Discovery of Glutamate Carboxypeptidase III Ligands to Compete the Uptake of [177Lu]Lu-PSMA-617 in Healthy Organs.

Prostate-specific membrane antigen (PSMA)-targeted radio ligand therapeutics (RLTs), such as [177Lu]Lu-PSMA-617 (Pluvicto), have been shown to accumulate in salivary glands and kidneys, potentially leading to undesired side effects. As unwanted accumulation in normal organs may derive from the cross-reactivity of PSMA ligands to glutamate carboxypeptidase III (GCPIII), it may be convenient to block this interaction with GCPIII-selective ligands. Parallel screening of a DNA-encoded chemical library (DEL) against GCPIII and PSMA allowed the identification of GCPIII binders. Structure-activity relationship (SAR) studies resulted in the identification of nanomolar GCPIII ligands with up to 1000-fold selectivity over PSMA. We studied the ability of GCPIII ligands to counteract the binding of [177Lu]Lu-PSMA-617 to human salivary glands by autoradiography and could demonstrate a partial radioprotection.

Overview of Prostaglandin E2 (PGE2)-Targeting Radiolabelled Imaging Probes from Preclinical Perspective: Lessons Learned and Road Ahead.

As malignancies still represent one of the major health concerns worldwide, early tumor identification is among the priorities of today's science. Given the strong association between cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), PGE2 receptors (EPs), and carcinogenesis, target-specific molecules directed towards the components of the COX2/PGE2/EP axis seem to be promising imaging probes in the diagnostics of PGE2pos. neoplasms and in the design of anti-cancer drugs. Featured with outstanding inclusion forming capability, ß-cyclodextrins (CDs) including randomly methylated ß-CD (RAMEB) were reported to complex with PGE2. Therefore, radiolabelled ß-CDs could be valuable vectors in the molecular imaging of PGE2-related tumorigenesis. In vivo preclinical small animal model systems applying positron emission tomography (PET) ensure a well-suited scenario for the assessment of PGE2-affine labelled CD derivatives. Previous translational studies dealt with the evaluation of the tumor-homing capability of Gallium-68 (68Ga) and Bismuth-205/206 (205/206Bi)-appended ß-CD compounds conjugated with chelator NODAGA or DOTAGA: [68Ga]Ga-NODAGA-2-hydroxypropyl-ß-cyclodextrin/HPBCD, [68Ga]Ga-NODAGA-RAMEB, [68Ga]Ga-DOTAGA-RAMEB, and [205/206Bi]Bi-DOTAGA-RAMEB in experimental tumors with different PGE2 expression. These imaging probes project the establishment of tailor-made PET diagnostics of PGE2pos. malignancies. In the present review, we provide a detailed overview of the in vivo investigations of radiolabelled PGE2-directed CDs, highlighting the importance of the integration of translational discoveries into routine clinical usage.

An Overview of Treatment Approaches for Octahydro-1, 3, 5, 7-tetranitro-1, 3, 5, 7-tetrazocine (HMX) Explosive in Soil, Groundwater, and Wastewater.

Octahydro-1, 3, 5, 7-tetranitro-1, 3, 5, 7-tetrazocine (HMX) is extensively exploited in the manufacturing of explosives; therefore, a significant level of HMX contamination can be encountered near explosive production plants. For instance, up to 12 ppm HMX concentrations have been observed in the wastewater effluent of a munitions manufacturing facility, while up to 45,000 mg/kg of HMX has been found in a soil sample taken from a location close to a high-explosive production site. Owing to their immense demand for a variety of applications, the large-scale production of explosives has culminated in severe environmental issues. Soil and water contaminated with HMX can pose a detrimental impact on flora and fauna and hence, remediation of HMX is paramount. There is a rising demand to establish a sustainable technology for HMX abatement. Physiochemical and bioremediation approaches have been employed to treat HMX in the soil, groundwater, and wastewater. It has been revealed that treatment methods such as photo-peroxidation and photo-Fenton oxidation can eliminate approximately 98% of HMX from wastewater. Fenton's reagents were found to be very effective at mineralizing HMX. In the photocatalytic degradation of HMX, approximately 59% TOC removal was achieved by using a TiO2 photocatalyst, and a dextrose co-substrate was used in a bioremediation approach to accomplish 98.5% HMX degradation under anaerobic conditions. However, each technology has some pros and cons which need to be taken into consideration when choosing an HMX remediation approach. In this review, various physiochemical and bioremediation approaches are considered and the mechanism of HMX degradation is discussed. Further, the advantages and disadvantages of the technologies are also discussed along with the challenges of HMX treatment technologies, thus giving an overview of the HMX remediation strategies.

