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Journal of Cancer Research and Therapeutics, Vol. 5, No. 3, July-September, 2009, pp. 148-153 Review Article Role of chelates in magnetic resonance imaging studies Tripathi Laxmi, Kumar Praveen, Singh Ranjit Department of Pharmaceutical Chemistry, SD College of Pharmacy and Vocational Studies, Muzaffarnagar Code Number: cr09040 PMID: 19841554 DOI: 10.4103/0973-1482.57118 Abstract Imaging studies are tests performed with a variety of techniques that produce pictures of the inside of a patient's body. Magnetic resonance imaging (MRI) is an imaging technique based on the principles of nuclear magnetic resonance. MRI uses a powerful magnetic field, radio waves, and a computer to produce detailed pictures of organs, soft tissues, bone, and virtually all other internal body structures. Chelates have a wide application in such imaging techniques. Chelates in imaging studies are used alone as radioactive agents or conjugated to monoclonal antibodies or to DNA as radioactive agents. Technetium chelates and gadolinium chelates are being widely used as magnetic resonance contrast media.Keywords: Chelates, radioactive agents, magnetic resonance imaging, magnetic resonance contrast media Introduction Imaging studies are tests performed with a variety of techniques that produce pictures of the inside of a patient′s body. [1] Magnetic resonance imaging (MRI) is an imaging technique based on the principles of nuclear magnetic resonance (NMR), a spectroscopic technique used by scientists to obtain microscopic chemical and physical information about molecules. Detailed MR images allow physicians to better evaluate parts of the body and certain diseases that may not be assessed adequately with other imaging methods such as x-ray, ultrasound, or computed tomography (also called CT or CAT scanning). They have become an indispensable tool in cancer screening and detection. [2],[3] Chelation refers to the formation of cyclic complex by co-ordination of a metal ion with a polydentate ligand. The resulting cyclic compound formed is known as a chelate. This complex formation results in precipitation of the metal or formation of a stable and a soluble compound. [4] A considerable number of metal complex compounds show use in cancer. Chelates can be useful in cancer by acting as cytotoxic drugs or radioactive agents in imaging studies or radioimmunotherapy. Chelates in Imaging Studies In recent years, scanning techniques have developed rapidly and are now among the most useful tools in diagnostic medicines. By means of scanning, tissues and organs can be visualized, and such visualization facilitates the detection of abnormalities in their function. Imaging studies have been an important tool in the diagnosis of cancer. [5],[6] Chelates have a wide application in such imaging techniques. Chelates in imaging studies are used by any of the following means:
Chelates can be used alone or in conjugation with monoclonal antibodies/DNA. Technetium chelates and gadolinium chelates are being widely used as MR contrast media. Chelates Used Alone as Radioactive Agents Technetium chelates Tc-99m is used as a diagnostic radiopharmaceutical. Over 80% of the radiopharmaceuticals currently being used make use of this short-lived, metastable radionuclide. The pre-eminence of 99m Tc is attributable to its optimal nuclear properties of a short half-life and a gamma photon emission of 140 keV, which is suitable for high-efficiency detection and which results in low-radiation exposure to the patient. 99m TcO 4 isreadily available as a column eluate from a 99 Mo/ 99m Tc generator is reduced in the presence of chelating agents. The versatile chemistry of technetium emerging from the eight possible oxidation states, along with a proper understanding of the structure-biological activity relationship, has been exploited to yield a plethora of products meant for morphologic and functional imaging of different organs. Newer methods of labeling involving bifunctional chelating agents (which encompass the "3 + 1" ligand system, Tc(CO)3(+1)-containing chelates, hydrazinonicotinamide, water-soluble phosphines, and other Tc-carrying moieties) have added a new dimension for the preparation of novel technetium compounds. These developments in technetium chemistry have opened new avenues in the field of diagnostic imaging. These include fundamental aspects in the design and development of target-specific agents, including antibodies, peptides, steroids and other small molecules that have a specific receptor affinity. [7] 99m Tc-labeled peptides have a tendency to accumulate in the liver and intestines due to hepatobiliary clearance as a result of the lipophilicity of the 99m Tc chelates. This makes the imaging of lesions in the abdominal area difficult. 