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The PET radiopharmaceutical [18F]Fluromisonidazole ([18F]FMISO) is presently the agent of choice for the clinical imaging of tumor hypoxia. Considering the logistic advantages of 99mTc and wider availability of SPECT machines, a 99mTc-radiopharmaceutical for this purpose constitutes an attractive choice. In the work presented here, a misonidazole analogue was radiolabeled with 99mTc(CO)3 core and the complex was evaluated in Swiss mice bearing fibrosarcoma tumor. The results obtained are compared with the biodistribution of [18F]FMISO carried out in the same tumor-bearing animal model. Misonidazole-99mTc(CO)3 complex showed significant uptake and retention in tumor. Notably, the rate of clearance of misonidazole complex from the tumor was slower than that of [18F]FMISO. The maximum tumor/muscle ratio obtained with misonidazole-99mTc(CO)3 complex was significantly higher than that of [18F]FMISO. The study constitutes a positive step toward the development of a 99mTc-analogue of [18F]FMISO. [ABSTRACT FROM AUTHOR]

Board of Radiation and Isotope Technology, India is a manufacturer and supplier of therapeutic doses of the I-meta-iodobenzylguanidine to various nuclear medicine centers in India. The therapeutic dosage of radiopharmaceutical involves a single variable dose of >3.7 GBq activity. Since the radiopharmaceutical produced is mainly by isotope exchange, which yields a low specific activity product, the determination of its accurate mass is a critical parameter for its safe administration in patients. In view of this, a suitable high performance liquid chromatography (HPLC) method has been developed for the determination of specific activity with high precision. Also, quantification of stability in terms of the % radiochemical purity of the formulation >370 MBq/mL supplied, under different storage conditions over time was carried out using the developed HPLC method. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: [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. [Copyright &y& Elsevier]

Abstract: 99mTc-tertiary butyl isonitrile (TBI), a complex structurally similar to 99mTc-sestamibi, has been reported to be taken up in the myocardium, albeit with significant retention in liver and lungs, thereby leading to obscure heart images when used for in vivo imaging. In the present study, tert-butyl xanthate, which is similar to TBI, but possesses two sulphur donors, has been synthesized in excellent yield by reacting tert-butanol with carbon disulphide and sodium hydroxide in dry ether. The prepared ligand was then labeled with [99mTcN]2+ core and the resultant complex was characterized by paper electrophoresis and HPLC. The complex was obtained in more than 95% yield and was found to be neutral. The preparation was evaluated in Swiss mice for its myocardial perfusion characteristics. The maximum heart uptake observed was 2.34%ID/g at 5min p.i., which was cleared rapidly, with retention of 0.50%ID/g of the activity at 60min p.i. However, owing to slow clearance from blood, liver and lungs, the heart/blood, heart/liver and heart/lung ratios at all the time points of study were not significantly high. [Copyright &y& Elsevier]

Abstract: In the present study, a series of 99mTc–nitrido dithiocarbamate complexes containing ether linkages have been prepared and their brain perfusion characteristics studied. Two primary dithiocarbamates and two secondary dithiocarbamates were synthesized in >80% yield and were characterized by elemental analyses. The ligands were then labeled using a 99mTc–nitrido intermediate, prepared from sodium pertechnetate using commercially available nitrido kit-vials, at a low ligand concentration of 0.1mg. The prepared complexes were obtained in more than 95% yield and were characterized by paper electrophoresis and HPLC. All the complexes were found to be neutral and eluted out as a single species in HPLC. Biodistribution studies were carried out in normal Swiss mice. All the complexes showed uptake in the brain. 99mTcN complexes of secondary dithiocarbamates showed higher initial brain uptake (5min p.i.) than their primary amine counterparts. However, all the complexes exhibited rapid washout from the brain. [Copyright &y& Elsevier]

A xanthate derivative (L) at the pendant hydroxy group of metronidazole, a nitroimidazole known to possess affinity for hypoxic tumors, has been used as the carrier molecule for targeted delivery of the gamma-emitting radioisotope 99mTc to tumors. The xanthate residues (S2 −) from two molecules of this ligand (L) were used for chelation with the [99mTcN]2+ intermediate to form a square pyramidal and neutral [99mTcN/L2] complex in >95% yield using a low ligand concentration of 1mg/mL (∼3×10−3 M). Biodistribution studies carried out in Swiss mice bearing fibrosarcoma tumor showed selective accumulation of the injected activity in the tumor (1.44±0.26% per gram 1h pi) with major clearance through hepatobiliary route. The complex showed high tumor/muscle ratio (2.15 and 3.35 at 1 and 3h post-injection, respectively) and tumor/blood ratio, which were comparable to hypoxia targeting agents 99mTc-BMS181321 and 99mTc-BRU59-21 reported earlier. [Copyright &y& Elsevier]

