Design, characterization and evaluation of a new 99m Tc-labeled folate derivative with affinity towards folate receptor

• Published in: Bioorganic & medicinal chemistry letters 2023-04, Vol.86, p.129240
• Main Authors: Das, Soumen, Sakhare, Navin, Kumar, Dheeraj, Mathur, Anupam, Mirapurkar, Shubhangi, Sheela, M, Mohanty, Bhabani, Chaudhari, Pradip, Chakraborty, Sudipta
• Format: Article
• Language: English
• Subjects: Carrier Proteins - metabolism; Folate Receptors, GPI-Anchored - metabolism; Folic Acid - chemistry; Humans; Neoplasms; Radiopharmaceuticals; Technetium - chemistry
• ISSN: 1464-3405

Folate receptors (FRs) are known to be over-expressed in several human malignancies and therefore serve as an important target for small radiolabeled folate derivatives for non-invasive imaging of tumor, which is an important tool for future treatment recourse. In the present article, we report the synthesis of a new Tc-labeled radiotracer for the aforementioned application following the well-established Tc-'4+1' chemistry. Formation of the desired [ Tc]Tc-complex with >95% radiochemical purity was confirmed by radio-HPLC and its structure was ascertained by characterizing a natural rhenium analogue of the said complex. Although the ligand exhibited a weaker affinity towards FRs compared to native folic acid (IC50 8.09 µM vs 29.46 nM), the Tc-labeled complex was found to bind folate receptor-positive KB cells with high specificity (∼90%). Similar studies in a folate receptor negative cell line viz. A549 further corroborated the receptor-specificity of the synthesized complex. In vivo studies in KB tumor xenograft showed moderate uptake of ∼2.6% upto 3 h post-injection with high specificity (∼80%). The favorable features observed warrant further screening of the current design towards achieving an improved molecular probe for the said application.