N-Succinimidyl 5-(trialkylstannyl)-3-pyridinecarboxylates: a new class of reagents for protein radioiodination

Abstract

N-Succinimidyl 5-(trialkylstannyl)-3-pyridinecarboxylates (alkyl = Me, Bu) have been prepared and used as a precursor to label N-succinimidyl 5-[131I]iodo-3-pyridinecarboxylate (SIPC). SIPC was obtained in greater than 80% yield from either the methyl or butyl precursor with N-chlorosuccinimide and heating at 60-65 degrees C. Significantly lower yields were observed with tert-butyl hydroperoxide. After a 30-min incubation with [131I]SIPC at pH 8.5, goat IgG, an intact monoclonal antibody (MAb), and a MAb F(ab')2 fragment were labeled in 60-65% yield. Specific binding of the MAb and MAb fragment after SIPC labeling was identical with that observed with N-succinimidyl 3-iodobenzoate and higher than that reported previously for these MAbs after labeling by using the Iodogen method. When 5-[131I]iodonicotinic acid was injected into normal mice, thyroid uptake was less than 0.2% of the injected dose, reflecting the inertness of this compound to deiodination. Paired-label biodistribution studies indicate that for both the MAb and the F(ab')2 labeled by using SIPC, accumulation of activity in the thyroid and other tissues is comparable to that observed when these proteins were labeled by using N-succinimidyl 3-iodobenzoate. The results of this study suggest that SIPC may be a reagent for labeling MAbs with halogen nuclides.

D-amino acid peptide residualizing agents bearing N-hydroxysuccinimido- and maleimido-functional groups and their application for trastuzumab radioiodination

“…This problem can be circumvented by the use of residualizing agents, which generate radiolabeled catabolites that are trapped within tumor cells after mAb degradation. Our approach for developing residualizing agents for the radioiodination of internalizing mAbs has focused on charged prosthetic groups, which yield labeled catabolites that are poorly transported across lysosomal/cell membranes [11-14]. One of the most promising reagents derived from this strategy is N ∊ -(3-[*I]iodobenzoyl)-Lys 5 - N α -maleimido-Gly- d -GEEEK (Mal- d -GEEEK-[*I]IB) [15,16].…”

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: Influence of isomeric substitution on radiolabeling and target cell residualization

“…The design hypothesis has been to utilize acylation agents that will result in the generation of labeled catabolites that would be charged at lysosomal pH and therefore will not be able to cross the lysosomal and cell membranes [10-14]. The most successful residualizing agent developed to date based on this premise is the guanidine-moiety-containing acylation agent, N -succinimidyl 4-guanidinomethyl-3-[ 131 I]iodobenzoate ([ 131 I]SGMIB) [15, 16], which likely reflects the fact that guanidine has a pKa of ∼13, and should remain exclusively positively charged at lysosomal pH.…”

“…However, the yields for the synthesis of Boc 2 -[ 131 I]SGMIB from its tin precursor were only 60-65%, significantly lower than that obtained with similar compounds [10, 20]. Hypothesizing that the lower radiochemical yield might be due to steric hindrance imparted by the bulky Boc 2 -guanidinomethyl group present at the ortho position of the tin moiety in the precursor, in the current study, we have developed an isomeric agent, N -succinimidyl 3-guanidinomethyl-5-[ 131 I]iodobenzoate ( iso -[ 131 I]SGMIB) wherein the guanidinomethyl moiety has been moved to the 3-position to give a 1,3,5-substitution.…”

Peptide‐based radiopharmaceuticals: Future tools for diagnostic imaging of cancers and other diseases

“…11 The commonly used labeling reagents (prosthetic groups) include Nsuccinimidyl-3-iodobenzoate (SIB) and N-succinimidyl-5-iodo-3-pyridinecarboxylate (SIPC). [34][35][36] For labeling, a radioiodinated succinimide ester is prepared and then conjugated via a covalent bond to the free amino group of the lysine residue in the peptide (Fig. 5).…”