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.

The prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) are identified as important targets on prostate cancer. Receptor-targeting radiolabeled imaging pharmaceuticals with high affinity and specificity are useful in studying and monitoring biological processes and responses. Two potential imaging pharmaceuticals, AMBA agonist (where AMBA = DO3A-CH2CO-G-[4-aminobenzyl]- Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH₂) and RM1 antagonist (where RM1 = DO3A-CH₂CO-G-[4-aminobenzyl]-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂), have demonstrated high binding affinity (IC₅₀) to GRP receptors and high tumor uptake. Antagonists, despite the poor tumor cell internalization properties, can show clearer images and pharmacokinetic profiles by virtue of their higher tumor uptake in animal models compared to agonists. For characterization, development, and translation of a potential imaging pharmaceutical into the clinic, it must be evaluated in a series of tests, including in vitro cell binding assays, in vitro buffer and serum stability studies, the biodistribution of the radiolabeled material, and finally imaging studies in preclinical animal models. Data related to acetate buffer, mouse, canine, and human sera stability of ¹⁷⁷Lu-labeled RM1 are presented here and compared with the acetate buffer and sera stability data of AMBA agonist. The samples of ¹⁷⁷Lu-labeled RM1 with a high radioconcentration degrade faster than low-radioconcentration samples upon storage at 2–8 °C. Addition of stabilizers, ascorbic acid and gentisic acid, improve the stability of ¹⁷⁷Lu-labeled RM1 significantly with gentisic acid being more efficient than ascorbic acid as a stabilizer. The degradation kinetics of ¹⁷⁷Lu-labeled AMBA and RM1 in sera follow the order (fastest to slowest): mouse > canine > human sera. Finally, ¹⁷⁷Lu-labeled RM1 antagonist is slower to degrade in mouse, canine, and human sera than ¹⁷⁷Lu-labeled AMBA agonist, further suggesting that an antagonist is a more promising candidate than agonist for the positron emission tomography (PET) imaging and therapy of prostate cancer patients.

Bacterial infections remain a significant global health concern, exacerbated by rising antimicrobial resistance and a growing immunocompromised population. Improved diagnostic tools are essential to accurately detect infections, distinguish them from sterile inflammation, and reduce unnecessary antibiotic use that drives resistance. Positron Emission Tomography (PET) has emerged as a powerful non-invasive modality for detecting and monitoring infections in vivo, especially when conventional diagnostics are inconclusive. [¹⁸F]Fluoromannitol is a novel PET radiopharmaceutical that selectively targets both Gram-positive and Gram-negative bacteria, enabling broad-spectrum imaging and differentiation from sterile inflammation. To support preclinical studies and facilitate broader research use, we report the automated synthesis of [¹⁸F]fluoromannitol using the ELIXYS FLEX/CHEM radiosynthesizer. The synthesis was adapted from a manual protocol into a fully automated, two-pot, three-step process involving a nucleophilic fluorination, acid deprotection, and sodium borohydride reduction. Reaction conditions were optimized on the ELIXYS FLEX/CHEM platform. The fluorination was optimized for temperature and time to a yield of 78 ± 1.5 %. Acid-catalyzed deprotection yielded an impurity when manual conditions were applied. A large increase in temperature was necessary in order to efficiently produced [¹⁸F]fluoromannose with >99 % radiochemical purity, which was then reduced to [¹⁸F]fluoromannitol. The complete synthesis required approximately 136 min, yielding a 15 ± 0.9 % activity yield, a 35 ± 2.0 % radiochemical yield, >99 % radiochemical purity, and a final pH of 5.5 ± 0.5. This automated synthesis protocol supports reliable production of [¹⁸F]fluoromannitol and its broader adoption in bacterial infection imaging, with the potential to enhance early diagnosis and improve clinical management.