Copper-64 (
64
Cu)-labeled antibody fragments such as
Fab are useful for molecular imaging (immuno-PET) and radioimmunotherapy.
However, these fragments cause high and persistent localization of
radioactivity in the kidneys after injection. To solve this problem,
this study assessed the applicability of a molecular design to
64
Cu, which reduces renal radioactivity levels by liberating
a urinary excretory radiometabolite from antibody fragments at the
renal brush border membrane (BBM). Since 1,4,7-triazacyclononane-1,4,7-triacetic
acid (NOTA) forms a stable complex with Cu, NOTA-conjugated Met-Val-Lys-maleimide
(NOTA-MVK-Mal), which is a radio-gallium labeling agent for antibody
fragments, was evaluated for applicability to
64
Cu. The
MVK linkage was recognized by the BBM enzymes to liberate [
64
Cu]Cu-NOTA-Met although the recognition of the MVK sequence for the
[
64
Cu]Cu-NOTA-MVK derivative was reduced compared with
that of its [
67
Ga]Ga-counterpart, probably due to the difference
in the charge of the metal-NOTA complexes. When injected into mice,
[
64
Cu]Cu-NOTA-MVK-Fab resulted in similar renal radioactivity
levels to the
67
Ga-labeled counterpart. In addition, [
64
Cu]Cu-NOTA-MVK-Fab resulted in lower renal radioactivity
levels than those from
64
Cu-labeled Fab using a conventional
method, without a reduction in the tumor radioactivity levels. These
findings indicate that our approach to reducing renal radioactivity
levels by liberating a radiolabeled compound from antibody fragments
at the renal BBM for urinary excretion is applicable to
64
Cu-labeled antibody fragments and useful for immuno-PET and radioimmunotherapy.
Various 7-substituted 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-ones are synthesized by the reaction of the corresponding 7-hydroxy derivatives with nucleophiles involving active methylene compounds, aromatics, alcohols, p-toluenethiol, benzenesulfinic acid, triethyl phosphite, ammonia, and amines under acidic or basic conditions. Some synthetic applications of the products obtained are demonstrated to give a 7-methylene derivative and fused tricyclic derivatives.
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