Tc-Labeled acetylated, 2,3,5-triiodobenzoic acid- and diethylenetriamine pentaacetic acid-conjugated, and PEGylated ethylenediamine-core generation 4 polyamidoamine dendrimers

Tc-Labeled acetylated, 2,3,5-triiodobenzoic acid (TIBA)- and diethylenetriamine pentaacetic acid (DTPA)-conjugated, and PEGylated ethylenediamine-core generation 4 polyamidoamine dendrimers (G4 PAMAM), abbreviated as Tc-G4-[[[[Ac]-TIBA]-DTPA]-mPEG], is a blood pool multimodal agent synthesized by Criscione et al. for single-photon emission computed tomography (SPECT)/computed tomography (2) (1). In the recent years, the fact that imaging modalities with high sensitivity have relatively poor resolution, while those with high resolution have relatively poor sensitivity, has triggered the integration of multiple modalities and the use of hybrid instrument technology in imaging (3, 4). This has also boosted the development of multimodal imaging agents, which further enhances the benefits of hybrid technology, allowing better characterization of diseases and disease processes (5-7). However, it is still challenging to incorporate enough labels for detection by the relatively low-sensitive modalities and to select an appropriate radionuclide in a radiotracer-based imaging approach in the development of multimodal agents (1). Criscione et al. synthesized a radiolabeled, multimodal contrast agent, Tc-G4-[[[[Ac]-TIBA]-DTPA]-mPEG], for preclinical microSPECT/CT imaging (1). The design of this agent is based on the G4 PAMAM dendrimers, which were used as the core structure of the multimodal agent. Dendrimers have been selected for two main reasons. First, their well-defined, multifunctional surface (64 primary amines) offers the ability to conjugate several different moieties with negligible steric hindrance. Second, dendrimer-based contrast agents have already been successfully designed and examined with different imaging modalities (1, 8, 9). However, PAMAM dendrimers have a highly cationic surface, which limits their water solubility and can cause hemolysis in humans (1). Dendrimers also have a relatively short circulation time when they are used for developing blood pool imaging agents. To overcome these problems, Criscione et al. partially acetylated the dendrimer surface to reduce the positive surface charge and PEGylated the remaining surface amines to enhance the circulation time and limit the clearance by the reticuloendothelial system (1). These modifications provided dendrimers the desired water solubility, long intravascular residence time, and predominant renal clearance (1). To induce the dendrimer construct's multimodal capability, Criscione et al. selected TIBA and Tc-DTPA for X-ray attenuation and radioactive signal, respectively (1). TIBA possesses X-ray attenuation properties similar to those of the clinically used, small-molecule triiodobenzoic acid derivative Omnipaque 350. The studies by Criscione et al. have also shown that sufficient iodine weight percent for effective X-ray attenuation without sacrificing aqueous solubility can be achieved by conjugating TIBA to dendrimers (1). The acyclic chelator DTPA was used to chelate tin(II)-reduced Tc because of its established chemistry and stability. and animal studies have confirmed the potential usefulness of this multimodal agent in the quantification of intramyocardial blood volume and blood flow (1).