We have developed a new class of magnetic resonance imaging contrast agents with large proton relaxation enhancements and high molecular relaxivities. The reagents are built from the polyamidoamine form of Starburst dendrimers in which free amines have been conjugated to the chelator 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid. The dendrimer gadolinium poly-chelates have enhancement factors, i.e., the ratio of the relaxivity per Gd(III) ion to that of Gd(III)-diethylenetriaminepentaacetic acid, of up to 6. These factors are more than twice those observed for analogous metal-chelate conjugates formed with serum albumins, polylysine, or dextran. One of the dendrimer-metal chelate conjugates has 170 gadolinium ions bound, which greatly exceeds the number bound to other macromolecular agents reported in the literature, and has a molecular relaxivity of 5,800 (mM.s)-1, at 25 MHz, 20 degrees C, and pH of 7.4. We observed that these dendrimer-based agents enhance conventional MR images and 3D time of flight MR angiograms, and that those with molecular weights of 8,508 and 139,000 g/mole have enhancement half lives of 40 +/- 10 and 200 +/- 100 min, much longer than the 24 +/- 4 min measured for Gd(III)-diethylenetriaminepentaacetic acid. Our results suggest that this new and powerful class of contrast agents have the potential for diverse and extensive application in MR imaging.

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Large macromolecular MRI contrast agents with albumin or dendrimer cores are useful for imaging blood vessels. However, their prolonged retention is a major limitation for clinical use. Although smaller dendrimer-based MRI contrast agents are more quickly excreted by the kidneys, they are also able to visualize vascular structures better than Gd-DTPA due to less extravasation. Additionally, unlike Gd-DTPA, they transiently accumulate in renal tubules and thus also can be used to visualize renal structural and functional damage. However, these dendrimer agents are retained in the body for a prolonged time. The purpose of this study was to obtain information from which a macromolecular dendrimer-based MRI contrast agents feasible for use in further clinical studies could be chosen. Six small dendrimer-based MRI contrast agents were synthesized, and their pharmacokinetics, whole-body retention, and dynamic MRI were evaluated in mice to determine an optimal agent in comparison to Gd-[DTPA]-dimeglumine. Diaminobutane (DAB) dendrimer-based agents cleared more rapidly from the body than polyamidoamine (PAMAM) dendrimer-based agents with the same numbers of branches. Smaller dendrimer conjugates were more rapidly excreted from the body than the larger dendrimer conjugates. Since PAMAM-G2, DAB-G3, and DAB-G2 dendrimer-based contrast agents showed relatively rapid excretion, these three conjugates might be acceptable for use in further clinical applications.

Only a handful of radiolabeled antibodies (Abs) have gained FDA approval for use in clinical oncology, including four immunodiagnostic agents and two targeted radioimmunotherapeutic agents. Despite the advent of non-immunogenic Abs and availability of a diverse library of radionuclides, progress beyond early Phase II RIT studies in solid tumors has been marginal. Furthermore, 18 F-FDG continues to dominate the molecular imaging domain, underscored by a decade-long absence of any newly approved antibody-based imaging agents (none since 1996!). Why has the development of clinically successful Abs for RIT been limited to lymphoma? What obstacles must be overcome to allow the FDA-approval of immunoPET imaging agents? How can we address the unique challenges that have thus far prevented the introduction of Ab-based imaging agents and therapeutics for solid tumors? Many poor decisions have been made regarding radiolabeled Abs, but useful insight can be gained from these mistakes. The following review addresses physical, chemical, biological, clinical, regulatory, and financial limitations that impede the progress of this increasingly important class of drugs. OverviewThe following review illustrates key components of a successful radiolabeled diagnostic or therapeutic antibody (Ab) from the inside out -that is, starting from the unstable nucleus itself and moving outwards. For each sequential topic, relevant theory will be examined and related to the practical use of various radiolabeled Abs that have succeeded to varying degrees in the clinic. This approach will present each important aspect of a rather complex multidisplinary phenomenon in a logical, stepwise manner: I. The radionuclide itselfPhysical properties of the unstable nucleus II. The radionuclide's chemical surroundingsChemical attachment of the radiometal or radiohalogen III. The antibodyBiological issues of the radioimmunoconjugate † Portions of this article were highlighted during a presentation at the Workshop on Molecular Imaging: After Bench to Bedside: Impact on Clinical Outcome Feb. [23][24][25] 2007. *Correspondence to: Martin W. Brechbiel, Ph.D., Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, NCI, NIH, Building 10, Room 1B40, 10 Center Drive, Bethesda, MD 20892-1088, Fax: (301) 402-1923, e-mail: martinwb@mail.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNucl Med Biol. Author manuscript; available in PMC 2008 October 1. Published in final edited form as:Nucl Med Biol. 2007 October ; 34(7): 757-778. NIH-PA Author ManuscriptNIH-PA...

Summation This update summarizes the growing application of “click” chemistry in diverse areas such as bioconjugation, drug discovery, materials science, and radiochemistry. This update also discusses click chemistry reactions that proceed rapidly with high selectivity, specificity and yield. Two important characteristics make click chemistry so attractive for assembling compounds, reagents, and biomolecules for pre-clinical and clinical applications. First, click reactions are bioorthogonal; neither the reactants nor their product’s functional groups interact with functionalized biomolecules. Second, the reactions proceed with ease under mild non-toxic conditions such as at room temperature and usually in water. The copper catalyzed Huisgen cycloaddition, azide-alkyne [3+2] dipolar cycloaddition, and Staudinger ligation, azide-phosphine ligation, each possess these unique qualities. These reactions can be used to modify one cellular component while leaving others unharmed or untouched. Click chemistry has found increasing applications in all aspects of drug discovery in medicinal chemistry such as for generating lead compounds through combinatorial methods. Bioconjugation via click chemistry is rigorously employed in proteomics and nucleic research. In radiochemistry, selective radiolabeling of biomolecules in cells and living organisms for imaging and therapy has been realized by this technology. Bifunctional chelating agents for several radionuclides useful for PET and SPECT imaging have also been prepared using click chemistry. This review concludes that click chemistry is not the perfect conjugation and assembly technology for all applications, but provides a powerful and attractive alternative to conventional chemistry. This chemistry has proven itself to be superior in satisfying many criteria (biocompatibility, selectivity, yield, stereospecificity, etc.); thus one can expect it will consequently become a more routine strategy in the near future for a wide range of applications.