Radiopharmaceuticals Program

Navi Mumbai, India

Radiopharmaceuticals Program

Navi Mumbai, India
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Vats K.,Bhabha Atomic Research Center | Subramanian S.,Bhabha Atomic Research Center | Mathur A.,Radiopharmaceuticals Program | Sarma H.D.,Bhabha Atomic Research Center | Banerjee S.,Bhabha Atomic Research Center
Bioorganic and Medicinal Chemistry Letters | Year: 2016

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 new 99mTc 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. © 2016 Elsevier Ltd.

Mathur A.,Radiopharmaceuticals Program | Sharma A.K.,Radiopharmaceuticals Program | Murhekar V.V.,Radiopharmaceuticals Program | Mallia M.B.,Bhabha Atomic Research Center | And 5 more authors.
RSC Advances | Year: 2015

The aim of the present study is to identify a 99mTc-labeled fatty acid tracer which could be a possible substitute of the widely used 123I-labeled fatty acids in studying myocardial metabolism and in detection of myocardial abnormalities in high-risk patients. The relevance of the study stems from the fact that in terms of wider applicability, a 99mTc-tracer is expected to be more advantageous compared to that of a 123I-based one. Two fatty acid (FA)-hydrazinopyridine-3-carboxylic acid (HYNIC) conjugates (11C-FA-HYNIC and 12C-FA-HYNIC) were synthesized and radiolabeled with 99mTc using two different co-ligands system viz. tricine/ethylenediamine diacetic acid (EDDA), and tricine/trisodium triphenylphosphine-3,3′,3′′-trisulfonate (TPPTS), to yield four radiolabeled complexes. While all four 99mTc-HYNIC-complexes showed uptake in the myocardium, 12C-FA-HYNIC-99mTc-EDDA complex showed higher uptake and retention in myocardium compared to other complexes. In general, uptake of the 99mTc-complexes in non-target organs was lower than that of 125I-iodophenyl pentadecanoic acid (IPPA). The 12C-FA-HYNIC-99mTc-EDDA complex, additionally exhibited lower liver accumulation compared to that of 125I-IPPA. Though these features were favorable for cardiac imaging, the heart-to-blood ratio of the complexes were low (<1). Nevertheless, a dynamic SPECT image of 12C-FA-HYNIC-99mTc-EDDA complex in Swiss mouse showed delineation of its myocardium from proximal non-target organs. The results merit further screening of synthetically modified 99mTc-HYNIC fatty acids for myocardial imaging. © 2015 The Royal Society of Chemistry.

Mathur A.,Radiopharmaceuticals Program | Mallia M.B.,Bhabha Atomic Research Center | Sarma H.D.,Bhabha Atomic Research Center | Banerjee S.,Bhabha Atomic Research Center | Venkatesh M.,Bhabha Atomic Research Center
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2010

Radiolabeled fatty acids are used as tracers for myocardial metabolic imaging and currently 123I-iodophenyl pentadecanoic acid (IPPA) or 123I-β-methyl-iodophenyl pentadecanoic acid (BMIPP) are the agents of choice. However, 123I being a cyclotron-produced isotope, 99mTc-labeled fatty acids are more desirable substitutes to 123I-labeled fatty acids. Toward this, two fatty acids, having 11 and 12 carbon atoms respectively, modified with cysteine were synthesized in a four-step procedure. These ligands were then radiolabeled with 99mTc using the [99mTcN(PNP6)]2+ core. Formation of the complexes and determination of radiochemical yields were ascertained by HPLC technique. In vivo distribution of the complexes was carried out in Swiss mice and the results are compared with 125I-IPPA. Both the complexes showed fast clearance from the myocardium till 10 min post injection (p.i.) followed by retention in the myocardium till 30 min p.i. However, compared with the result obtained with 125I-IPPA, the amount of activity retained in the myocardium by the present complexes were low. Both the complexes showed rapid clearance from liver, lungs, and blood unlike the case with 125I-IPPA. Copyright © 2010 John Wiley & Sons, Ltd.

