Radiochemistry, Production Processes, Labeling Methods, and ImmunoPET Imaging Pharmaceuticals of Iodine-124

Abstract

Target-specific biomolecules, monoclonal antibodies (mAb), proteins, and protein fragments are known to have high specificity and affinity for receptors associated with tumors and other pathological conditions. However, the large biomolecules have relatively intermediate to long circulation half-lives (>day) and tumor localization times. Combining superior target specificity of mAbs and high sensitivity and resolution of the PET (Positron Emission Tomography) imaging technique has created a paradigm-shifting imaging modality, ImmunoPET. In addition to metallic PET radionuclides, ¹²⁴I is an attractive radionuclide for radiolabeling of mAbs as potential immunoPET imaging pharmaceuticals due to its physical properties (decay characteristics and half-life), easy and routine production by cyclotrons, and well-established methodologies for radioiodination. The objective of this report is to provide a comprehensive review of the physical properties of iodine and iodine radionuclides, production processes of ¹²⁴I, various ¹²⁴I-labeling methodologies for large biomolecules, mAbs, and the development of ¹²⁴I-labeled immunoPET imaging pharmaceuticals for various cancer targets in preclinical and clinical environments. A summary of several production processes, including ¹²³Te(d,n)¹²⁴I, ¹²⁴Te(d,2n)¹²⁴I, ¹²¹Sb(α,n)¹²⁴I, ¹²³Sb(α,3n)¹²⁴I, ¹²³Sb(³He,2n)¹²⁴I, ^natSb(α, xn)¹²⁴I, ^natSb(³He,n)¹²⁴I reactions, a detailed overview of the ¹²⁴Te(p,n)¹²⁴I reaction (including target selection, preparation, processing, and recovery of ¹²⁴I), and a fully automated process that can be scaled up for GMP (Good Manufacturing Practices) production of large quantities of ¹²⁴I is provided. Direct, using inorganic and organic oxidizing agents and enzyme catalysis, and indirect, using prosthetic groups, ¹²⁴I-labeling techniques have been discussed. Significant research has been conducted, in more than the last two decades, in the development of ¹²⁴I-labeled immunoPET imaging pharmaceuticals for target-specific cancer detection. Details of preclinical and clinical evaluations of the potential ¹²⁴I-labeled immunoPET imaging pharmaceuticals are described here.

Keywords: 124I-labeled monoclonal antibodies; PET; cancer; immunoPET imaging pharmaceuticals; positron emission tomography; production processes; radiolabeling; radiotracers; target-specific biomolecules.

Figure 1

Simplified decay scheme of ¹²⁴I radionuclide (taken from reference [42]).

Figure 2

Comparison of reaction cross sections for the ¹²⁴Te(p,n)¹²⁴I and ¹²⁴Te(p,2n)¹²³I reactions (taken from reference [21]).

Figure 3

Excitation functions of ¹²⁵Te(p,xn)^123,124,125I reactions (taken from reference [65]). The broken lines show the results of nuclear model calculations using the code ALICE-IPPE. The shaded area gives a suitable energy range for the production of ¹²⁴I.

Figure 4

The schematic process diagram for the production of ¹²⁴I from ¹²⁴Te(p,n)¹²⁴I reaction using Comecer ALCEO halogen system (Courtesy Comecer S.p.A.).

Figure 5

Recovery of ¹²⁴I from irradiated ¹²⁴Te target in a Comecer ALCEO halogen evaporation unit (EVP) module (courtesy of Comecer S.p. A.).

Figure 6

Radioiodination reactions of tyrosine and histidine residues in proteins.

Figure 7

Structures of Chloramine-T (1) and Penta-O-acetyl-N-chloro-N-methylglucamine (NCMGE) (2).

Figure 8

Structures of IODO beads (Chloramine-T attached to polystyrene bead, (3), and Iodogen (1,3,4,6-Tetrachloro-3α,6α-diphenyl-glycoluril, (4).

Figure 9

Structures of N-hydroxysuccinimide ester of 3-(4-Hydroxyphenyl) propionic acid (Bolton Hunter reagent, 5), p-Hydroxybenzimidate (Wood’s reagent, 6), p-Hydroxy benzaldehyde (7), and p-Hydroxybenzaacetaldehyde (8).