A sketch of microbiological remediation of explosives-contaminated soil focused on state of art and the impact of technological advancement on hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) degradation.

When high-energy explosives such as hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), 2,4,6-trinitrotoluene (TNT) are discharged into the surrounding soil and water during production, testing, open dumping, military, or civil activities, they leave a toxic footprint. The US Environmental Protection Agency has labeled RDX as a potential human carcinogen that must be degraded from contaminated sites quickly. Bioremediation of RDX is an exciting prospect that has received much attention in recent years. However, a lack of understanding of RDX biodegradation and the limitations of current approaches have hampered the widespread use of biodegradation-based strategies for RDX remediation at contamination sites. Consequently, new bioremediation technologies are required to enhance performance. In this review, we explore the requirements for in-silico analysis for producing biological models of microbial remediation of RDX in soil. On the other hand, potential gene editing methods for getting the host with target gene sequences responsible for the breakdown of RDX are also reported. Microbial formulations and biosensors for detection and bioremediation are also briefly described. The biodegradation of RDX offers an alternative remediation method that is both cost-effective and ecologically acceptable. It has the potential to be used in conjunction with other cutting-edge technologies to further increase the efficiency of RDX degradation.

Prostate-Specific Membrane Antigen Radioligand Therapy Using 177Lu-PSMA I&T and 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: Comparison of Safety, Biodistribution, and Dosimetry.

The objective of this study was to determine the safety, kinetics, and dosimetry of the 177Lu-labeled prostate-specific membrane antigen (PSMA) small molecules 177Lu-PSMA I&T and 177Lu-PSMA-617 in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing PSMA radioligand therapy (PRLT). Methods: In total, 138 patients (mean age, 70 ± 9 y; age range, 46-90 y) with progressive mCRPC and PSMA expression verified by 68Ga-PSMA-11 PET/CT underwent PRLT. Fifty-one patients received 6.1 ± 1.0 GBq (range, 3.4-7.6 GBq) of 177Lu-PSMA I&T, and 87 patients received 6.5 ± 1.1 GBq (range, 3.5-9.0 GBq) of 177Lu-PSMA-617. Dosimetry was performed on all patients using an identical protocol. The mean absorbed doses were estimated with OLINDA software (MIRD Scheme). Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 5.0, of the National Cancer Institute. Results: The whole-body half-lives were shorter for 177Lu-PSMA I&T (35 h) than for 177Lu-PSMA-617 (42 h). The mean whole-body dose of 177Lu-PSMA-617 was higher than that of 177Lu-PSMA I&T (0.04 vs. 0.03 Gy/GBq, P < 0.00001). Despite the longer half-life of 177Lu-PSMA-617, the renal dose was lower for 177Lu-PSMA-617 than for 177Lu-PSMA I&T (0.77 vs. 0.92 Gy/GBq, P = 0.0015). Both PSMA small molecules demonstrated a comparable dose to the parotid glands (0.5 Gy/GBq, P = 0.27). Among all normal organs, the lacrimal glands exhibited the highest mean absorbed doses, 5.1 and 3.7 Gy/GBq, for 177Lu-PSMA-617 and 177Lu-PSMA I&T, respectively. All tumor metastases exhibited a higher initial uptake when using 177Lu-PSMA I&T than when using 177Lu-PSMA-617, as well as a shorter tumor half-life (P < 0.00001). The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617 (5.8 vs. 5.9 Gy/GBq, P = 0.96). All patients tolerated the therapy without any acute adverse effects. After 177Lu-PSMA-617 and 177Lu-PSMA I&T, there was a small, statistically significant reduction in hemoglobin, leukocyte counts, and platelet counts that did not need any clinical intervention. No nephrotoxicity was observed after either 177Lu-PSMA I&T or 177Lu-PSMA-617 PRLT. Conclusion: Both 177Lu-PSMA I&T and 177Lu-PSMA-617 PRLT demonstrated favorable safety in mCRPC patients. The highest absorbed doses among healthy organs were in the lacrimal and parotid glands-not, however, resulting in any significant clinical sequel. 177Lu-PSMA-617 demonstrated a higher absorbed dose to the whole-body and lacrimal glands but a lower renal dose than did 177Lu-PSMA I&T. The mean absorbed tumor doses were comparable for both 177Lu-PSMA I&T and 177Lu-PSMA-617. There was a large interpatient variability in the dosimetry parameters. Therefore, individual patient-based dosimetry seems favorable for personalized PRLT.

