Synthesis and preliminary evaluation of mono-[I-123]iodohypericin monocarboxylic acid as a necrosis avid imaging agent

University of Leuven, Louvain, Flemish, Belgium
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 07/2007; 17(14):4001-5. DOI: 10.1016/j.bmcl.2007.04.083
Source: PubMed


Hypericin monocarboxylic acid was synthesized in an overall yield of 25% in four steps and radiolabelled with iodine-123 in good yield (>75%). The resulting mono-[(123)I]iodohypericin monocarboxylic acid was evaluated in normal mice and in rats with ethanol induced liver necrosis. In this model, tracer concentration in necrotic liver tissue was 14 times higher than in the viable liver tissue as quantified by autoradiography at 24h post injection. The results indicate the feasibility of visualization of necrotic tissue with the novel tracer.

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    • "It was recently discovered that hypericin has a peculiar affinity for necrotic tissues 10-18, independent of its photosensitivity. Several radiolabeled derivatives of hypericin, such as [123I]iodohypericin 19-24 and [131I]iodohypericin 25, have shown similar necrotic affinity in a number of pathological processes, including in animal models with organ infarctions or tumor necrosis. Thus, hypericin has also been recognized as a necrosis-avid contrast agent (NACA) 10, 18, 19, and is a focus of interest in relation to necrosis imaging. "
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    ABSTRACT: Hypericin has been widely studied as a potent photosensitizer for photodynamic therapy in both preclinical and clinical settings. Recently, hypericin has also been discovered to have a specific avidity for necrotic tissue. This affinity is also observed in a series of radiolabeled derivatives of hypericin, including [(123)I]iodohypericin, [(124)I]iodohypericin, and [(131)I]iodohypericin. Hypericin, along with other necrosis-avid contrast agents, has been investigated for use in noninvasively targeting necrotic tissues in numerous disorders. Potential clinical applications of hypericin include the identification of acute myocardial infarction, evaluation of tissue viability, assessment of therapeutic responses to treatments, and interventional procedures for solid tumors. The mechanisms of necrosis avidity in hypericin remain to be fully elucidated, although several hypotheses have been suggested. In particular, it has been proposed that the necrosis avidity of hypericin is compound specific; for instance, cholesterol, phosphatidylserine, or phosphatidylethanolamine components in the phospholipid bilayer of cellular membranes may be the major targets for its observed selectivity. Further investigations are needed to identify the specific binding moiety that is responsible for the necrosis avidity of hypericin.
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    ABSTRACT: De voorbije tien jaar zijn zowel SPECT als PET uitgebreid bestudeerd ter verbetering van de kwaliteit van functionele beeldvorming in kleine proefdieren. In dit werk hebben we ons toegespitst op SPECT van kleine dieren, wat veel toepassingsmogelijkheden heeft en de ruimtelijke resolutie van de micro-PET kan overtroeven. Het reconstructieprogramma werd verbeterd door het nauwkeuriger modelleren van het beeldvormingsproces, wat superieure beelden oplevert. Bovendien werd een efficiënte methode ontwikkeld voor beeldkwaliteitsevaluatie, die gevalideerd werd voor enkel- en meervoudige pinhole SPECT. Hiermee werd de invloed van vele ontwerpparameters voor pinholecollimatoren op de reconstructiebeeldkwaliteit onderzocht, de hoeveelheid overlap in multipinhole SPECT projecties incluis. Op basis van die resultaten werd een multipinhole-ontwerp voor muisbeeldvorming geoptimaliseerd, vervaardigd, en getest op een klinische gammacamera uitgerust met twee pinholecollimatoren. Dezelfde methode werd ook toegepast om de eigenschappen van time-of-flight PET te bestuderen. Tot slot werd een overzicht van onze