99m Tc-labeled bombesin (BN) analogs have shown promise for noninvasive detection of many tumors that express BN/gastrin-releasing peptide (GRP) receptors. The analog synthesized was a high-affinity 99m Tc-labeled BN analog, [DTPA1, Lys 3( 99m Tc-Pm-DADT), Tyr4] BN, having a built-in pharmacokinetic modifier DTPA, and labeled with 99m Tc using a hydrophilic di-amine-di-thiol chelator (Pm-DADT) to affect low hepatobiliary clearance. In addition, [ 99m TcOAADT]-(CH 2 ) 2-NEt2 acts as a potential small-molecule single-photon emission computed tomographic probe for imaging metastatic melanoma. Evaluation of [ 99m Tc]oxotechnetium(V) complexes of the amine-amide-di-thiol (AADT) chelates containing tertiary amine substituents as small-molecule probes for the diagnostic imaging of metastatic melanoma has shown that technetium-99m-labeled AADT-(CH 2 )2-NEt2 ( 99m Tc-1) has the highest tumor uptake and other favorable biological properties. In vivo studies coupled with additional in vitro and ex vivo assessment show that 99m Tc-1 has high and specific uptake in melanoma metastases in lungs and can potentially follow the temporal growth of these tumors. [8] [ 99m Tc]oxotechnetium(V) complexes of amine-amide-di-thiol chelates with dialkylaminoalkyl substituents are also used as potential diagnostic probes for malignant melanoma. [ 99m Tc]oxotechnetium(V) complexes of amine-amide-di-thiol (AADT) chelates containing tertiary amine substituents were synthesized and shown to have affinity for melanoma. For complexation, the AADT-CH 2- [CH 2 ]nNR 2 (n = 1, 2; R = Et, n-Bu) ligand was mixed with a [ 99m Tc]oxotechnetium(V)-glucoheptonate precursor to make the AADT-[ 99m Tc]oxotechnetium(V) complexes in nearly quantitative yield. [9] Gadolinium chelates Gadolinium chelates are used in MRI. [10] Weak protein binding substantially increases the efficacy of gadolinium chelates as general purpose contrast agents for MRI. The effect of weak protein binding on the efficacy of gadolinium chelates as contrast agents for MRI was measured in the following way. Chelates with no (gadopentetate dimeglumine), weak (gadobenate dimeglumine), and strong (B-21326/7) protein binding were compared by in vitro MRI at 2T (spin echo [SE]: repetition time [TR]/echo time [TE] 350/8 ms) on solutions in 0.5 mM bovine serum albumin and in rat whole blood and by in vivo MRI at 2T on rat models of brain tumors (SE TR/TE 350/10 ms) and of focal blood-brain barrier disruption (SE TR/TE 400/15 ms) after injection of MPP+. Relaxation rate enhancement in the blood of normal rabbits was measured in vivo after administration of contrast agents using IR Snapshot. [11] Macromolecular gadolinium (Gd)(III) complexes have a prolonged blood circulation time and can preferentially accumulate in solid tumors, depending on the tumor blood vessel hyperpermeability, resulting in superior contrast enhancement in MR cardiovascular imaging and cancer imaging as shown in animal models. Unfortunately, safety concerns related to these agents′ slow elimination from the body impede their clinical development. Polydisulfide Gd(III) complexes have been designed and developed as biodegradable macromolecular MRI contrast agents to facilitate the clearance of Gd(III) complexes from the body after MRI examinations. Polydisulfide Gd(III) complexes have a relatively long blood circulation time and gradually degrade into small Gd(III) complexes, which are rapidly excreted via renal filtration. These agents result in effective and prolonged in vivo contrast enhancement in the blood pool and tumor tissue in animal models, yet demonstrate minimal Gd(III) tissue retention as the clinically used low-molecular-weight agents. Structural modification of the agents can readily alter the contrast-enhancement kinetics. [12] oly(l-glutamic acid) (PGA)-cystamine-[gadolinium (Gd)-DO3A] was prepared by loading approximately 55% of the carboxylic groups in PGA with Gd-DO3A via cystamine as the spacer. Cystamine can be readily cleaved by endogenous thiols to release the Gd(III) chelates from the conjugate facilitating Gd (III) excretion after the MRI, and a high-yield Gd-DO3A conjugation efficiency is obtained. This conjugation of Gd(III) chelates with biomedical copolymers via the degradable disulfide spacer resulted in significant contrast enhancement in the blood pool and tumor tissue but minimum long-term Gd(III) tissue retention. [13] Biodegradable Gd-DTPA l-cystine bisamide copolymers (GCACs) were also developed as safe and effective macromolecular contrast agents for MRI. Three new biodegradable GCACs with different substituents at the cystine bisamide [R = H (GCAC), CH 2 CH 2 CH 3 (Gd-DTPA L-cystine bispropyl amide copolymers, GCPCs), and CH (CH 3 ) 2 (Gd-DTPA cystine bisisopropyl copolymers, GCICs)] were prepared by the condensation copolymerization of diethylenetriamine pentaacetic acid (DTPA) dianhydride with cystine bisamide or bisalkyl amides, followed