Mathur A.,Radiopharmaceuticals Program | Mallia M.B.,Bhabha Atomic Research Center | Banerjee S.,Bhabha Atomic Research Center | Sarma H.D.,Bhabha Atomic Research Center | Pillai M.R.A.,Bhabha Atomic Research Center
Bioorganic and Medicinal Chemistry Letters | Year: 2013

A sanazole derivative, having a favorable single electron reduction potential (SERP) value compared to that of misonidazole, was synthesized and radiolabeled with [99mTcN(PNP)] precursor to evaluate its potential as a hypoxia imaging agent. The complex, which was lipophilic, could be prepared in good yields and challenging studies with cysteine showed stability of the complex against trans-chelation. However, despite being lipophilic as well as possessing favorable SERP value, biodistribution studies of this complex in fibrosarcoma tumor bearing Swiss mice showed low uptake in tumor. This observation is possibly attributed to fast clearance of the complex from blood, whereby the complex spends insufficient time in tumor to get reduced and trapped. Though uptake in tumor was low, slow clearance of activity from tumor suggests reduction and trapping of the complex in hypoxic cells. The present 99mTc-complex demonstrated acceptable values of tumor to blood (TBR) and tumor to muscle (TMR) ratios. However, low uptake in tumor which may not be indicative of the actual hypoxic status of the tumor, limit the utility of the complex to detect tumor hypoxia. © 2012 Elsevier Ltd. All rights reserved.

Sakhare N.,Radiopharmaceuticals Program | Das S.,Radiopharmaceuticals Program | Mathur A.,Radiopharmaceuticals Program | Mirapurkar S.,Radiopharmaceuticals Program | And 3 more authors.
RSC Advances | Year: 2016

Radio-iodine (123I/131I) labeled meta-iodobenzylguanidine (mIBG) is a proven radiopharmaceutical used for diagnosis of neuroendocrine tumors (NET) related to neural crest origin. Here, a 99mTc analogue of ∗I-mIBG using 99mTc-4+1 labeling approach has been synthesized and evaluated for its potential in NET imaging. This involved preparation of benzylguanidine precursor (mono-dentate donor) which was isolated in a five step synthetic procedure. The precursor was designed such that, in presence of a tetra-dentate NS3 co-ligand, [99mTcO4]- and Sn2+ reducing agent, it formed the desired 99mTc-4+1 complex. Complex formation was identified by radio-HPLC and structural details were affirmed by characterizing its rhenium analogue. Bio-evaluation studies of the complex were carried, both in vitro and in vivo, and the results obtained were compared with no-carrier added-125I-mIBG (nca-125I-mIBG). In vitro studies, in SK-N-SH neuroblastoma cell line showed affinity of the tracer towards nor-epinephrine transporters. Although the absolute uptake was lower compared to nca-125I-mIBG, its specificity was similar (∼90%) as the uptake reduced on inhibition with specific transport blocker, desmethylimipramine (DMI). Biodistribution studies in normal Wistar rats, pre-treated with mIBG and DMI, respectively, showed reduced myocardial uptake than its control. The results thus obtained merits high potential of synthesized 99mTc-4+1 complex for NET imaging. © 2016 The Royal Society of Chemistry.

Mathur A.,Radiopharmaceuticals Program | Mallia M.B.,Bhabha Atomic Research Center | Sarma H.D.,Bhabha Atomic Research Center | Banerjee S.,Bhabha Atomic Research Center | Venkatesh M.,Bhabha Atomic Research Center
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2011

