An ⁸⁶Y-Labeled Mirror-Image Oligonucleotide: Influence of Y-DOTA Isomers on the Biodistribution in Rats

Abstract

A mirror-image oligonucleotide (L-RNA) was radiolabeled with the positron emitting radionuclide (86)Y (t(1/2) = 14.7 h) via the bifunctional chelator approach. DOTA-modification of the L-RNA (sequence: 5'-aminohexyl UGA CUG ACU GAC-3'; MW 3975) was performed using (S)-p-SCN-Bn-DOTA. (86)Y radiolabeling of the DOTA-L-RNA produced more than one species as evidenced by HPLC radiometric detection. For the identification of the (86)Y-labeled L-RNA, the structural analogue nonradioactive precursor [Y((S)-p-NH2-Bn-DOTA)](-) was synthesized. Two coordination isomers were separated via HPLC adopting the square antiprismatic (SAP) and the twisted square antiprismatic (TSAP) geometry, respectively. Their stereochemical configuration in the solution state was assessed by NMR and circular dichroism spectroscopy. Both [Y((S)-p-NH2-Bn-DOTA)](-) isomers were converted into isothiocyanate derivatives [Y((S)-p-SCN-Bn-DOTA)](-) and conjugated to the L-RNA. The identity of the [(86)Y-DOTA]-L-RNA species was finally established by comparison of the radiometric ((86)Y) and UV-visible chromatographic profiles. Biodistribution studies in Wistar rats showed minor changes in the biodistribution profile of the [(86)Y((S)-p-NH2-Bn-DOTA)](-) complex isomers, while no significant differences were observed for the [(86)Y-DOTA]-L-RNA isomers. High renal excretions were found for the [(86)Y((S)-p-NH 2-Bn-DOTA)](-) complex isomers as well as for the L-RNA isomers.

Preparation, 99mTc-labeling and biodistribution studies of a PNA oligomer containing a new ligand derivative of 2,2′-dipicolylamine

“…Interestingly, the log D o/w value of [ 99m Tc(CO) 3 (Dpa-PNA)] is practically constant in the pH range investigated, indicating that the protonation state of the PNA remained unchanged. All together, these results show that these compounds should be predestined to give rapid blood clearance and preferential renal excretion as recently found for 68 Ga-and 86 Y-labeled L-RNA oligonucleotides [84,85].…”

Preparation and Long-Term Biodistribution Studies of a Pamam Dendrimer G5–Gd-BnDOTA Conjugate for Lymphatic Imaging

“…These two peaks were attributed to the formation of two coordination isomers most common for DOTA-type complexes: the square antiprism (SAP) and the twisted square antiprism (TSAP). The two HPLC peaks were also observed for the complex, Y- p -NH 2 -BnDOTA, which were assigned to SAP and TSAP [20]. These isomers are in dynamic equilibrium in solution, and interconvert either by macrocyclic ring inversion or by pendant arm rotation [21].…”

Coordinating Radiometals of Copper, Gallium, Indium, Yttrium, and Zirconium for PET and SPECT Imaging of Disease

“…Likely as a result of the symmetrical nature of this type of complex, only modest differences in binding affinities were found for enantiomers of opposite helicity. Additionally, C-functionalized DOTA ( L39 ) chelators have recently been investigated as BFC’s for yttrium-86 194. The ( S )- p -aminobenzyl derivative’s Y(III) complex was successfully separated into SA (major M) and TSA (minor m) isomeric forms which were assigned by solution 2-D NMR as well as CD spectroscopy.…”

“…There are several reports in the literature of the use of 86 Y, 68 Ga and 64 Cu radiometals to image mRNA expression 194,507-510. Schlesinger et al investigated the application of 86 Y labeled L-oligonucleotides 194,509.…”

“…Schlesinger et al investigated the application of 86 Y labeled L-oligonucleotides 194,509. These mirror-image oligonucleotides have an extended biological half-life due to their high resistance to enzyme degradation.…”