18F-AlF Labeled Peptide and Protein Conjugates as Positron Emission Tomography Imaging Pharmaceuticals

Abstract

The clinical applications of positron emission tomography (PET) imaging pharmaceuticals have increased tremendously over the past several years since the approval of ¹⁸fluorine-fluorodeoxyglucose (¹⁸F-FDG) by the Food and Drug Administration (FDA). Numerous ¹⁸F-labeled target-specific potential imaging pharmaceuticals, based on small and large molecules, have been evaluated in preclinical and clinical settings. ¹⁸F-labeling of organic moieties involves the introduction of the radioisotope by C-¹⁸F bond formation via a nucleophilic or an electrophilic substitution reaction. However, biomolecules, such as peptides, proteins, and oligonucleotides, cannot be radiolabeled via a C-¹⁸F bond formation as these reactions involve harsh conditions, including organic solvents, high temperature, and nonphysiological conditions. Several approaches, including ¹⁸F-labeled prosthetic groups, silicon, boron, and aluminum fluoride acceptor chemistry, and click chemistry have been developed, in the past, for ¹⁸F labeling of biomolecules. Linear and macrocyclic polyaminocarboxylates and their analogs and derivatives form thermodynamically stable and kinetically inert aluminum chelates. Hence, macrocyclic polyaminocarboxylates have been used for conjugation with biomolecules, such as folate, peptides, affibodies, and protein fragments, followed by ¹⁸F-AlF chelation, and evaluation of their targeting abilities in preclinical and clinical environments. The goal of this report is to provide an overview of the ¹⁸F radiochemistry and ¹⁸F-labeling methodologies for small molecules and target-specific biomolecules, a comprehensive review of coordination chemistry of Al³⁺, ¹⁸F-AlF labeling of peptide and protein conjugates, and evaluation of ¹⁸F-labeled biomolecule conjugates as potential imaging pharmaceuticals.

Figure 1.

Structures of DTPA (1), NOTA (2), NODA-GA (3), DOTA (4), p-SCN-Bz-NOTA (5), SCN-Bz-NODA (6), p-SCN-Bz-NOTA-Biomolecule (7), DTTA-CH₂CONH-Biomolecule (8), NODA-CH₂CONH-Biomolecule (9), NODA-GA-CH₂CONH-Biomolecule (10), DO3A-CH₂CONH-Biomolecule (11), and NODA-MAL-CS-Biomolecule (12).

Figure 2.

Tetrahedral, trigonal bipyramidal, and octahedral molecular geometries of Al³⁺ complexes.

Figure 3.

Correlation between log K_ML of Al³⁺ chelates and the sum of the pK_a values of the neutral form of some linear and macrocyclic polyaminocarboxylates.

Figure 4.

Plot of log K_F (equilibrium constants for formation of fluoro ternary complexes of aluminum polyaminocarboxylates) vs pK_OH (deprotonation constants of coordinated water of aluminum polyaminocarboxylates).

Figure 5.

Structure of NODA (13), Bz-NODA (14), NODA-MPAA (15), C-NETA (16), and C-NETA-CONH-biomolecule (17).

Figure 6.

Structure of octreotide (18), DOTA-TOC (19), DOTA-NOC (20), and DOTA-TATE (21).

Figure 7.

Structures of HBED-CC or PSMA 11 (22) and NOTA-DUPA-Pep (23).