Introduction Hypoxia plays a negative role in the clinical management of cancer. Detection of hypoxic status of a cancer is important for selecting patients for hypoxia directed therapy. Though [18 F]fluoromisonidazole ([18 F]FMISO), a PET radiopharmaceutical, is presently being used in the clinic for the detection of hypoxia, considering the logistical advantages of 99mTc and wider availability of SPECT scanners, a radiopharmaceutical based on this isotope may find wider applicability. Methods Nine nitroimidazole (2-, 4- and 5-nitroimidazole) ligands were synthesized and radiolabeled using [99mTc(CO)3(H2O)3]+ precursor to obtain a group of complexes possessing different single electron reduction potential (SERP), overall charge and lipophilicity, the three attributes which decide the efficacy of the complex to detect hypoxic cells in vivo. The nitroimidazole-99mTc(CO)3 complexes as well as [18 F]FMISO were evaluated in fibrosarcoma tumor bearing mice. Results The 99mTc(CO)3 complexes of nitroimidazole iminodiacetic acid (IDA) showed better tumor uptake and retention than nitroimidazole diethylenetriamine (DETA) and nitroimidazole aminoethylglycine (AEG) complexes. Tumor uptake observed with [18 F]FMISO was higher than any of the nitroimidazole-IDA- 99mTc(CO)3 complexes. However, [18 F]FMISO clearance from tumor was found to be faster compared to 2-nitroimidazole-IDA-99mTc(CO)3 complex. Observed tumor uptake and retention of the radiotracers evaluated could be correlated to its blood clearance pattern and SERP. Conclusions Results of the present study indicated that uptake of the radiotracer in tumor is closely associated with its rate of clearance from blood. The study also indicated that along with SERP, clearance of radiotracer from blood (net effect of charge and lipophilicity) is a critical factor which decides the in vivo efficacy of the hypoxia detecting radiopharmaceutical. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: A 2-nitroimidazole-99mTc(CO)3 complex reported earlier showed promise with respect to its uptake and retention in hypoxic tumor. However, significant uptake and slow clearance from liver imposed severe limitations towards advocating its possible practical utility. In an attempt to improving its liver clearance, an ether linkage, which is known to help in liver clearance, was introduced in the molecule. Methods: The 2-nitroimidazole iminodiacetic acid (IDA) derivative containing an ether linkage was synthesized in a five step procedure from 2-nitroimidazole. This derivative was radiolabeled using [99mTc(CO)3(H2O)3]+ precursor complex. The corresponding Re(CO)3 analogue was also synthesized in the macroscopic level for structural characterization. The 99mTc(CO)3 complex was evaluated in an animal model bearing fibrosarcoma tumor. Results: The in vivo evaluation of the complex indicated that, as envisaged, introduction of the ether linkage has improved clearance from the liver. The complex also showed higher retention in tumor compared to the 2-nitroimidazole-IDA-99mTc(CO)3 complex reported earlier. Though the tumor to muscle ratio improved with time, the tumor to blood ratio did not show any significant improvement. Despite improved liver clearance, there was significant liver activity present even at 3h p.i. attributable to gradual accumulation of activity cleared from muscle and blood. Conclusions: Though the introduction of ether linkage improved liver clearance of the modified 2-nitroimidazole complex, it was found that a single ether linkage was not sufficient to achieve the desirable level of clearance. Probably, a linker with multiple ether groups, such as a di- or tri-ethylene glycol spacer, may be a possible solution to this issue. [Copyright &y& Elsevier]