Synthesis and evaluation of radiogallium-labeled long-chain fatty acid derivatives as myocardial metabolic imaging agents.

Since long-chain fatty acids work as the primary energy source for the myocardium, radiolabeled long-chain fatty acids play an important role as imaging agents to diagnose metabolic heart dysfunction and heart diseases. With the aim of developing radiogallium-labeled fatty acids, herein four fatty acid-based tracers, [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA, which are [67Ga]Ga-HBED-CC and [67Ga]Ga-DOTA conjugated with pentadecanoic acid (PDA) and 3-methylhexadecanoic acid (MHDA), were synthesized, and their potential for myocardial metabolic imaging was evaluated. Those tracers were found to be chemically stable in 0.1 M phosphate buffered saline. Initial [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA uptakes in the heart at 0.5 min postinjection were 5.01 ± 0.30%ID/g, 5.74 ± 1.02%ID/g, 5.67 ± 0.22%ID/g, and 5.29 ± 0.10%ID/g, respectively. These values were significantly lower than that of [123I]BMIPP (21.36 ± 2.73%ID/g). For their clinical application as myocardial metabolic imaging agents, further structural modifications are required to increase their uptake in the heart.

Total tumor volume reduction and low PSMA expression in patients receiving Lu-PSMA therapy.

Background: [177Lu]-PSMA-617 (Lu-PSMA) therapy is a promising therapeutic option for end-stage prostate cancer patients. Early treatment response at the first restaging after two therapy cycles might correlate with high treatment efficacy and long overall survival (OS). Therefore, the aim of this study was to evaluate whether early reduction in tumor volume is a positive prognosticator for OS. To this end, PSMA PET prior to therapy (baseline) and at first restaging after two therapy cycles (interim; i.e., 12 weeks) were compared. Methods: Patients with metastatic castration-resistant prostate cancer who received Lu-PSMA therapy were reviewed for this analysis. All patients with available baseline and interim [68Ga]-PSMA-11 PET/CT were included in this analysis (n = 33). All PSMA avid metastases in baseline and interim PETs were semi-automatically segmented. The average PSMA expression (mean SUVmax of all metastases), total tumor volume (PSMA-TV) and TLQ (quotients of tumor volume and SUVmean summed over all metastases) were quantified at baseline and interim timepoints. Response in PSMA-TV was assumed when a decline > 30% was present. OS and biochemical response were available for all patients. Results: Baseline PSMA-TV was a statistically significant prognosticator of OS (HR = 1.618 95%CI: 1.117 - 2.343, p = 0.011). Reduction in PSMA-TV was not a statistically significant positive prognosticator of OS in the total cohort (HR = 0.829 95%CI: 0.559 - 1.230, p = 0.352). Likewise, there was no statistical difference in survival time comparing patients with PSMA-TV response to those without (13.2 vs. 15.6 months, p = 0.1). In the subgroup of patients with PSMA-TV response, mean SUVmax was a statistically significant prognosticator of OS (binarized by median; HR = 0.15; 95%CI: 0.03 - 0.83; p < 0.05). If patients with low PSMA expression at baseline were excluded from the analysis, reduction in PSMA-TV became a positive prognosticator of OS in uni- and multivariable Cox regression (HR = 0.290; 95%CI: 0.108 - 0.782; p = 0.015). Conclusion: PSMA-TV reduction was a positive prognosticator of OS only if patients with low PSMA expression were excluded. This might indicate that the PSMA-PETs of patients with low PSMA expression may not be suited for assessing PSMA-TV reduction. Future studies investigating the interplay of PSMA-TV and low PSMA expression response are warranted.

