Synthesis and Preclinical Evaluation of a ⁶⁸Ga-Labeled Pyridine-Based Benzamide Dimer for Malignant Melanoma Imaging

Abstract

Benzamide (BZA), a small molecule that can freely cross cell membranes and bind to melanin, has served as an effective targeting group for melanoma theranostics. In this study, a novel pyridine-based BZA dimer (denoted as H-2) was labeled with 68 Ga ([ 68 Ga]Ga-H-2) for positron emission tomography (PET) imaging of malignant melanomas. [ 68 Ga]Ga-H-2 was obtained with high radiochemical yield (98.0 ± 2.0%) and satisfactory radiochemical purity (>95.0%). The specificity and affinity of [ 68 Ga]Ga-H-2 were confirmed in melanoma B16F10 cells and in vivo PET imaging of multiple tumor models (B16F10 tumors, A375 melanoma, and lung metastases). Monomeric [ 68 Ga]Ga-H-1 was prepared as a control radiotracer to verify the effects of the molecular structure on pharmacokinetics. The values of the lipid−water partition coefficient of [ 68 Ga]Ga-H-2 and [ 68 Ga]Ga-H-1 demonstrated hydrophilicity with log P = −2.37 ± 0.07 and −2.02 ± 0.09, respectively. PET imaging and biodistribution showed a higher uptake of [ 68 Ga]Ga-H-2 in B16F10 primary and metastatic melanomas than that in A375 melanomas. However, the relatively low uptake of monomeric [ 68 Ga]Ga-H-1 in B16F10 tumors and high accumulation in nontarget organs resulted in poor PET imaging quality. This study demonstrates the synthesis and preclinical evaluation of the novel pyridine-based BZA dimer [ 68 Ga]Ga-H-2 and indicates that the dimer tracer has promising applications in malignant melanoma-specific PET imaging because of its high uptake and long-time retention in malignant melanoma.

Rational Design and Comparison of Novel 99mTc-Labeled FAPI Dimers for Visualization of Multiple Tumor Types

“…In some cases, dimerization or multimerization proves to be an effective strategy for enhancing the tumor uptake and retention of radiopharmaceuticals compared with monomers. , Representative examples benefiting from the homodimeric approach include radiolabeled RGD/FAPI/PSMA/folic acid/benzamide dimers, which target integrin α v β 3 , FAP, PSMA, folate receptor, and melanin, respectively. − Furthermore, previous studies have demonstrated that polyethylene glycol linkers (PEGylation) acted as hydrophilic modification to modulate the pharmacokinetics of dimeric small molecule–radio conjugates. ,,,,− In the present study (Figure ), on the basis of the OncoFAP (an ultrahigh-affinity small organic motif for FAP reported by Millul et al), a bivalent FAPI precursor (HYNIC-BiOncoFAP, denoted as HF 2 ) coupled with mini-PEG spacers and the hydrazinonicotinamide (HYNIC) group was designed and synthesized with the goal of improving tumor uptake and image contrast. As illustrated in Figure A, with the introduction of coligands such as tricine, trisodium triphenylphosphine-3,3′,3″-trisulfonate (TPPTS), ethylenediamine- N,N′ -diacetic acid (EDDA), and sodium triphenylphosphine-3-monosulfonate (TPPMS), HF 2 was radiolabeled with 99m Tc through one-pot synthesis to form [ 99m Tc]­Tc-TPPTS-HF 2 , [ 99m Tc]­Tc-EDDA-HF 2 , and [ 99m Tc]­Tc-TPPMS-HF 2 complexes, respectively.…”

Superior Drug Delivery Performance of Multifunctional Bilosomes: Innovative Strategy to Kill Skin Cancer Cells for Nanomedicine Application

“…Prominent among them is malignant melanoma, diagnosed each year in about 1.7% of primary malignancies and contributing to 0.7% of cancer-related deaths. 1 Melanocyte-derived melanoma, usually found in the innermost part of the epidermis (basal layer), is the most malignant type of skin cancer due to its rapid growth rate and numerous metastases. It can spread to various body parts, from draining lymph nodes to distant visceral organs, especially the brain, lungs, bones, and liver.…”