Transporter Imaging Agent

Meltzer etal, US Patent 6,171,576 (January 9, 2001) Assignee Organix Inc. and President Fellows of Harvard College and Massachusetts Institute of Technology Utility Early Diagnosis Agent for Neurodegenerative Disorders 

N- 2-((3 -Chloropropyl)(2((triphenylmethyl)thio)ethyl)amino)-acetyl -S-(triphenylmethyl)-2-aminoethanethiol 

N- 2-((2-((Triphenylmethyl)thio)ethyl)amino)acetyl -S-(triphenylmethyl)-2-amino-ethanethiol (16 mmol) was dissolved in 10 ml CH2CI2, 3-chloropropyltriflate (8 mmol) added, the mixture stirred at ambient room temperature 2 hours, and an additional 90 ml CH2CI2 added. The solution was filtered, purified by chromatography using silica gel with EtOAc/hexanes, 1 1, and the product isolated in 72%, mp = 55-56°C. H-NMR, IR, elemental analysis data supplied. 

To a solution of nor-3-/3-(4-fluorophenyl)tropane-2-/3-carboxylic acid methyl ester (0.2 mmol) dissolved in 10 ml acetonitrile was added in succession the product from Step 1 (0.2 mmol), KI (0.2 mmol), and K2CO3 (2.0 mmol), and the slurry refluxed overnight. The solution was cooled, 2 g silica gel added, and concentrated. The residue was purified by chromatography on a silica gel column with NH40H/EtOAc/hexanes, 0.5%1 1, and the product isolated in 72% yield. The product was then converted into the dihydrogen chloride salt which had a mp = 166-168 °C. H-NMR, IR, elemental analysis data supplied. 

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Recently, the development of " Tc-labcled tropane derivatives used as dopamine transporter imaging agents has been reported. The dopamine transporter is a protein complex located prcsynaptically at dopaminergic nerve terminals [247]. It is depleted in Parkinson s disease, and the extent of depletion correlates with the loss of dopamine [248], Among a series of tropane derivatives [249,250] labeled with " Tc, two compounds deserve more attention. 

Newberg AB, Plossl K, Mozley PD, Stubbs JB, Wintering N, Udeshi M, Alavi A, Kauppinen T, Kung HE. Biodistribution and imaging with I-ADAM a serotonin transporter imaging agent. J Nucl Med 2004 45 834-841. 

Meltzer, P. C.,Blundell, P., Jones,A. G. etal. A technetium-99m SPECT imaging agent which targets the dopamine transporter in primate brain. J. Med. Chem. 40 1835-1844, 1997. 

Serum transferrin is normally only about 30% saturated with iron. This explains why it has a relatively high capacity for binding other metals and so is implicated in the transport of 67Ga,1139 which is used as an imaging agent for various soft tissue tumours and inflammatory abscesses.1140 Transferrin also facilitates movement of gallium across tumour cell membranes.1141... 

Tremendous efforts in the last several decades have resulted in numerous invendons of CNS drug delivery systems. Many of these innovadve systems have a significant potendal for the development of new biomedical applicadons. The wide variety of strategies reflects the inherent difficulty in transport of therapeudc and imaging agents across the BBB. In fact, the... 

Goswami, R., Kung, M.-R, Ponde, D. E., et al. (2006) Fluoro alkyl derivatives of dihydro-tetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters. Nucl. Med. Biol., 33, 685-694. 

Polymer vesicles are also suitable to transport and target imaging agents such as fluorescent dyes and paramagnetic contrast agents. Hammer and coworkers encapsulated porphyrin-based near-infrared (NIR) fluorophores into PBD-PEO... 

Several gamma-emitting compounds have been synthesized, vahdated, and characterized as sensitive probes for Pgp and MRPl functional activity. Most of these compounds are cationic and modestly hydrophobic similar to the chemotherapeutic agents in the MDR phenotype. The radiopharmaceutical hexakis(2-methoxy-isobutyl-isonitrile)technetium-99m commonly known as [ Tc]Sestamibi or [ Tc]MIBI (Cardiolite ) was the first imaging agent recognized as transport substrate of Pgp and the most widely used in clinical and pre-clinical studies for functional evaluation of MDR [53]. 

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