Flexibly labeling peptides

#A portion of the disclosure of this patent document contains material subject to copyright protection. The copyright owner has no objection to the facsimile reproduction of the patent document or the patent disclosure as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.

#Macrocyclic metal chelates using 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (DOTA) may be administered to patients and animals to create or enhance contrast in biomedical imaging studies. Examples include paramagnetic Gd(III)-DOTA for magnetic resonance imaging (MRI), radioactive Tc-DOTA for single photon emission computed tomography (SPECT), and fluorescent Eu(III)-DOTA for fluorescence imaging. DOTA provides flexibility for synthetic derivatization that can change the pharmacokinetics of a chelate in vivo. This facilitates providing additional imaging information about biological processes.

#Metal-DOTA chelates have been conjugated to peptides to affect the pharmacokinetics of a metal-DOTA imaging agent in vivo. This facilitates acquiring additional information about biological processes at the molecular level. A variety of peptidyl ligands have been employed for these molecular imaging studies, including peptides that bind to specific cell surface receptors, peptides that penetrate cell membranes, peptides that nonspecifically interact with the extracellular matrix, and peptide homopolymers that alter renal clearance rates.

#The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate various example methods, and other embodiments of various aspects of the invention. It will be appreciated that the illustrated element boundaries (e.g., boxes, groups of boxes, or other shapes) in the figures represent one example of the boundaries. One of ordinary skill in the art will appreciate that in some embodiments one element may be designed as multiple elements, multiple elements may be designed as one element, an element shown as an internal component of another element may be implemented as an external component and vice versa, and so on. Furthermore, elements may not be drawn to scale.

#FIG. 1 illustrates an example synthesis strategy to create a DOTA-loaded resin for solid phase peptide synthesis (SPPS).

#FIG. 2 illustrates an example method for step-wise coupling of amino acids to the aminoDOTA Wang resin using a SPPS method. The peptide Asp-Glu-Val-Asp corresponds to SEQ ID NO: 1.

#The following includes definitions of selected terms employed herein. The definitions include various examples and/or forms of components that fall within the scope of a term and that may be used for implementation. The examples are not intended to be limiting. Both singular and plural forms of terms may be within the definitions.

#References to “one embodiment”, “an embodiment”, “one example”, “an example”, and so on, indicate that the embodiment(s) or example(s) so described may include a particular feature, structure, characteristic, property, element, or limitation, but that not every embodiment or example necessarily includes that particular feature, structure, characteristic, property, element or limitation. Furthermore, repeated use of the phrase “in one embodiment” does not necessarily refer to the same embodiment, though it may.

#“Molecular Imaging”, as used herein, refers to the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems. The techniques used for molecular imaging may include nuclear medicine, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and optical imaging. In one example, molecular imaging may be facilitated by an aminoDOTA-peptide contrast agent that creates or enhances differentiation between a cell expressing a normal level of caspase and a cell expressing an elevated level of caspase.