Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe

Abstract

Tissue hypoxia occurs in pathologic conditions such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium complex of 1,4,7,10-tetraaza-1,4,7,10-tetraacetate (DOTA) having a 2-nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia-sensitive MRI agent. A control complex, Gd(DO3A-monobutylamide), was also prepared in order to test whether the nitroimidazole side-chain alters either the water proton T1 relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)− as expected for mono-amide derivatives. The water proton T1 relaxivity (r1), bound water residence lifetime (τM) and rotational correlation time (τR) of both complexes was determined by relaxivity measurements, variable temperature 17O NMR and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r1 = 6.38 mm−1s−1 at 20 MHz, τM = 0.71 µs, τR = 141 ps) determined for the nitroimidazole derivative closely parallel those of other Gd(DO3A-monoamide) complexes of similar molecular size. In vitro MR imaging experiments using 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative is trapped in cells maintained under N2 as evidenced by ~2-fold decrease in T1 measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative may serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.

Nyíltláncú és makrociklusos aminokarboxilát ligandumok szintézise és fémkomplexeik vizsgálata: koordinációs kémia az orvosi képalkotás szolgálatában

“…A ligandum szerkezetébol adódóan a Gd 3+ -komplex termodinamikailag stabil, kinetikailag inert, amely képes hipoxiás sejtekben dúsulni (a nitroimidazol "egység" nitrocsoportja reduktív közegben aminocsoporttá redukálódik, amely képes kovalens kötés kialakítására a sejten belül található különbözo makromolekulákkal, ez pedig gátolja a komplex "kiürülését"). 33 Nyolc aril-foszfonát és fluórozott-aril-foszfonát oldalláncot tartalmazó DO3A származék Ca 2+ -, Zn 2+ -, Cu 2+ A makrociklus üregméretének a Mn 2+ -komplexek fizikai-kémiai tulajdonságaira és szerkezetére gyakorolt hatásáról a 9-aneN3, 12-aneN4 és 14-aneN4 makrociklusok monopikolinát-származékainak vizsgálatával (NOMPA, DOMPA és TEMPA) kaphattunk információt. 37 37 A háromszorosan helyettesített 1,4,7,10-tetraazaciklododekán származékok Mn 2+ -komplexeinek a relaxometriás vizsgálata alapján megállapítottuk, hogy ezek belsõ koordinációs szférájában nincs vízmolekula, tehát a donoratomok számát tovább kell csökkenteni.…”

Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

“…A gadolinium-based 2-nitroimidazole derivative was developed and evaluated for its potential to detect hypoxic cells by MRI [80]. The target chelator was synthesized via acid-amine coupling between DO3A-monobutylamide (DO3A= 1,4,7,10-tetraazacylododecane-1,4,7-tri(acetic acid tert-butyl ester)) and nitroimidazolyl hexanoic acid.…”

Synthesis and Characterization of Ligands and their Gadolinium(III) Complexes

“…In the case of the symmetrical substitution, the "naked" macrocycle is prepared in the first step and the pendants are introduced in the second step. This strategy was used for preparation of tri(substituted) ligands with acetate (H 3 PCTA) [340,350], glutarate [351], propionate [352], and acetamide pendant arms [353] as well as for phosphonate derivative (H 6 PCTP) [354,355]. A different strategy can be used for ligands with mixed pendant arms.…”