A QM/MM Study on the Initiation Reaction of Firefly Bioluminescence-Enzymatic Oxidation of Luciferin.

Among all bioluminescent organisms, the firefly is the most famous, with a high luminescent efficiency of 41%, which is widely used in the fields of biotechnology, biomedicine and so on. The entire bioluminescence (BL) process involves a series of complicated in-vivo chemical reactions. The BL is initiated by the enzymatic oxidation of luciferin (LH2). However, the mechanism of the efficient spin-forbidden oxygenation is far from being totally understood. Via MD simulation and QM/MM calculations, this article describes the complete process of oxygenation in real protein. The oxygenation of luciferin is initiated by a single electron transfer from the trivalent anionic LH2 (L3-) to O2 to form 1[L•2-…O2•-]; the entire reaction is carried out along the ground-state potential energy surface to produce the dioxetanone (FDO-) via three transition states and two intermediates. The low energy barriers of the oxygenation reaction and biradical annihilation involved in the reaction explain this spin-forbidden reaction with high efficiency. This study is helpful for understanding the BL initiation of fireflies and the other oxygen-dependent bioluminescent organisms.

Molecular Imaging and Preclinical Studies of Radiolabeled Long-Term RGD Peptides in U-87 MG Tumor-Bearing Mice.

The Arg-Gly-Asp (RGD) peptide shows a high affinity for αvß3 integrin, which is overexpressed in new tumor blood vessels and many types of tumor cells. The radiolabeled RGD peptide has been studied for cancer imaging and radionuclide therapy. We have developed a long-term tumor-targeting peptide DOTA-EB-cRGDfK, which combines a DOTA chelator, a truncated Evans blue dye (EB), a modified linker, and cRGDfK peptide. The aim of this study was to evaluate the potential of indium-111(111In) radiolabeled DOTA-EB-cRGDfK in αvß3 integrin-expressing tumors. The human glioblastoma cell line U-87 MG was used to determine the in vitro binding affinity of the radiolabeled peptide. The in vivo distribution of radiolabeled peptides in U-87 MG xenografts was investigated by biodistribution, nanoSPECT/CT, pharmacokinetic and excretion studies. The in vitro competition assay showed that 111In-DOTA-EB-cRGDfK had a significant binding affinity to U-87 MG cancer cells (IC50 = 71.7 nM). NanoSPECT/CT imaging showed 111In-DOTA-EB-cRGDfK has higher tumor uptake than control peptides (111In-DOTA-cRGDfK and 111In-DOTA-EB), and there is still a clear signal until 72 h after injection. The biodistribution results showed significant tumor accumulation (27.1 ± 2.7% ID/g) and the tumor to non-tumor ratio was 22.85 at 24 h after injection. In addition, the pharmacokinetics results indicated that the 111In-DOTA-EB-cRGDfK peptide has a long-term half-life (T1/2λz = 77.3 h) and that the calculated absorbed dose was safe for humans. We demonstrated that radiolabeled DOTA-EB-cRGDfK may be a promising agent for glioblastoma tumor imaging and has the potential as a theranostic radiopharmaceutical.

Discovery of novel antibacterial agents: Recent developments in D-alanyl-D-alanine ligase inhibitors.

