acid (PNA) hybridization probes would provide a magnetic resonance genetic imaging agent capable of hybridization to a specific mRNA. Because of the low sensitivity of Gd(III) as an magnetic resonance imaging (MRI) contrast agent, a single Gd-DO3A complex per PNA hybridization agent could not provide enough contrast for detection of cancer gene mRNAs, even at thousands of mRNA copies per cell. To increase the Gd(III) shift intensity of MRI genetic imaging agents, we extended a novel DO3An-polydiamidopropanoyl (PDAPm) dendrimer, up to n = 16, from the N-terminus of KRAS PNA hybridization agents by solid phase synthesis. A C-terminal D(Cys-Ser-Lys-Cys) cyclized peptide analog of insulin-like growth factor 1 (IGF1) was included to enable receptor-mediated cellular uptake. Molecular dynamic simulation of the (Gd-DO3A-AEEA)16-PDAP4-AEEA2-KRAS PNA-AEEA-D(Cys-Ser-Lys-Cys) genetic imaging nanoparticles in explicit water yielded a pair correlation function similar to that of PAMAM dendrimers, and a predicted structure in which the PDAP dendron did not sequester the PNA. Thermal melting measurements indicated that the size of the PDAP dendron included in the (DO3A-AEEA)n-PDAPm-AEEA2-KRAS PNA-AEEA-D(Cys-Ser-Lys-Cys) probes (up to 16 Gd(III) cations per PNA) did not depress the melting temperatures (Tm) of the complementary PNA/RNA hybrid duplexes. The Gd(III) dendrimer PNA genetic imaging agents in phantom solutions displayed significantly greater T1 relaxivity per probe (r1 = 30.64 +/- 2.68 mM(-1) s(-1) for n = 2, r1 = 153.84 +/- 11.28 mM(-1) s(-1) for n = 8) than Gd-DTPA (r1 = 10.35 +/- 0.37 mM(-1) s(-1)), but less than that of (Gd-DO3A)32-PAMAM dendrimer (r1 = 771.84 +/- 20.48 mM(-1) s(-1)) (P < 0.05). Higher generations of PDAP dendrimers with 32 or more Gd-DO3A residues attached to PNA-D(Cys-Ser-Lys-Cys) genetic imaging agents might provide greater contrast for more sensitive detection.

Dataset Information

Gd Complexes of DO3A-(Biphenyl-2,2'-bisamides) Conjugates as MRI Blood-Pool Contrast Agents.

Publications

Gd Complexes of DO3A-(Biphenyl-2,2'-bisamides) Conjugates as MRI Blood-Pool Contrast Agents.

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