Radiosynthesis and evaluation of a99mTc-folic acid radiotracer prepared using [99mTcN(PNP)]2+metal fragment.
Folate receptors (FR) are over-expressed on a wide variety of tumor cells and are a potential molecular target for radiolabeled folates. In this respect, several SPECT and PET based radiofolates have been evaluated in the past albeit with their high renal uptake posing limitation towards their clinical use. To overcome this, a new99mTc labeled folic acid was synthesized via the use of [99mTcN(PNP)]2+metal fragment, where the presence of the latter pharmacophore redirects in vivo clearance via the hepatobiliary pathway. In this respect, folic acid was derivatized at the γ-acid group with a cysteine BFCA (bifunctional chelating agent) and subsequently reacted with the preformed [99mTcN]2+intermediate in presence of PNP2 (bisphosphine) ligand, to yield the final complex. While preliminary, in vivo distribution of the complex exhibited high association of activity with liver and intestines and provided support to the rationality of the present design as clearance of labeled folic acid could be effected via the hepatic route, the in vitro studies of the folic acid-cysteine conjugate carried out in KB-31 cells, did not show much promise with reduction in receptor affinity in comparison with the native folic acid. The route followed herein to prepare a folic-acid based radiotracer constitutes the first report of radiolabeling folic acid using the [99mTcN(PNP)]2+as a radiosynthon. Modification in the structure of conjugate by linking the BFCA through a long-chain linker can be envisaged to improve the affinity of [99mTcN(PNP)]-folic acid complex towards FRs.
Radiopharmaceuticals Chemistry Section, Radiochemistry & Isotope Group, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India.
Kusum
K
Vats
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
Suresh
S
Subramanian
Radiopharmaceuticals Program, Board of Radiation and Isotope Technology, Navi Mumbai 400703, India.
Anupam
A
Mathur
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
Haladhar Dev
HD
Sarma
Radiopharmaceuticals Chemistry Section, Radiochemistry & Isotope Group, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai 400094, India. Electronic address: sharmila@barc.gov.in.
Sharmila
S
Banerjee
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D056831:Coordination Complexes / Q000737:chemistry*; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry*; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008670:Metals / Q000737:chemistry; D051379:Mice; D015394:Molecular Structure; D015609:Organotechnetium Compounds / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution
D056831:Coordination Complexes; D058973:Folate Receptors, GPI-Anchored; D008670:Metals; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D005492:Folic Acid
Biodistribution; Folate receptors; Folic acid; HPLC; KB-31; [(99m)TcN(PNP)](2+)