Bacterial infections can cause serious problems that threaten public health over a long period of time. Moreover, the continuous emergence of drug-resistant bacteria necessitates the development of novel antibacterial agents. D-alanyl-D-alanine ligase (Ddl) is an indispensable adenosine triphosphate-dependent bacterial enzyme involved in the biosynthesis of peptidoglycan precursor, which catalyzes the ligation of two D-alanine molecules into one D-alanyl-D-alanine dipeptide. This dipeptide is an essential component of the intracellular peptidoglycan precursor, uridine diphospho-N-acetylmuramic acid (UDP-MurNAc)-pentapeptide, that maintains the integrity of the bacterial cell wall by cross-linking the peptidoglycan chain, and is crucial for the survival of pathogens. Consequently, Ddl is expected to be a promising target for the development of antibacterial agents. In this review, we present a brief introduction regarding the structure and function of Ddl, as well as an overview of the various Ddl inhibitors currently being used as antibacterial agents, specifically highlighting their inhibitory activities, structure-activity relationships and mechanisms of action.

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [177Lu]Lu-PSMA-617.

In recent years, radiolabeled tracers targeting prostate-specific membrane antigen (PSMA) have had a tremendous impact on prostate cancer management. Here, we report on the formation of radioactive impurities formed during the clinical production of 177Lu-labeled PSMA-617. We provide compelling evidence that these impurities are the result of a spontaneous, thermally mediated condensation reaction of the Glu-CO-Lys moiety resulting in the formation of three different five-membered ring systems. Density functional theory (DFT) calculations show that the condensation and cyclization of the Glu-CO-Lys moiety is thermodynamically spontaneous. In cell experiments, no affinity of these cyclized compounds toward PSMA was observed. HPLC analyses of urine samples from patient studies showed rapid renal excretion of these radioactive cyclized species. Radiolabeling conditions were identified that significantly reduced the formation of cyclized side products yielding 177Lu-labeled PSMA-617 in high radiochemical yield and purity in concordance with current good manufacturing practice (cGMP) requirements.

Molecular imaging and biochemical response assessment after a single cycle of [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy in mCRPC patients who have progressed on [177Lu]Lu-PSMA-617 monotherapy.

Rationale: Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted 177Lu radioligand therapy in metastatic castration-resistant prostate carcinoma (mCRPC), some patients do not respond and other patients with initially good response develop resistance to this treatment. In this study, we investigated molecular imaging and biochemical responses after a single cycle of [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy in patients who had progressed on [177Lu]Lu-PSMA-617 monotherapy. Methods: Seventeen patients with mCRPC were included in a retrospective, monocenter study. Molecular imaging-based response was assessed by modified PERCIST criteria using the whole-body total lesion PSMA (TLP) and molecular tumour volume (MTV) derived from [68Ga]Ga-PSMA-11 PET/CT. Biochemical response was evaluated according to PCWG3 criteria using the prostate-specific antigen (PSA) serum value. Concordance and correlation statistics as well as survival analyses were performed. Results: Based on the molecular imaging-based response assessment, 5 (29.4%) patients showed partial remission and 7 (41.2%) had stable disease. The remaining 5 (29.4%) patients had further progression, four with an increase in TLP/MTV of >30% and one with stable TLP/MTV but appearance of new metastases. Based on the biochemical response assessment, 5 (29.4%), 8 (47.1%), and 4 (23.5%) patients showed partial remission, stable disease, and progressive disease, respectively. A comparison of the response assessment methods showed a concordance of 100% (17/17) between TLP and MTV and 70.6% (12/17) between TLP/MTV and PSA. Patients with partial remission, independently assessed by each method, had better overall survival (OS) than patients with either stable or progressive disease. The difference in OS was statistically significant for the molecular imaging response assessment (median OS not reached vs. 8.3 m, p = 0.044), but not for the biochemical response assessment (median OS 18.1 m vs. 9.4 m, p = 0.468). Conclusion: Based on both assessment methods, [225Ac]Ac-PSMA-617/[177Lu]Lu-PSMA-617 tandem therapy is an effective treatment for the highly challenging cohort of patients with mCRPC who have progressed on [177Lu]Lu-PSMA-617 monotherapy. Molecular imaging response and biochemical PSA response were mostly concordant, though a considerable number of cases (29.4%) were discordant. Molecular imaging response reflecting the change in total viable tumour burden appears to be superior to PSA change in estimating survival outcome after tandem therapy.

