Synthesis and evaluation of modified NOTA chelators labeled with [99mTc]Tc/Re-tricarbonyl cores for potential theranostic agent development
No Thumbnail Available
Authors
Meeting name
Sponsors
Date
Journal Title
Format
Thesis
Subject
Abstract
To further optimize [99mTc]Tc/Re-tricarbonyl-NOTA complexes as potential theranostic agents, here we present the synthesis and evaluation of 1,4,7- triazacyclononane (TACN) chelators having different pendant arm functionalities. Briefly, we report the metal complexes of the general formula fac-[M(CO)3(L)]+ (M=Re, 99mTc), where L indicates the different TACN chelators bearing different pendant arm functionalities. Three new bifunctional chelators, namely, NOTAM-BA (TACN with two acetamide arms and one benzylamine arm), NOTAL-BA (TACN with two ethyl alcohol arms and one benzylamine arm), and NOTACE-BA (TACN with two acetone arms and one benzylamine arm), in addition to the existing chelator NOTA-BA (TACN with two acetic acid arms and one benzylamine arm), were successfully synthesized and characterized. Since this is a fundamental science project, we have used chromophore-containing group benzylamine (BA) as a biomolecule surrogate. The complexation of the chelators was explored with fac- [99mTc][Tc(CO)3]+ and fac-[Re(CO)3]+ cores. NOTA-BA, NOTAM-BA, and NOTALBA formed complexes with [99mTc]Tc/Re-tricarbonyl cores. The corresponding Re complexes, namely, [Re(CO)3(NOTA-BA)]+ (Re-1), [Re(CO)3(NOTAM-BA)]+ (Re- 2), and [Re(CO)3(NOTAL-BA)]+ (Re-3) were purified in small batches using multiple xiii HPLC runs and characterized spectroscopically. The [99mTc]Tc-tricarbonyl labeled complexes [99mTc][Tc(CO)3(NOTA-BA)]+ (Tc-1), [99mTc][Tc(CO)3(NOTAM-BA)]+ (Tc-2), and [99mTc][Tc(CO)3(NOTAL-BA)]+ (Tc-3) were prepared in 92 percent, 40 percent, and 27 percent radiochemical yields, respectively (observed by radio-HPLC analysis) by reacting the chelators NOTA-BA, NOTAM-BA, and NOTAL-BA with [99mTc][Tc(OH2)3(CO)3]+. Under comparative HPLC studies, these radiotracers correlated well with their respective natural rhenium-labeled standards (Re-1, Re-2, Re-3). All 99mTc-labeled complexes remained stable through 18 h against challenge experiments with 1 mM L-cysteine and 1 mM L-histidine. Stability studies showed that the radiotracers remained stable through 18 h in rat serum. The log D7.4 values indicated that [99mTc][Tc(CO)3(NOTA-BA)]+ was more hydrophilic than [99mTc][Tc(CO)3(NOTAM-BA)]+ followed by [99mTc][Tc(CO)3(NOTAL-BA)]+. These findings establish that the [M(CO)3]+ complexes of NOTA-BA, NOTAM-BA, and NOTAL-BA are stable under in vitro challenge experiments and are hydrophilic in nature. In the future, labeling of the model bifunctional chelators with [186Re][Re(CO)3]+ can be explored. After that, the Log D7.4 studies and stability of the corresponding 186Re labeled complexes can be tested under challenge experiments.
Table of Contents
DOI
PubMed ID
Degree
M.S.