belangrijkste pinhole SPECT toepassingen gegeven ter illustratie van de beeldkwaliteitsevolutie. The past decade, both SPECT and PET have extensively been studied to improve the quality of functional imaging in small laboratory animals. In this work, we focused on small animal SPECT, which has many applications and the potential to outperform the spatial resolution of the micro-PET. The reconstruction software was improved by more accurately modeling the imaging process, yielding superior images. In addition, an efficient image quality evaluation method was developed, and validated for single and multipinhole SPECT. Using this technique, the influence of many pinhole collimator design parameters, including the amount of overlap in multipinhole projections, on the reconstruction image quality was investigated. Based on these results, a multipinhole design was optimized for mouse imaging, manufactured, and tested on a clinical gamma camera equipped with two pinhole collimators. The same method was also applied to study the properties of time-of-flight PET. Finally, an overview of our most important pinhole SPECT applications is provided, illustrating the image quality evolution. Doctor in de ingenieurswetenschappen Afdeling Nucleaire Geneeskunde Dept. Medisch Diagnostische Wetensch. Faculteit Ingenieurswetenschappen Doctoral thesis Doctoraatsthesis
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    ABSTRACT: In a search for an infarct avid tracer agent with improved properties, we have observed that bis-DTPA derivatives of pamoic acid have a high avidity for necrotic tissue. Here, we report the synthesis, radiolabeling, and preliminary evaluation in normal mice and rats with hepatic infarction of the (99m)Tc-tricarbonyl complexes of N, N'-bis(diethylenetriaminopentaacetato)-4,4'-methylene bis(2-hydroxy-3-naphthoic hydrazide) ( (99m)Tc(CO) 3-bis-DTPA-pamoate) and [ N-(5-aminopentyl)pyridin-2-yl-methylamino]methylacetato-4,4'-methylene-2-hydroxy-3-napthalenecarboxamide-(2'-hydroxy-3'-naphthoic acid methyl ester) ( (99m)Tc(CO) 3 -12). Radiolabeling with (99m)Tc(CO) 3 (+) was achieved with a radiochemical yield of over 95% for both tracer agents. In normal mice, the polar (99m)Tc(CO) 3-bis-DTPA-pamoate was cleared from plasma via both the liver and the kidneys, while the more lipophilic (99m)Tc(CO) 3 -12 was rapidly cleared via the liver. Blood clearance in mice was faster for (99m)Tc(CO) 3 -12 (0.1% injected dose per gram at 4 h postinjection) than for (99m)Tc(CO) 3-bis-DTPA-pamoate (9.3% injected dose per gram at 4 h postinjection). Affinity and specificity of the tracers for necrotic tissue was studied in rats with hepatic infarction and ethanol-induced necrosis of the liver or muscles. Activity ratios of infarct to viable liver tissue of (99m)Tc(CO) 3-bis-DTPA-pamoate quantified by autoradiography of tissue slices ranged from 4 to 18, depending on the necrosis model and time postinjection of the tracer. Infarcts were also visualized in vivo by (99m)Tc(CO) 3-bis-DTPA-pamoate planar gamma imaging. After injection of (99m)Tc(CO) 3-bis-DTPA-pamoate, in vivo and ex vivo images correlated well with histochemical staining with triphenyltetrazolium chloride and hematoxylin and eosin. (99m)Tc(CO) 3 -12 on the other hand showed no uptake in necrotic tissue. Stability of the tracers was determined in vitro after storage at room temperature and by histidine challenge experiments, and in vivo in mouse plasma and in urine (for (99m)Tc(CO) 3-bis-DTPA-pamoate). (99m)Tc(CO) 3-bis-DTPA-pamoate was unstable in vitro to histidine challenge, while (99m)Tc(CO) 3 -12 was 98% stable in vitro in the same conditions. Both tracers showed good in vivo stability. (99m)Tc(CO) 3-bis-DTPA-pamoate shows high specificity for necrotic tissue and merits further evaluation as a necrosis avid imaging agent. (99m)Tc(CO) 3 -12 is not useful for visualization of necrotic tissue.
    No preview · Article · Oct 2007 · Bioconjugate Chemistry
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