A simple strategy to reduce the salivary gland and kidney uptake of PSMA-targeting small molecule radiopharmaceuticals.

PURPOSE: Peptide-based prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) agent [177Lu]-PSMA-617 has emerged as leading TRT candidate for treatment of castration-resistant prostate cancer (mCRPC). [177Lu]-PSMA-617 and other small molecule-based PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to the salivary gland and kidneys is a concern and dose-limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Herein, we report that addition of cold PSMA ligand PSMA-11 can aid in reducing the uptake of [177Lu]-PSMA-617 in the salivary glands and kidneys. METHODS: Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [177Lu]-PSMA-617 along with 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 and biodistribution studies were performed at 1 h. RESULTS: Biodistribution studies at 1 h post-administration revealed that [177Lu]-PSMA-617 uptake in PC3-PIP tumors was 21.71 ± 6.13, 18.7 ± 2.03, 26.44 ± 2.94, 16.21 ± 3.5, 13.52 ± 3.68, and 12.03 ± 1.96 %ID/g when 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 were added, respectively. Corresponding uptake values in kidney were 123.14 ± 52.52, 132.31 ± 47.4, 84.29 ± 78.25, 2.12 ± 1.88, 1.16 ± 0.36, and 0.64 ± 0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48 ± 0.11, 0.45 ± 0.15, 0.38 ± 0.3, 0.08 ± 0.03, 0.09 ± 0.07, and 0.05 ± 0.02 % ID/g, respectively. CONCLUSION: The uptake of [177Lu]-PSMA-617 in the salivary gland and kidney can be substantially reduced without significantly impacting tumor uptake by adding cold PSMA-11.

A laboratory study on dissipation and risk assessment of the proinsecticide thiocyclam and its metabolite nereistoxin in tomato using liquid chromatography high resolution mass spectrometry.

Reduced pesticides use, alongside increased organic farming, has created a need for new biological products, such as thiocyclam, to control pests. Thiocyclam has scarcely been studied, making the study of its degradation in fruits and vegetables, such as tomatoes, an urgent requirement. To monitor thiocyclam metabolites in tomato, dissipation studies were carried out using a liquid chromatography-Orbitrap mass spectrometry (UHPLC-Orbitrap MS) method for 60-days after foliar application. Thiocyclam was not persistent (DT50 < 15 days), but nereistoxin - its primary metabolite - remained present in the tomatoes for >60 days. Four nereistoxin metabolites, detected at low concentrations (<100 µg/kg), were also monitored. This is the first time a study has provided dissipation patterns for thiocyclam and nereistoxin. The results obtained suggest revising the legislation concerning these compounds is required. Toxicological studies must also be carried out because there is no toxicity data currently for thiocyclam or nereistoxin.

Cyclotron Production and Separation of Scandium Radionuclides from Natural Titanium Metal and Titanium Dioxide Targets.