by complexation with gadolinium triacetate. These novel GCACs are promising contrast agents for cardiovascular and tumor MRI, which are later cleaved into low-molecular-weight Gd(III) chelates and rapidly cleared from the body. [14] The use of gadolinium chelates has become an essential element in the comprehensive MR examination of the liver. [15] The gadolinium chelates uniquely provide important information about tumor perfusion that is key in our assessment of liver masses. These paramagnetic contrast agents assist with liver lesion detection, characterization, and in establishing the volume of viable perfused tumor. The major classes of contrast agents currently used for MRI of the liver include extracellular agents (e.g., low-molecular-weight gadolinium chelates), reticuloendothelial agents (e.g., ferumoxides), hepatobiliary agents (e.g., mangafodipir), blood pool agents, and combined agents. Mechanisms of action, dosage, elimination, toxic effects, indications for use, and MRI technical considerations vary according to the class. Gadolinium chelates are the most widely used. Ferumoxides are a useful adjunct for the detection of hepatocellular carcinoma, particularly when used in combination with gadolinium to achieve improved lesion-to-liver contrasts over those achievable with gadolinium alone. [16] Noncovalent or covalent binding of low-molecular-weight Gd(III) chelates to macromolecules or polymers improves in vivo efficacy, pharmacokinetic properties, and specificity. The grafting of these high-spin paramagnetic gadolinium chelates on metal oxide nanoparticles (SiO 2 , Al 2 O 3 ) is done. This new synthetic strategy presents two main advantages: a high T1-relaxivity for MRI with a 275% increase of the MRI signal and the ability of nanoparticles to be internalized in cells. Results indicate that these new contrast agents lead to a huge reconcentration of Gd(III) paramagnetic species inside microglial cells. This reconcentration phenomenon gives rise to high signal-to-noise ratios on MR images of cells after particle internalization, from 1.4 to 3.75, using Al 2 O 3 or SiO 2 particles, respectively. [17] Gadolinium chelates are equally important for MRI of the extrahepatic abdomen. The interstitial accumulation of these agents within peritoneal and gastrointestinal tumor produces marked enhancement and is key in accurate tumor staging. Depiction of lesions within solid visceral organs such as the pancreas, kidneys, and spleen is also improved following gadolinium injection. [18],[19] Gadolinium chelates are also used in MRI of lumbar spine, [20] breast, [21],[22] lesions of the extracranial, [23] head and neck, [24] brain, [25],[26] pancreas, [27] and extracranial pediatric mass lesions .[28] Polyaspartamide gadolinium complexes containing sulfadiazine groups are used as potential macromolecular MRI contrast agents. [29] The sequential administration of superparamagnetic iron oxide (SPIO) and extracellular gadolinium chelates combines the sensitivity of SPIO for lesion detection with the specificity of dynamic gadolinium-enhanced imaging for lesion characterization. [30],[31] Dynamic contrast-enhanced (DCE-MRI) using low-molecular-weight gadolinium chelates enables noninvasive imaging characterization of tissue vascularity. Depending on the technique used, data reflecting tissue perfusion, microvessel permeability surface area product, and extracellular leakage space can be obtained. Two dynamic MRI techniques (T2FNx01-weighted or susceptibility-based and T1-weighted or relaxivity-enhanced methods) for prostate gland evaluations are developed. [32] Miscellaneous Luminescent lanthanide chelates are also used as contrast agents and detect lesions in the hamster oral cancer model. The ability of these molecules to produce fluorescence in the low- or zero-background regime makes this class of molecules excellent candidates for use as contrast agents. Terbium chelate contrast agent, based on the 1, 4, 7, 10-tetraazacyclododecane macrocycle (cyclen), is used for detection of early-stage malignant lesions in the Syrian hamster cheek pouch. Tb- (CTMB) delivers bright blue-green luminescence when excited with low-photon fluxes of UV light. It was used as a topical agent for the visual detection of diseased tissue, and aids in identifying early-stage oral cancer lesions. [33] Gold chelates are used in breast MRI. Four different nonselective gold chelates are available for contrast-enhanced MR breast imaging. [34] Chromium EDTA complex (Cr-EDTA) enhances contrast of MRI. Cr-EDTA was evaluated as an intravenous contrast agent for in vitro and in vivo MRI in rabbits and rats. The effect of Cr-EDTA on T1 and T2 values in vitro was first quantitated by spectroscopy at 2.5 MHz, followed by animal trials in which the effects of intravenous injection of Cr-EDTA on calculated T1 MR images (obtained by the