Necrosis-Avid Contrast Agents

Although originally introduced as tumor-specific contrast media ( 1 Furmanski P Longley C Metalloporphyrin enhancement of magnetic resonance imaging of human tumor xenografts in nude mice. Cancer Res. 1988; 48: 4604-4610 PubMed Google Scholar , 2 Hindré F LePlouzennec M de Certained JD Foultier MT Patrice T Simonneaux G Tetra-p-amonophenylporphyrin conjugated with Gd-DTPA: tumor-specific contrast agent for MR imaging. J Magn Reson Imaging. 1993; 3: 59-65 Crossref PubMed Scopus (44) Google Scholar , 3 Nelson J Schmiedl U Shankland E Metalloporphyrins as tumor-seeking MRI contrast media and as potential selective treatment sensitizers. Invest Radiol. 1990; 25: S71-S73 Crossref PubMed Scopus (25) Google Scholar ), Gadophrin-2 (bis-Gd-mesoporphyrin; IDF, Berlin, Germany) and some other metalloporphyrins have been proven to be avid for necrosis instead of for viable tumors ( 4 Ni Y Marchal G Yu J et al. Localization of metalloporphyrin induced "specific" enhancement in experimental liver tumors: a comparison between MRI, microangiographic and histologic findings. Acad Radiol. 1995; 2: 687-699 Abstract Full Text PDF PubMed Scopus (62) Google Scholar , 5 Ni Y Petré C Miao Y et al. Magnetic resonance imaging—histomorphologic correlation studies on paramagnetic metalloporphyrins in rat models of necrosis. Invest Radiol. 1997; 32: 770-779 Crossref PubMed Scopus (57) Google Scholar , 6 Al-Hallaq HA Ebert W Semmler W Lewis MZ River JN Lipton MJ 3-D MR imaging of rodent tumors using a paramagnetic metalloporphyrin indicates binding to necrotic tissue areas. Radiology. 1997; 205: 434 Google Scholar ). This unique targetability has elicited novel applications for magnetic resonance imaging (MRI) visualization of acute myocardial infarction ( 7 Ni Y Marchal G Petré C et al. Metalloporphyrin enhanced magnetic resonance imaging of acute myocardial infarction (abstr). Circulation. 1994; 90: 2512 Google Scholar , 8 Marchal G Ni Y Herijgers P et al. Paramagnetic metalloporphyrins: infarct avid contrast agents for diagnosis of acute myocardial infarction by magnetic resonance imaging. Eur Radiol. 1996; 6: 2-8 Crossref PubMed Scopus (78) Google Scholar , 9 Ni Y Marchal G Herijgers P et al. Paramagnetic metalloporphyrins: from enhancers for malignant tumors to markers of myocardial infarcts. Acad Radiol. 1996; 3: S395-S397 Abstract Full Text PDF PubMed Google Scholar , 10 Ni Y Pislaru C Bosmans H et al. Validation of intracoronary delivery of metalloporphyrin as an in vivo "histochemical staining" for myocardial infarction with MR imaging. Acad Radiol. 1998; 5: S37-S41 PubMed Google Scholar , 11 Pislaru S Ni Y Pislaru C et al. Noninvasive measurements of infarct size after thrombolysis with a necrosis-avid MRI contrast agent. Circulation. 1999; 99: 690-696 Crossref PubMed Scopus (76) Google Scholar , 12 Wilke NM Zenovich A Jerosch-Herold M et al. Myocardial necrosis severity and extent assessed with bis-gadolinium mesoporphyrin (abstr). Circulation. 1998; 98: I-372 Google Scholar , 13 Saeed M Bremerich J Wendland MF Wyttenbach R Weinmann HJ Higgins CB Quantification of myocardial salvage after ischemia/reperfusion by contrast enhanced MR imaging (abstr). Radiology. 1998; 209: 228 Google Scholar ) and therapeutic necrosis ( 14 Ni Y Miao Y Bosmans H et al. Evaluation of interventional liver tumor ablation with Gd-mesoporphyrin enhanced magnetic resonance imaging (abstr). Radiology. 1997; 205: 319 PubMed Google Scholar ). However, phototoxicity, discoloration, and other side effects may prevent clinical use of porphyrin-based agents. It has been demonstrated previously that a nonporphyrin chelate, gadolinium texaphyrin, shares "similar" target specificity with porphyrins ( 15 Young SW Sidhu MK Qing F et al. Preclinical evaluation of gadolinium (III) texaphyrin complex: A new paramagnetic contrast agent for magnetic resonance imaging. Invest Radiol. 1994; 29: 330-338 Crossref PubMed Scopus (75) Google Scholar ), whereas the cyclic tetrapyrrole ring characteristic of all porphyrins does not inevitably lead to the observed necrosis affinity ( 16 Ni Y Miao Y Cresens E et al. Paramagnetic metalloporphyrins: there exist necrosis-avid and non-avid species. Proceedings of 7th Annual Scientific Meeting for ISMRM. 1999; 1: 346 Google Scholar ). Other chelates derived from either tetrapyrrole analogues such as bilirubin and biliverdin or smaller constituents such as mono-, bi- and tri-pyrrole ligands also failed to exhibit a necrosis specificity (Ni et al, unpublished data). These findings not only suggest the absence of a direct link between porphyrin-related structures and the affinity for necrosis but also imply the possibility of producing new generations of necrosis-avid agents that can be totally different from porphyrins in their chemical structures and, therefore, without the side effects seen with porphyrins. Our strategy is to search for more effective, less colored, and less toxic necrosis-avid molecules.