Design and development of novel folate compound for targeted imaging of folate receptor positive carcinomas

Almost all cancers show modified metabolism, which is easily detected by SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography), these modalities are widely used in oncology imaging for prognosis and disease management. There are many altered metabolisms, and Folate metabolism is among them. Folic acid has been frequently exploited for targeting over expressed folate receptors on malignant cells. It is well known that many malignant tissues consistently express high levels of folate receptors, which have been presented as an attractive target for tumor-selective drug delivery and imaging through the specific combination with relevant ligands of folate molecules. The folic acid/folate-receptor high-affinity interaction can be used to image cancer cells. High Tumour uptake of malignant tissues are found in biodistribution studies that allowed imaging of FR positive cancers. Clinical biomarkers are still needed to improveearly detection, predict malignant transformation and optimize therapies. Synthesis and preclinical evaluation of ^99m Tc labeled FR positive conjugated derivative proclaimed that the reactions were very complex so there is need to make a simple and easy chemistry to synthesize a novel ^99m Tc-Folate derivative so as to promote clinical application by simplifying the preparation process, and improving drug targeting in vivo are the problems to be solved. The synthesis of a SPECT radioprobe involves different conjugation method with different radionuclides which shall be explored by trying different synthetic reactions. There is certain synthetic strategy followed for obtaining any chemical compound. Modified folate derivatives were purified by HPLC column and characterized by 1H NMR and HRMS. Numerous radiopharmaceutical were synthesized such as ^99m Tc-1,4,7-tris (carboxymethyl)-10-(4- aminoethyl)-1,4,7,10-tetraazacyclo-dodecane (DO3A-EA)-Folate by conjugating DO3A-EA to the γ-carboxyl group of folic acid and ^99m Tc-labeled gold nanoparticle (NP) modified with folic acid. Feng et.al developed ( ^99m Tc)Tc-CN5FA and (^99m Tc) Tc- CNPFA in 2021 using isonitrile as a BFC, methylene chain and PEG chain as linkers. In vitro and in vivo studies demonstrated the high affinity and specificity of these probes for targeting FR. Radioactive probe shall be linked to Folic acid (pteroylglutamic acid) via glutamic acid or pteroic acid moiety. The Folate conjugates have the ability to be used as a receptor specific targeted radiopharmaceuticals for imaging over-expressed folate-binding protein in folate receptor positive carcinomas. The novel ^99m Tc labeled Folate derivative will be synthesized taking lead from the synthetic reactions of ^99m Tc-TEPA-Folate where they have used tetraethylenepentamine as a strong chelating agent on the γ -carboxyl group of folic acid which provides binding site to the reduced technetium. (author)