spin-warp technique at 1.7 MHz) were determined. Following administration of Cr-EDTA, differences in T1 values between normal and abnormal kidneys were noted, renal hydronephrosis and renal ischemia were readily identified by the pattern of change in T1, and changes were observed in the normal rabbit brain and in tumors implanted in rats. It is concluded that the use of stable paramagnetic metal ion chelates, such as Cr-EDTA, as intravenous contrast agents in MRI is feasible and that such agents would make possible the observation of tissue vascularity, breakdown of the blood-brain barrier, and renal function. [35] Iron and gadolinium chelates are also used as NMR contrast agents. [36] The use of fluorescent europium chelates as labels in microscopy leads to reduced autofluorescence and good long-term stability. Europium chelates were introduced as alternative fluorescent labels for microscopy, and their effect on enhanced autofluorescence caused by the glutaraldehyde fixative was investigated. Glutaraldehyde fixation was used to stabilize the cells for a permanent mount after the immunocytochemical reaction. The europium signal in time-resolved fluorescence microscopy was shown to be free of autofluorescence when strong cross-linking fixation with glutaraldehyde was used, and the signal-to-background ratio obtained was 2,400 or better. It was also shown that the europium signal was stable in daylight and at room temperature. Fluorescent europium chelate used in this experiment provides excellent contrast and long-term stability for the samples with glutaraldehyde fixation and permanent mounting. [37] Development of targeted MR contrast agents directed to specific molecular entities could dramatically expand the range of MR applications by combining the noninvasiveness and high spatial resolution of MRI with specific localization of molecular targets. However, due to the intrinsically low sensitivity of MRI (in comparison with nuclear imaging), high local concentrations of the contrast agents at the target site are required to generate detectable MR contrast. To meet these requirements, the MR targeted contrast agents should recognize targeted cells with high affinity and specificity. They should also be characterized by high relaxivity, which for a wide variety of contrast agents depends on the number of contrast-generating groups per single molecule of the agent. [38] Chelates Conjugated to Monoclonal Antibodies as Radioactive Agents Tumor imaging can also be done with radioactive metal chelates conjugated to monoclonal antibodies. Chelate-derivatized monoclonal antibodies permit targeting of a broad spectrum of radioisotopes, including those that are optimum for gamma camera imaging or positron tomography as well as those that are tumoricidal. [39] The use of radiolabeled antibodies for tumor detection and therapy has provided some striking success. The specificity of antibodies offers unique opportunities to target tumors with radionuclides. However, due to the slow clearance of radiolabeled antibody, relatively high background is observed in non-target organs. Pretargeting protocols using bispecific monoclonal antibodies (bsMAbs) and radiolabeled chelates may overcome this problem. Renal-cell-carcinoma (RCC) xenografts can be targeted efficiently using G250 ΄ DTIn1 and 111In-DTPA. However, this requires careful tuning of the bsMAb protein dose and 111In-DTPA dose. Using the optimal protein dose and 111In-DTPA dose, high 111In-DTPA tumor uptake and tumor-to-blood ratios can be obtained, thus providing good perspectives for diagnostic and therapeutic use in humans. [40] But, a radiometal-labeled monoclonal antibody has an unfavorable tumor-to-normal tissue radioactivity ratio due, in part, to the accumulation of the label in normal tissues. One approach is to reduce unwanted background levels, is the improvement of ways in which radiolabels are attached to antibody, especially with the goal of increasing in vivo stability. Monoclonal antibody-chelate conjugates reduce uptake of metals such as indium by normal organs while maximizing the dose to tumor cells. Biodistribution of five different backbone-substituted derivatives of SCN-Bz-DTPA (1B4M-DTPA, 1M3B-DTPA, 1B3M-DTPA, GEM-DTPA, and 2B-DTPA) linked to MAb B72.3 was compared to that of the parent molecule after labeling with 111In. The results reviewed that the in vivo use of backbone-substituted forms of the SCN-Bz-DTPA, such as 1B4M-DTPA, 1M3B-DTPA, and 1B3M-DTPA bound to MAbs, can reduce uptake of indium by normal organs while maximizing the dose to the tumor. [41] Important developments have recently been reported in the labeling of antibodies with radiolabels, namely, radio-iodine, 111In, and 99m Tc. Antibodies labeled with radioisotopes of iodine in ways that minimize the extent of in vivo dehalogenation leads to reduced thyroid, stomach, and gut