Multidrug resistance (MDR) mediated by over-expression of P-glycoprotein (Pgp) is one of the major causes of failure of chemotherapy in cancer treatment. Colchicine, a naturally occurring alkaloid, is a Pgp substrate and acts as an antimitotic agent by binding to microtubules. Hence, Colchicine and its analogues radiolabeled with 99mTc may have potential for visualization of MDR in tumors. Here we report 99mTc-labeling of colchicine derivatives using [99mTc(CO)3(H2O)3]+ and [99mTc≡N2+ cores. Trimethylcolchicinic acid synthesized from colchicine was used as the precursor to prepare iminodiacetic acid and dithiocarbamate derivatives which were then radiolabeled with [99mTc(CO)3(H2O)3]+ and [99mTc≡N]2+ cores, respectively. Radiolabeling yield for both the complexes was >98% as observed by HPLC and TLC patterns. In vitro studies in tumor cell lines showed significant uptake for 99mTc-carbonyl as well as for 99mTc-nitrido colchicine complexes. Biodistribution studies in Swiss mice bearing fibrosarcoma tumor showed 4.1±1.2% ID/g of uptake at 30min pi for 99mTc(CO)3-complex as against 0.42±0.24% ID/g for the 99mTcN-complex. 99mTc(CO)3–colchicine complex exhibited better pharmacokinetics with lower liver accumulation as compared to the 99mTcN-complex. Thus, colchicine radiolabeled with [99mTc(CO)3(H2O)3]+ core is more promising with respect to in vivo distribution characteristics in tumor model. [Copyright &y& Elsevier]

The present work describes the formulation of a lyophilized Fibroblast Activation Protein Inhibitor-4 (FAPI-4) kit for preparation of [68Ga]Ga-FAPI-4 in high radiochemical yield (RCY) using either generator or cyclotron produced 68GaCl3, suitable for Positron Emission Tomography (PET) based diagnosis of cancers over-expressing Fibroblast Activation Protein (FAP). Experimental parameters such as concentration of FAPI-4, buffer content, storage conditions and shelf-life were optimized to ensure > 95% RCY to utilize the kit for multi-patient dose formulations. A lyophilized FAPI-4 kit containing 50 µg of FAPI-4 ligand could be successfully optimized which consistently yielded [68Ga]Ga-FAPI-4 in > 95% RCY on labeling with ~ 1.11 GBq of 68GaCl3. [68Ga]Ga-FAPI-4 retained > 95% radiochemical purity (RCP) even after 2 h post labeling when stored at ambient temperature. The kits stored below − 20  °C reproduced the labeling profile up to a period of ~ 3 months (period of study). In the in vitro cell binding experiments performed in HT29 cells, [68Ga]Ga-FAPI-4 exhibited specific binding to FAP (16.1 ± 1.8%ID in 106 cells). In the biodistribution studies performed in female SCID mice bearing HT29 colorectal adenocarcinoma, [68Ga]Ga-FAPI-4 exhibited tumor uptake of 3.8 ± 0.3% ID/g at 1 h post-injection. The above results demonstrate the utility of developed FAPI-4 kits for formulation of [68Ga]Ga-FAPI-4 for PET imaging of FAP over-expressing cancers. [ABSTRACT FROM AUTHOR]

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 99m Tc-labeled radiotracer for the aforementioned application following the well-established 99m Tc-'4+1' chemistry. Formation of the desired [ 99m 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 99m 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Porphyrins are tetrapyrrolic macrocyclic ligands known for their affinity towards neoplastic tissues and once radiolabeled with a suitable diagnostic radioisotope could potentially be used for the imaging of tumorous lesions. In the present study, an unsymmetrically substituted porphyrin derivative namely 5-( p -amino-propyloxyphenyl)-10,15,20-tris(carboxymethyleneoxyphenyl)-porphyrin was synthesized and modified further to enable radiolabeling with 99m Tc using two different 99m Tc-cores viz. 99m Tc-HYNIC (hydrazino nicotinic acid) and 99m Tc(N)PNP2 (PNP2 = bis-[(2-dimethylphosphino)ethyl]-methoxy-ethylamine) in order to study the effect of employing different 99m Tc-cores on tumor affinity and pharmacokinetic behavior of the resultant 99m Tc-labeled porphyrin complexes. 99m Tc-Porphyrin complexes were characterized by reversed phase HPLC studies and could be prepared with >95% radiochemical purity under optimized radiolabeling conditions. Both 99m Tc-complexes were found to be adequately stable in human blood serum till 3 h post-preparation. Bio-distribution studies, carried out in Swiss mice bearing fibrosarcoma tumors, revealed relatively higher tumor uptake for the 99m Tc-HYNIC-porphyrin complex (3.95 ± 1.42 and 3.28 ± 0.27% IA per g) compared to that exhibited by the 99m Tc(N)PNP-DTC-porphyrin complex (1.52 ± 0.53 and 1.56 ± 0.10% IA per g) at 1.5 and 3 h post-administration, although the former complex exhibited comparatively lower lipophilicity in the octanol-water system. Higher uptake and longer retention in the blood were observed for the 99m Tc-HYNIC-porphyrin complex (6.63 ± 0.75 and 4.36 ± 0.25% IA per g) compared to that exhibited by the 99m Tc(N)PNP-DTC-porphyrin complex (2.41 ± 0.54 and 2.30 ± 0.16% IA per g) at both 1.5 and 3 h post-administration. However, relatively lower liver uptake was observed for the former complex (19.26 ± 3.48 and 18.45 ± 1.05% IA per g) than that exhibited by the latter one (39.37 ± 3.88 and 34.15 ± 8.25% IA per g) at both 1.5 and 3 h post-administration. This study indicates that the in vivo behavior exhibited by the 99m Tc-labeled porphyrins not only depends on their lipophilicity/hydrophilicity but is also governed by the Tc-cores employed for radiolabeling.

