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Patient specific treatments for different cancers are currently being actively addressed through nuclear medicine. More recently, the identification of biomarker namely; prostate-specific membrane antigen (PSMA) expressed on the prostate cancer cell surface has been considered as a turning point in prostate cancer management using radiopharmaceuticals. In this treatment method, apart from radionuclide, organic ligands that target PSMA constitute an essential component. PSMA-11 and PSMA-617 are two important ligands that form the radiopharmaceuticals, [68Ga]Ga-PSMA-11, [177Lu]Lu-PSMA-617, which are currently powering the prostate cancer management, especially metastatic castration resistant prostate cancer (mCRPC) in most part of the world. Identification of efficient synthetic routes towards these highly expensive ligands is an important prerequisite to make this treatment modality more popular. In this account, the synthetic challenges that we circumvent during the solution phase synthesis of PSMA-11 and PSMA-617, through different chemical synthetic routes are demonstrated. Post-synthesis, both the ligands, PSMA-11 and PSMA-617 were successfully radiolabelled using 68Ga, and 177Lu, respectively, to generate corresponding labelled products [68Ga]Ga-PSMA-11, and [177Lu]Lu-PSMA-617, in good radiochemical purity. [ABSTRACT FROM AUTHOR]

Synthesis of PSMA-617, a peptide based ligand used in the preparation of nuclear medicine, 177Lu-PSMA-617, for the treatment of prostate cancer, is demonstrated in 6 steps, starting from appropriately protected amino acid building blocks. A solution phase Boc-strategy was adopted for the synthesis of peptide, wherein deprotection of carbamate group using HCl (g), was employed as the key step. The synthesis furnished PSMA-617 in purity >99.5 % as confirmed by HPLC analysis. ESI-MS and NMR analysis supported the structural integrity of the compound. The synthesized ligand was radiolabelled using 177Lu to generate the desired radiopharmaceutical, 177Lu-PSMA-617, in radiochemical purity >98 %, as revealed by radio HPLC and TLC analysis. This establishes its potential as a nuclear medicine for therapeutic application. [ABSTRACT FROM AUTHOR]

123I‐Iodophenylpentadecanoic acid (IPPA) is a metabolic agent used in nuclear medicine for diagnosis of myocardial defects. Efforts are underway worldwide to develop a 99mTc substitute of the above radiopharmaceutical for the aforementioned application. Herein, we report synthesis and biodistribution studies of 99mTc labeled fatty acids (8, 11, and 15 carbons) obtained via "click chemistry" for its potential use in myocardial imaging. ω‐Bromo fatty acids (8C/11C/15C) were synthetically modified at bromo terminal to introduce a heterocyclic triazole with glycine sidearm in a five step procedure. Modified fatty acids were subsequently radiolabeled with preformed [99mTc(CO)3]+ synthon to yield the desired fatty acid complexes which were evaluated in Swiss mice. All the radiolabeled complexes were obtained with radiochemical purities >80%, as characterized by HPLC. Biodistribution studies of all three complexes in Swiss mice showed myocardial uptake of ~6‐9% ID/g at 2 minutes post‐injection, close to*I‐IPPA (~9% ID/g). Complexes exhibited significant retention in the myocardium up to 30 minutes (~1% ID/g) but were lower to the standard agent (~7% ID/g). Similar uptake of activity in myocardium for the newly synthesized complexes in comparison to 125I‐IPPA along with favorable in vivo pharmacokinetics merits potential for the present "click" design of complexes for myocardial imaging. 123I‐Iodophenylpentadecanoic acid (IPPA) is a metabolic agent used for diagnosis of myocardial defects. Herein, we report 99mTc‐labeled fatty acids (8, 11, and 15 carbons) obtained via "click chemistry" as a rationale substitute. ω‐Bromo fatty acids were synthetically modified at ω terminal and radiolabeled via [99mTc(CO)3(H2O)3]+ synthon. Biodistribution of complexes in Swiss mice showed myocardial uptake similar to*I‐IPPA at 2 min pi with favorable in vivo pharmacokinetics which merits potential for the present "click" design of complexes for myocardial imaging. [ABSTRACT FROM AUTHOR]