123I-labeled fatty acids and 18F-FDG are used as metabolic markers for detecting myocardial abnormalities. However, a 99mTc-based molecule may find wider application. In the present work, a new 99mTc-labeled, uni-positively charged, 16-carbon fatty acid has been prepared and evaluated in normal Swiss mice. The results are then compared with the neutral analogue reported earlier. A 16-cysteinyl hexadecanoic acid conjugate was synthesized in a six-step synthetic procedure starting with 16-bromohexadecanoic acid. The ligand upon incubation with [ 99mTcN(PNP6)]2+ core formed the required positively charged complex in ∼85% yield. The complex, which was obtained as a mixture of syn-anti isomers, was purified by HPLC and the major fraction was used for in vivo studies in Swiss mice. The biodistribution studies in Swiss mice showed initial uptake similar to 125I-IPPA followed by rapid clearance from the myocardium till 10 min p.i. Thereafter, the rate of clearance was significantly decreased, an observation reported earlier for positively charged fatty acid complexes. In terms of absolute uptake, the positively charged complex performed better than the neutral analogue reported earlier. The positively charged fatty acid complexes, prepared using [99mTcN(PNP)] 2+ core, seems to be better candidates for the development of myocardial metabolic tracers than their neutral counterparts. Copyright © 2010 John Wiley & Sons, Ltd.

Jindal A.,Bhabha Atomic Research Center | Mathur A.,Radiopharmaceuticals Program | Pandey U.,Bhabha Atomic Research Center | Sarma H.D.,Bhabha Atomic Research Center | And 2 more authors.
Journal of Labelled Compounds and Radiopharmaceuticals | Year: 2014

While [11C]palmitate continues to be a promising tracer for cardiovascular Positron Emission Tomography (PET) imaging, unfavourable logistics due to the short half-life of 11C (20-min) and cumbersome labeling methodologies are the major impediments that limit its widespread use. In order to circumvent such limitations, an attempt has been made to explore the potential of 68Ga-labeled fatty acid analogs for metabolic imaging owing to the availability of 68Ga through a 68Ge/ 68Ga generator on an on-demand basis. In this study, two fatty acid conjugates were synthesized by conjugation of p-SCN-benzyl NOTA with the ω-amino group of 11-amino undecanoic acid and 12-amino dodecanoic acid, respectively, under alkaline conditions. Both derivatives were radiolabeled in high yields with 68Ga obtained from an in-house 68Ge/ 68Ga generator. Biodistribution studies in Swiss mice showed reasonable myocardial uptake at 2-min for both derivatives (7.4-±-2.8% ID/g for 11-carbon fatty acid-NOTA conjugate and 6.4-±-2.1% ID/g for 12-carbon fatty acid-NOTA conjugate), which cleared rapidly over 30-min. However, significant activity was found in blood for both tracers, with heart/blood ratios observed to be below 0.5 at all time points, diminishing the potential of the synthesized complexes for cardiac imaging. Copyright © 2014 John Wiley & Sons, Ltd.

PubMed | Radiopharmaceuticals Program and Bhabha Atomic Research Center
Type: | Journal: Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine | Year: 2016

Present work evaluates the potential of a newly synthesized (68)Ga-NOTA-folic acid conjugate for PET imaging of tumors over-expressing folate receptors (FRs). NOTA-folic acid conjugate was synthesized and characterized. It was radiolabeled with (68)Ga in 95% radiolabeling yields. In vitro cell binding studies showed a maximum cell uptake of 1.70.4% per million KB cells which was completely blocked on addition of cold folic acid showing specificity towards the FRs. However, further studies in tumor xenografts are warranted in order to assess the potential of (68)Ga-folic acid complex for imaging tumors over-expressing FRs.

Prabhakar G.,Radiopharmaceuticals Program | Mathur A.,Radiopharmaceuticals Program | Shunmugam G.,Radiopharmaceuticals Program | Teje Y.D.,Radiopharmaceuticals Program | And 2 more authors.
Applied Radiation and Isotopes | Year: 2011

[131I]-metaiodobenzylguanidine (mIBG) is a known radiopharmaceutical used for the treatment of neuroendocrine tumors. The development of therapeutic [131I]-mIBG doses at production level is highly challenging due to rapid product degradation and high radiation exposures to the production plant personnel. In the present work, a working module for the production of 10 doses (100mCi each) in a single operation was developed following copper (I) assisted isotope exchange. The labeled product complies with the pharmaceutical specifications suitable for in-vivo patient use. © 2010 Elsevier Ltd.

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