This work evaluates the potential of a 68 Ga labeled long chain 16C fatty acid for cardiac metabolic imaging. For radiolabeling with 68 Ga, hexadecanedioic acid was coupled with the chelator p-NH 2 -Bn-NOTA. Under the optimized conditions, NOTA-hexadecanoic acid could be radiolabeled with 68 Ga in ≥95% yields. In biodistribution studies carried out in Swiss mice, 68 Ga-NOTA-hexadecanoic acid showed low myocardial uptake at 2 min p.i. (3.7 ± 1.3%ID/g). While 68 Ga-NOTA-hexadecanoic acid cleared rapidly from non-target organs such as blood, lungs, intestine and kidney, wash out from liver was slow. Radio-HPLC analyses of myocardial extracts of rats injected with 68 Ga-NOTA-hexadecanoic acid confirmed its metabolic transformation in the myocardium., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: 177 Lu-DOTA-TATE is a clinically useful and promising therapeutic radiopharmaceutical for peptide receptor radionuclide therapy of neuroendocrine tumors (NETs) overexpressing somatostatin receptors. Currently, the radiopharmaceutical is prepared in-house at nuclear medicine centers, thereby restricting its use to limited centers only. In this article, the authors describe systematic studies toward bulk scale formulation of "ready-to-use" 177 Lu-DOTA-TATE using medium specific activity 177 Lu (740-1110 GBq/mg) at a centralized radiopharmacy facility., Methods: In an optimized protocol, 177 Lu-DOTA-TATE synthesis was carried out by direct heating of 177 LuCl 3 (Sp. act. 740-1110 GBq/mg) with DOTA-TATE peptide (1.5-3.0 equivalents) in ammonium acetate buffer (0.2 M) containing 2,5-dihydroxy benzoic acid (gentisic acid). Thereafter, the crude labeled product was purified using a Sep-Pak ® C18 column and diluted with acetate buffer-gentisic acid (1.5% w/v) solution to final radioactive concentration of 740 MBq/mL. This was further sterilized and dispensed as 7.4 GBq patient dose/vial with 2 days postformulation calibration., Results: A peptide/metal ratio of 1.5-3.0 is essential for complexation wherein radiolabeling yields >90% are obtained minimizing free 177 Lu waste. For formulation of 7.4 GBq patient dose (2 days postproduction), even specific activity of about 555 GBq/mg was found to be adequate for the radiometal. The ready-to-use 740 MBq/mL 177 Lu-DOTA-TATE formulation with gentisic acid (1.5% w/v) is observed to be safe for human use for more than 1 week (radiochemical purity >98%) from the day of production when stored at -70°C. However, the target specificity may get affected beyond 2 days as the total peptide content for 7.4 GBq dose may exceed the critical peptide limit of 300 μg. Patient treatment carried with several batches of present formulation in diseased NET patients exhibited desired distribution at the tumor and its metastatic site., Conclusions: A ready-to-use formulation of 177 Lu-DOTA-TATE was successfully prepared and optimized for regular bulk scale production and supply to distant nuclear medicine centers.

While [(11)C]palmitate continues to be a promising tracer for cardiovascular Positron Emission Tomography (PET) imaging, unfavourable logistics due to the short half-life of (11)C (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 (68)Ga-labeled fatty acid analogs for metabolic imaging owing to the availability of (68)Ga through a (68)Ge/(68)Ga 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 (68)Ga obtained from an in-house (68)Ge/(68)Ga 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.)