Theranostic strategies involve select radionuclides that allow diagnostic imaging and tailored radionuclide therapy in the same patient. An example of a Food and Drug Administration-approved theranostic pair is the 68Ga- and 177Lu-labeled DOTATATE peptides, which are used to image neuroendocrine tumors, predict treatment response, and treat disease. However, when using radionuclides of 2 different elements, differences in the pharmacokinetic and pharmacodynamic profile of the agent can occur. Theranostic agents that incorporate the matched-pair radionuclides of scandium-43Sc/47Sc or 44Sc/47Sc-would guarantee identical chemistries and pharmacologic profiles. The aim of this study was to investigate production of 43,44,47Sc via proton-induced nuclear reactions on titanium nuclei using a 24-MeV cyclotron. Methods: Aluminum, niobium, and tantalum target holders were used with titanium foils and pressed TiO2 to produce scandium radionuclides with proton energies of up to 24 MeV. Irradiated targets were digested using NH4HF2 and HCl in a closed perfluoroalkoxy alkane vessel in 90 min. Scandium radionuclides were purified via ion-exchange chromatography using branched N,N,N',N'-tetra-2-ethylhexyldiglycolamide. The titanium target material was recovered via alkali precipitation with ammonia solution. Results: Titanium foil and TiO2 were digested with an average efficiency of 98% ± 3% and 95% ± 1%, respectively. The typical digestion time was 45 min for titanium foil and 75 min for TiO2 The average scandium recovery was 94% ± 3%, and the average titanium recoveries from digested titanium foil and TiO2 after precipitation as TiO2 were 108% ± 8% and 104% ± 5% of initial mass, respectively. Conclusion: This work demonstrated a robust method for the cyclotron production of scandium radionuclides that could be used with natural or enriched TiO2 target material.

Stabilization Strategies for Linear Minigastrin Analogues: Further Improvements via the Inclusion of Proline into the Peptide Sequence.

Minigastrin (MG) analogues, known for their high potential to target cholecystokinin-2 receptor (CCK2R) expressing tumors, have limited clinical applicability due to low enzymatic stability. By introducing site-specific substitutions within the C-terminal receptor-binding sequence, reduced metabolization and improved tumor targeting can be achieved. In this work, the influence of additional modification within the N-terminal sequence has been explored. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R ligands with proline substitution at different positions were synthesized. Substitution did not affect CCK2R affinity, and the conjugates labeled with indium-111 and lutetium-177 showed a high enzymatic stability in different incubation media as well as in vivo (57-79% intact radiopeptide in blood of BALB/c mice at 1 h p.i.) combined with enhanced tumor uptake (29-46% IA/g at 4 h in xenografted BALB/c nude mice). The inclusion of Pro contributes significantly to the development of CCK2R ligands with optimal targeting properties for application in targeted radiotherapy.

Evolution and Correlation of cis-2-Methyl-4-propyl-1,3-oxathiane, Varietal Thiols, and Acetaldehyde during Fermentation of Sauvignon blanc Juice.

cis-2-Methyl-4-propyl-1,3-oxathiane (cis-2-MPO) was recently identified in wine and proposed to arise from the reaction of 3-sulfanylhexan-1-ol (3-SH) and acetaldehyde. However, the evolution profile of cis-2-MPO during alcoholic fermentation (AF) and storage and its relationship with varietal thiols and acetaldehyde production were unknown. These aspects were investigated by fermenting Sauvignon blanc juice with J7 and/or VIN13 yeast strains and assessing the stability of cis-2-MPO during wine storage. Moderate to strong Pearson correlations verified similar evolution trends between acetaldehyde, 3-sulfanylhexyl acetate, and cis-2-MPO, with initial increases and a peak during the early to middle stages of AF before consecutive decreases until the end. Contrarily, 3-SH correlated moderately only at the end of AF. A consistent decrease observed for cis-2-MPO when spiked into Sauvignon blanc wine and assessed during 1-year storage revealed its general instability, but acetaldehyde addition (100 mg/L), pH 3.0, and storage at 4 °C all appeared to retain cis-2-MPO. These results have implications for wine aroma and the potential for cis-2-MPO to act as a sink (or source) for 3-SH in wine over time.

Imaging and biodistribution of radiolabeled SP90 peptide in BT-483 tumor bearing mice.

The objective of this study was to evaluate radiolabeled DOTA-SP90 as a radiotracer for breast cancer. The in vitro competition assay showed that radiolabeled DOTA-SP90 had significant binding affinity to BT-483 cancer cells. Biodistribution, nanoSPECT/CT and nanoPET/CT imaging results indicated that radiolabeled DOTA-SP90 can accumulate in tumors. In addition, radiolabeled DOTA-SP90 peptides can also detect metastatic tumors. Therefore, radiolabeled SP90 peptide may provide the potential capability as diagnostic agent for breast cancer patients.