radioactivity uptake. Thus, the use of stably radio-iodinated antibodies appears to have resulted in modest improvements in patient images. Newer and stronger chelates for 111In have been developed in the hope that their use would result in lower radioactivity levels in the liver. Finally, newer methods, both direct and indirect, for the attachment of 99m Tc to antibodies have been developed and are now being clinically tested. [42] The tumor localization can be effectively blocked by coadministration of folic acid with the 111In-1 complex, consistent with a folate receptor-mediated targeting process. The cell membrane folate receptor is a potential molecular target for tumor-selective drug delivery. To probe structural requirements for folate receptor targeting with low-molecular-weight radiometal chelates, specifically the role of the amino acid fragment of folic acid (pteroylglutamic acid in mediating targeting selectivity, the amide-linked conjugate pteroyl-NHCH(2)CH(2)OCH(2)CH(2)OCH(2)CH(2)NH-DTPA was prepared by a three-step procedure. [43] Metabolizable 111In chelate conjugated anti-idio-type MAbs are used for radioimmunodetection of lymphoma in mice. 111In-labeled MAbs coupled with a new, enzyme metabolizable, bifunctional chelate (BCM) showed a substantial decrease in the blood background activity, a shorter biological half-life, and an increase in the tumor-to-blood ratio at the expense of a moderate decrease in the absolute tumor uptake. The versatile chemistry of these C-1-substituted BCMs provides a variety of possible enzyme cleavable moieties for further investigation. [44] Prostate-specific membrane antigen (PSMA) is a well-characterized cell surface antigen expressed by virtually all prostate cancers (PCas). PSMA has been successfully targeted in vivo with the 111In-labeled 7E11 MAb, which binds to an intracellular epitope of PSMA. The work reports the in vitro characterization of three recently developed MAbs, namely, murine MAbs J415, J533, J591 that bind the extracellular domain of PSMA (PSMAext). [45] Monoclonal antibodies with the specific ability to bind metal chelates such as 111In benzyl EDTA acts as reversible equilibrium carriers of radiopharmaceuticals. 01, 10, 50 and 100 mg MAb CHA255 Kb = 4 X 10E9 was complexed with 111In BLEDTA II, BLEDTA IV, and benzyl EDTA and injected i.v. in Balb/c mice with the KHJJ tumor. The biological half-life by whole body counting was profoundly altered for all three compounds: from minutes to hours with 10 mg, and to days with 100 mg. Tumor uptake increased 50-fold at 24 h with increasing MAbs but satisfactory tumor concentrations (3% per gram) and tumor/blood ratios (1.8:1) were obtained with an amount equivalent to 7 mg for a human. Blood level and whole body activity were decreased 30-50% within 3 h or with an i.v. injection of a "flushing" dose of unlabeled indium benzyl EDTA, increasing tumor/blood ratios to 50:1. [46] In addition, a time-resolved fluorescence imaging (TRFI) technique is developed for quantitative histochemistry using lanthanide chelates in nanoparticles conjugated to MAbs. Immunohistochemical (IHC) detection of PSA and human glandular kallikrein from prostatic tissueis a suitable method for obtaining quantitative data from biological samples and the signal response is linear. Eu-chelate containing particles in the nanometer range are suitable labels for the quantitative IHC detection. Even single-nanoparticle molecules can be detected by TRFI and the signals measured can be readily quantitated. The signal intensity correlates very well with the amount of bound label, and the use of nanoparticles could markedly improve the sensitivity of quantitative IHC methods. TRFI provides a powerful tool for providing quantitative data about antigens or transcripts in tissue sections or cultured cells. It is also of major importance in standardization and optimization of protocols for fixation and tissue preparation, including antigen-retrieval methods. [47] Chelates Conjugated to DNA as Radioactive Agents DNA-binding chelates are also used for nonviral gene delivery imaging. Noninvasive in vivo monitoring of gene delivery provides critically important information regarding the spatial distribution, local concentration, kinetics of removal, and/or biodegradation of the expression vector. A novel approach to noninvasive gene delivery imaging using heterobifunctional peptide-based chelates (PBC) bearing double-stranded DNA-binding groups and a technetium-binding amino acid motif was developed. One of such chelates, Gly-Cys(Acm)-Gly-Cys(Acm)-Gly-Lys(4)-Lys-(N-epsilon-[4-(psoralen-8-yloxy)]butyrate)-NH(2), has been characterized and labeled with reduced (99m)Tc pertechnetate (oxotechnetate). A higher expression of marker mRNA and green fluorescent protein was determined. [48] References
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