What a Difference a Carbon Makes: H₄octapa vs H₄C3octapa, Ligands for In-111 and Lu-177 Radiochemistry

Abstract

The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal–ligand matching. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by 1H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]− and [Lu(octapa)]− revealed very symmetric complexes; in contrast, the [In(C3octapa)]− and [Lu(C3octapa)]− complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log KML, pM) were ∼2 units lower for the In3+ and Lu3+ complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (∼2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa– and 111In-C3octapa–trastuzumab immunoconjugates were determined to be ∼91 and ∼24% stable, respectively, and 177Lu-octapa– and 177Lu-C3octapa–trastuzumab, ∼89% and ∼4% stable, respectively. This work suggests that 5-membered chelate rings are superior to 6-membered chelate rings for large metal ions like In3+ and Lu3+, which is a crucial consideration for the design of bifunctional chelates for bioconjugation to targeting vectors for in vivo work.

Rigidified Derivative of the Non-macrocyclic Ligand H4OCTAPA for Stable Lanthanide(III) Complexation

“…Orvig and co-workers showed that OCTAPA presents very promising properties for the development of 111 In, 90 Y, and 177 Lu radiopharmaceuticals. 32 , 33 Bifunctional derivatives of H 4 OCTAPA were also reported and successfully tested in vivo upon radiolabeling with these radioisotopes. 34 − 36 The rigidified ligand CHX OCTAPA 4– (also known as H 4 CDDADPA 4– ) was reported almost simultaneously by the group of Orvig and us.…”

Total Synthesis of the Proposed Structure for Protoaculeine B, a Polycationic Marine Sponge Metabolite, with a Homogeneous Long-Chain Polyamine

“…Next, we attempted to deprotect the two N -Ns groups of 10 under standard conditions (PhSH, Cs 2 CO 3 , THF) . Since the triamine product 11 and the possible diamine intermediate (structure not shown) are too polar on TLC, the progress of the stepwise deprotection of two Ns groups was monitored by mass spectrometry (ESIMS).…”

“…Similar to the synthesis of trimer analogue 3 , in the subsequent deprotections, the reaction mixture was monitored using ESIMS. Thus, after removing five N -Ns groups with PhSH and Cs 2 CO 3 ( 15 → 16 ), tetradecaamine 17 was synthesized by the deprotection of eight N -Boc groups by TFA at 0 °C. The TFA treatment had to be performed twice, since the reaction stops before completion probably due to the deactivation of TFA by the generated amines and/or isobutene .…”

Improved Access to Linear Tetrameric Hydroxamic Acids with Potential as Radiochemical Ligands for Zirconium(iv)-89 PET Imaging

“…Second, other work has shown that the introduction of a single methylene group into a radiochemical ligand can significantly modulate properties and the stability of corresponding radiometal complexes. [44] Zr IV -1 (0-72 h) Compound 3 was reacted with 1,4-phenylenediisothiocyanate (Scheme 1) to generate DFOB-PPH-p-Bn-SCN (5) for conjugation of amine-bearing biological vectors. Compound 5 was characterised using LC-MS ( Fig.…”