An efficient synthetic approach toward a sporadic heterocyclic scaffold: 1,3-Oxathiol-2-ylidenes; alkaline phosphatase inhibition and molecular docking studies.

We developed a simple and robust method for synthesis of 1,3-oxathiol-2-ylidene benzamides (4a-m) a sporadic class of heterocycles, by reacting freshly prepared aroyl isothiocyanates, with ethyl 2-chloroacetoacetate in presence of N-methylimidazole in dry acetonitrile. The synthesized compounds were explored for their inhibition against alkaline phosphatases and HeLa cancer cell lines. The results suggest that almost all the compounds possess good % inhibition against both enzymes, with compound 4m showing dual inhibition while 4g and 4i as potent and selective inhibitors of TNAP and c-IAP respectively. Structure activity relationship for the active members of series has been carried out based on molecular docking studies. The result of SAR shows the involvement of active inhibitors in H-bonding at various sites with different amino acid residues in addition to secondary metal ion interactions with Zn ions inside the active pocket of the enzyme. The π-π interactions between the 1,3-oxathiole ring and imidazole ring of His321 and His 317 further defines the dual mode of inhibition by compound 4m. These compounds also possess inhibition potential against cervical cell lines in the range of 2.42-69.03% with the maximum inhibition shown by the unsubstituted member 4a compared to the reference drug cisplatin.

Automated radiosynthesis and preclinical evaluation of Al[18F]F-NOTA-P-GnRH for PET imaging of GnRH receptor-positive tumors.

INTRODUCTION: Gonadotropin releasing hormone (GnRH) receptor is overexpressed in many human tumors. Previously we developed a 18F-labelled GnRH peptide. Although the GnRH-targeted PET probe can be clearly visualized by microPET imaging in a PC-3 xenograft model, clinical applications of the probe have been limited by complex labeling procedures, poor radiochemical yield, and unwanted accumulation in GnRH receptor negative tissues. In this study, we have designed a new 18F-labelled GnRH peptide that is more amenable to clinical development. METHODS: GnRH peptide analogues NOTA-P-GnRH was synthesized and automated radiolabeled with 18F using a Al[18F]F complex on a modified PET-MF-2V-IT-I synthesis module. The GnRH receptor affinities of AlF-NOTA-P-GnRH and NOTA-P-GnRH were determined by in vitro competitive binding assay. For in vitro characterization determination of stability and partition coefficients were carried out, respectively. Dynamic microPET and biodistribution studies of Al[18F]F-NOTA-P-GnRH were evaluated in xenograft tumor mouse models. RESULTS: The total radiochemical synthesis and purification of Al[18F]F-NOTA-P-GnRH was completed within 35 min with a decay-corrected yield of 35 ± 10%. The logP value of Al[18F]F-NOTA-P-GnRH was -2.74 ± 0.04 and the tracer was stable in phosphate-buffered saline, and bovine and human serum. The IC50 values of AlF-NOTA-P-GnRH and NOTA-P-GnRH were 116 nM and 56.2 nM, respectively. Dynamic PET imaging together with ex vivo biodistribution analyses revealed that Al[18F]F-NOTA-P-GnRH was clearly delineated in both PC-3 and MDA-MB-231 xenografted tumors. CONCLUSION: Al[18F]F-NOTA-P-GnRH can be efficiently produced on a commercially available automated synthesis module and has potential for use in clinical diagnosis of GnRH receptor-positive tumors. ADVANCES IN KNOWLEDGE: Our studies developed the automated radiosynthesis of a new 18F-labelled GnRH tracer and preclinical evaluation for future clinical application. IMPLICATIONS FOR PATIENT CARE: Quantitative and noninvasive imaging of GnRH expression would provide information for diagnosis and treatment of cancer patients.