Nitrilase mediated mild hydrolysis of a carbon-14 nitrile for the radiosynthesis of 4-(7-hydroxycarbamoyl-[1-14 C-heptanoyl]-oxy)-benzoic acid methyl ester, [14 C]-SHP-141: A novel class I/II histone deacetylase (HDAC) inhibitor.

A strategy has been developed for the carbon-14 radiosynthesis of [14 C]-SHP-141, a 4-(7-hydroxycarbamoyl-heptanoyloxy)-benzoic acid methyl ester derivative containing a terminal hydroxamic acid. The synthesis involved four radiochemical transformations. The key step in the radiosynthesis was the conversion of the 7-[14 C]-cyano-heptanoic acid benzyloxyamide [14 C]-4 directly into the carboxylic acid derivative, 7-benzyloxycarbamoyl-[14 C]-heptanoic acid [14 C]-8 using nitrilase-113 biocatalyst. The final step involved deprotection of the benzyloxy group using catalytic hydrogenation to facilitate the release of the hydroxamic acid without cleaving the phenoxy ester. [14 C]-SHP-141 was isolated with a radiochemical purity of 90% and a specific activity of 190 µCi/mg from four radiochemical steps starting from potassium [14 C]-cyanide in a radiochemical yield of 45%.

The Alleviating Effect of Herniarin Against Ionizing Radiation-Induced Genotoxicity and Cytotoxicity in Human Peripheral Blood Lymphocytes.

BACKGROUND AND OBJECTIVE: Herniarin is a simple coumarin that is found naturally in some plant species. In this study, we aimed to evaluate the protective effect of herniarin against ionizing radiation-induced genotoxicity and cytotoxicity in human peripheral blood lymphocytes. METHODS: Herniarin was added to human lymphocytes before irradiation with a dose of 2 Gy of Xrays. The antagonistic potential of herniarin against radiation was measured by MTT [3-(4,5- dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] assay, micronucleus assay, flow cytometry, and reactive oxygen species (ROS) level analysis. RESULTS: The maximum survival of lymphocytes against radiation was observed at a concentration of 50 µM of herniarin and a treatment time of 1 h. Pretreatment with 50 µM herniarin significantly decreased the micronuclei frequency, the percentage of apoptotic lymphocytes, and the ROS level in irradiated human lymphocytes. Moreover, 50 µM herniarin significantly increased the cytokinesis blocked proliferation index in irradiated lymphocytes. CONCLUSION: Herniarin could reduce radiation-induced cytotoxicity and genotoxicity in human lymphocytes. To complete the results of this study, it is suggested that in the future, more preclinical studies with larger samples or animal models be performed on herniarin.

The Screening of Renoprotective Agents by 99mTc-DMSA: A Review of Preclinical Studies.

BACKGROUND: Nephrotoxicity is a prevalent consequence of cancer treatment using radiotherapy and chemotherapy or their combination. There are two methods; histological and biochemical, to assess the kidney damage caused by toxic agents in animal studies. Although these methods are used for the try-out of renoprotective factors, these methods are invasive and time-consuming, and also, lack the necessary sensitivity for primary diagnosis. Quantitative renal 99mTc-DMSA scintigraphy is a noninvasive, precise and sensitive radionuclide technique which is used to assess the extent of kidney damage, so that the extent of injury to the kidney will be indicated by the renal uptake rate of 99mTc-DMSA in the kidney. In addition, this scintigraphy evaluates the effect of the toxic agents by quantifying the alterations in the biodistribution of the radiopharmaceutical. CONCLUSION: In this review, the recent findings about the renoprotective agents were evaluated and screened with respect to the use of 99mTc-DMSA , which is preclinically and clinically used for animal cases and cancer patients under the treatment by radiotherapy and chemotherapy.

Synthesis of carbon-14-labelled peptides.

Carbon-14 (14 C)-labelled active pharmaceutical ingredients (APIs) and investigational medicinal products (IMPs) are required for phase 0/I to phase III mass balance and micro-dosing clinical trials. In some cases, this may involve the synthesis of 14 C-labelled peptides, and the analysis can be performed by accelerated mass spectrometry (AMS). The 14 C-peptide is typically prepared by the solid-phase peptide synthesis (SPPS) approach using custom-made glassware for the key coupling steps. Further modification of the purified 14 C-peptide can then be performed.

Preliminary Human Radiation Dose Estimates of PET Renal Agents, Para-18F-Fluorohippuric Acid and Ortho-124I-Iodohippuric Acid from Rat Biodistribution Data.