99mTc-ethylene dicysteine diethyl ester (99mTc-ECD) is an established radiopharmaceutical used for brain perfusion imaging; however it does not have any recognized biological quality control to ascertain its in vivo efficacy. The present paper describes an in vitro enzymatic method that can be adapted as a regular biological quality control for ECD kit evaluation before its release for patient end use. The method involves reaction of 99mTc-ECD (< 74 MBq; 0.1 mg ECD) with pig liver esterase enzyme (≥ 20 mg/mL) yielding metabolites in quantitative yield post 1 h incubation. Methodology developed is precise for routine quality control analyses of ECD kits. [ABSTRACT FROM AUTHOR]

Conventional 99mTc-radiopharmaceuticals for the detection of tumor hypoxia generally possess a single nitroimidazole moiety. Herein, we report the synthesis and evaluation of a 99mTc-complex with three-nitroimidazole moieties in an attempt to improve hypoxic cell detection. Isocyanide derivative of metronidazole (MetroNC) was synthesized and subsequently radiolabeled with [99mTc(CO)3(H2O)3]+ precursor complex, wherein the three labile water molecules were replaced with MetroNC ligand to form a pseudo-octahedral [99mTc(CO)3(MetroNC)3]+ complex. Analysis of corresponding Re(CO)3-analog prepared in macroscopic scale confirmed the formation of expected complex. Cyclic voltammetric studies of [Re(CO)3(MetroNC)3]+ complex showed no significant change in single-electron reduction potential (SERP) of MetroNC ligand (− 0.96 V) upon forming the [Re(CO)3(MetroNC)3]+ complex (− 0.90 V). In vitro studies in Chinese hamster ovary (CHO) cells showed three-fold preferential accumulation of [99mTc(CO)3(MetroNC)3]+ complex in hypoxic cells over normoxic cells. Biodistribution studies of [99mTc(CO)3(MetroNC)3]+ complex in Swiss mice bearing fibrosarcoma tumor showed tumor uptake and steady retention till 60 min post injection. Present study constitutes a novel design approach towards development of a 99mTc-radiopharmaceutical for hypoxia imaging application, which could be extended to other potential nitroimidazole ligands. [ABSTRACT FROM AUTHOR]

Introduction: 177Lu-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" 177Lu-DOTA-TATE using medium specific activity 177Lu (740-1110 GBq/mg) at a centralized radiopharmacy facility.Methods: In an optimized protocol, 177Lu-DOTA-TATE synthesis was carried out by direct heating of 177LuCl3 (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 177Lu 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 177Lu-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 177Lu-DOTA-TATE was successfully prepared and optimized for regular bulk scale production and supply to distant nuclear medicine centers. [ABSTRACT FROM AUTHOR]

The [TcN(PNP)] core offers a unique route for the preparation of asymmetric Tc-complexes. Though bidentate chelators such as dithiocarbamates are most commonly used ligands in this approach, present study explores the possibility of using a monodentate ligand, a isocyanide derivative of metronidazole (MetroNC), for preparing a TcN(PNP) complex for detecting tumor hypoxia. MetroNC could be prepared in good yield and subsequently radiolabeled with [TcN(PNP)] precursor complex prepared from [TcN] core and N-(2-methoxyethyl)-2-(diphenylphosphino)- N-(2-(diphenylphosphino)ethyl)ethanamine (PNP2) ligand. Preliminary biodistribution studies showed tumor uptake pattern similar to previous studies wherein, about 75 % of the tumor activity observed at 60 min post injection (p.i.) was still found to remain in tumor at 180 min p.i. [ABSTRACT FROM AUTHOR]