Synthesis of peptide radiopharmaceuticals for the therapy and diagnosis of tumor diseases

Abstract

Despite the advances in molecular biology and biochemistry, the prognosis of patients suffering from tumor diseases remains poor. The limited therapeutic success can be explained by the insufficient performance of the common chemotherapeutic drugs that lack the ability to specifically target tumor tissues. Recently peptide radiopharmaceuticals have been developed that enable the concurrent imaging and therapy of tumors expressing a specific target. Here, with a special emphasis on the synthesis of the building blocks required for the complexation of metallic radioisotopes, the requirements to the.

Figure 1

Binding of ligand to target like a peptide-receptor has been visualized by a “lock and key” arrangement, where the peptide fits into a binding pocket of the receptor on the surface of tumor cells in a similar manner to a key fitting into a lock.

Figure 2

Chemical structures of DOTA-TATE and [¹⁸F]Galacto-RGD, two typical radiolabeled peptide tracers.

Figure 3

Chemical structure of N-chloroamide oxidizing agents and prosthetic groups for radioiodination of peptides.

Figure 4

Chemical structure of prosthetic groups for the fluorination of peptides.

Figure 5

Chemical structure of chelators for the labeling of peptides with ^99mTc.

Figure 6

Chemical structures of chelators that are suited for the labeling of peptides with radiometals such as ¹¹¹In/^67/68Ga/^86/90Y/¹⁷⁷Lu/^64/67Cu.

Figure 7

The chemical structure of BFCAs derived from DTPA.

Scheme 1

Synthesis of CHX-A''-DTPA.

Scheme 2

Synthesis of activated ester of HBED-CC.

Scheme 3

Synthesis of the N₄-chelator.

Scheme 4

Synthesis of DOTA, DOTA active ester and DOTA-tris(t-Bu ester) and their coupling with peptides.

Scheme 5

Synthesis of DOTAGA.

Scheme 6

Synthesis of DOTA-derivatives for chemoselective conjugation to peptides.

Scheme 7

Synthesis of DOTA bearing benzyl-isothiocyanate.

Figure 8

Chemical structures of DOTA-monoamide derivatives for the chemoselective conjugation to peptides.

Scheme 8

Synthesis of TETA bearing benzyl-isothiocyanate.

Figure 9

Chemical structures of the CB-TE2A derivatives.

Scheme 9

Synthesis of NOTA-Bz-NCS.

Scheme 10

Synthesis of NODAGA.