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Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI.

ABSTRACT: The water molecule exchange rates in a series of DyDOTA-(amide)X chelates were fine-tuned to maximize the effects of T2-exchange line broadening and improve T2 contrast.Four DyDOTA-(amide)X chelates having a variable number of glycinate side-arms were prepared and characterized as T2-exchange agents. The nonexchanging DyTETA chelate was also used to measure the bulk water T2 reduction due solely to T2*. The total transverse relaxivity (r2tot) at 22, 37, and 52°C for each chelate was measured in vitro at 9.4 Tesla (400 MHz) by fitting plots of total T2 (-1) versus concentration. The water molecule exchange rates for each complex were measured by fitting (17)O line-width versus temperature data taken at 9.4 Tesla (54.3 MHz).The measured transverse relaxivities due to water molecule exchange (r2ex) and bound water lifetimes (?M) were in excellent agreement with Swift-Connick theory, with DyDOTA-(gly)3 giving the largest r2ex?=?11.8 s(-1) mM(-1) at 37°C.By fine-tuning the water molecule exchange rate at 37°C, the transverse relaxivity has been increased by 2 to 30 times compared with previously studied Dy(3+)-based chelates. Polymerization or dendrimerization of the optimal chelate could yield a highly sensitive, molecule-sized T2 contrast agent for improved molecular imaging applications.

SUBMITTER: Soesbe TC

PROVIDER: S-EPMC4219925 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI.

Soesbe Todd C TC Ratnakar S James SJ Milne Mark M Zhang Shanrong S Do Quyen N QN Kovacs Zoltan Z Sherry A Dean AD

Magnetic resonance in medicine 20140301 3

<h4>Purpose</h4>The water molecule exchange rates in a series of DyDOTA-(amide)X chelates were fine-tuned to maximize the effects of T2-exchange line broadening and improve T2 contrast.<h4>Methods</h4>Four DyDOTA-(amide)X chelates having a variable number of glycinate side-arms were prepared and characterized as T2-exchange agents. The nonexchanging DyTETA chelate was also used to measure the bulk water T2 reduction due solely to T2*. The total transverse relaxivity (r2tot) at 22, 37, and 52°C f ...[more]

PMID: 24390729

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Project description:Site-specific enzymatic reactions with microbial transglutaminase (mTGase) lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N'-N''-N'''-tetraacetic acid (DOTA) chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA)1-decalysine, (DOTA)3-decalysine or (DOTA)5-decalysine to the antibody heavy chain (via Gln295/297) gave rise to immunoconjugates containing two, six or ten DOTA moieties respectively. Radiolabeling of the immunoconjugates with (177)Lu yielded specific activities of approximately 70 MBq/mg, 400 MBq/mg and 700 MBq/mg with increasing numbers of DOTA chelates. Biodistribution experiments in SKOV3ip human ovarian cancer cell xenografts demonstrated a high and specific accumulation of radioactivity at the tumor site for all antibody derivatives with a maximal tumor accumulation of 43.6±4.3% ID/g at 24 h for chCE7agl-[(DOTA)-decalysine]2, 30.6±12.0% ID/g at 24 h for chCE7agl-[(DOTA)3-decalysine]2 and 49.9±3.1% ID/g at 48 h for chCE7agl-[(DOTA)5-decalysine)]2. The rapid elimination from the blood of chCE7agl-[(DOTA)-decalysine]2 (1.0±0.1% ID/g at 24 h) is associated with a high liver accumulation (23.2±4.6% ID/g at 24 h). This behavior changed depending on the numbers of DOTA moieties coupled to the decalysine peptide with a slower blood clearance (5.1±1.0 (DOTA)3 versus 11.7±1.4% ID/g (DOTA)5, p<0.005 at 24 h) and lower radioactivity levels in the liver (21.4±3.4 (DOTA)3 versus 5.8±0.7 (DOTA)5, p<0.005 at 24 h). We conclude that the site-specific and stoichiometric uniform conjugation of the highly DOTA-substituted decalysine ((DOTA)5-decalysine) to an anti-tumor antibody leads to the formation of immunoconjugates with high specific activity and excellent in vivo behavior and is a valuable option for radioimmunotherapy and potentially antibody-drug conjugates (ADCs).

Dataset Information

Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI.

Publications

Maximizing T2-exchange in Dy(3+)DOTA-(amide)X chelates: fine-tuning the water molecule exchange rate for enhanced T2 contrast in MRI.

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