BACKGROUND: Para-18F-fluorohippuric acid (18F-PFH) and ortho-124I-iodohippuric acid (124IOIH) were recently identified as potential radiotracers suitable for conducting renography using positron emission tomography (PET). The aim of this work was to estimate preliminary human-equivalent internal radiation dose of 18F-PFH and 124I-OIH using the biodistribution data reported in healthy rats. The results were compared with the absorbed dose data of technetium-99m-mercaptoacetyltriglycine (99mTc- MAG3) as documented in the International Commission on Radiological Protection (ICRP) publication 80. METHODS: The medical internal radiation dose (MIRD) formula was applied to extrapolate data from rats to human and to project the absorbed radiation dose for various organs in humans. S factor was calculated by Monte-Carlo N-particle (MCNP) simulation. RESULTS: Our dose prediction shows that an injection of 18F-PFH or 124I-OIH in humans would result in an estimated effective absorbed dose of 0.09 or 0.17 µSv/MBq respectively for whole body, which is about 135 or 73 times respectively lower than that obtained with an injection of 99mTc-MAG3. All organs except kidneys would receive an estimated effective absorbed dose of <0.1 µSv/MBq for 18F-PFH or 124I-OIH. Kidneys would receive a dose of 0.83 or 0.77 µSv/MBq respectively for 18F-PFH or 124I-OIH. CONCLUSIONS: Our results indicate that 18F-PFH and 124I-OIH would deliver much safer levels and lower radiation doses to the patients compared to 99mTc-MAG3 and warrants a clinical trial to estimate the radiation doses more accurately.

Targeted Therapy Towards Cancer-A Perspective.

Radionuclide antibody conjugates (RACs) and antibody-drug conjugates (ADCs) can function as biotherapeutic missiles in order to target cancer cells and destroy them. The advent of new technology platforms consisting of imaging modalities, drug design and radiochemistry will facilitate the personalised approach for cancer patient treatment programmes. The utilisation of radionuclides and cytotoxic drugs conjugated to biovectors can deliver a cytotoxic drug payload with the ability to emit alpha and/or beta particles in the vicinity of the tumour by binding onto the cancer cells surface antigens initiating cell death. This perspective aims to provide an insight into targeted therapies in the treatment of various cancerous disease states including breast cancer, prostate bone metastases, lymphoma and leukaemia.

Radionuclide antibody-conjugates, a targeted therapy towards cancer.

Targeted alpha therapy (TAT) is an investigational procedure which utilises monoclonal antibodies (mAbs), peptide conjugates and/or other chemical compounds. These bio-vectors are able to transport a dose of alpha particles to destroy cancer cells. Radionuclide antibody-conjugates (RACs), labelled with beta emitters, have already been used in humans. More recently, TAT has been introduced to treat oncological diseases mainly leukaemia and lymphoma. Encouraging results have also been obtained in solid neoplasms with the administration of anti-tenascin. This chimeric antibody labelled with astatine-211 was delivered in patients with recurrent brain tumours into a surgically created cavity. Conversely, a clinical trial using a standard TAT approach to treat patients with metastatic melanoma, observed the shrinkage of the solid tumour mass. This response in melanoma may lead to an alternative mechanism for TAT, called tumour-antivascular- alpha-therapy (TAVAT), and forms the basis of a novel approach to the treatment of cancer disease states. In this paper, we will concentrate mainly on the application of TAT using antibodies. In particular, an investigation into the major general features connected with the use of alpha emitters in cancer therapy will be discussed. The prospective role of TAT with RACs will also be outlined briefly, especially focussing on the most important therapeutic strategies to date based on antibodies radiolabelled with beta emitters.

5-hydroxytryptamine (5-HT) receptor ligands.

Serotonin (5-HT) receptors are part of the G protein-coupled and ligand-gated ion channel families. 5-HT exerts its diverse actions by binding to cell surface receptors which can be classified into seven distinct families (5-HT1 to 5-HT7) according to their structural diversity and mode of action. Some of the 5-HT families are comprised of multiple receptors which share similar structural and mechanistic properties but display very different operational profiles. Evidence continues to mount in support of the important roles of the 5-HT receptors in various neuropsychiatric disorders such as anxiety, depression, schizophrenia, migraine and drug addiction. The 5-HT receptors may also play an important role in obesity, aggression, sexual behaviour and cardiovascular disorders. A number of selective/non-selective 5-HT agonist and antagonist ligands (drugs) have been developed to challenge many of these disease states.