Prostate-Specific Membrane Antigen Expression in Patients with Primary Prostate Cancer: Diagnostic and Prognostic Value in Positron Emission Tomography-Prostate-Specific Membrane Antigen.

Prostate cancer represents a significant public health challenge, with its management requiring precise diagnostic and prognostic tools. Prostate-specific membrane antigen (PSMA), a cell surface enzyme overexpressed in prostate cancer cells, has emerged as a pivotal biomarker. PSMA's ability to increase the sensitivity of PET imaging has revolutionized its application in the clinical management of prostate cancer. The advancements in PET-PSMA imaging technologies and methodologies, including the development of PSMA-targeted radiotracers and optimized imaging protocols, led to diagnostic accuracy and clinical utility across different stages of prostate cancer. This highlights its superiority in staging and its comparative effectiveness against conventional imaging modalities. This paper analyzes the impact of PET-PSMA on prostate cancer management, discussing the existing challenges and suggesting future research directions. The integration of recent studies and reviews underscores the evolving understanding of PET-PSMA imaging, marking its significant but still expanding role in clinical practice. This comprehensive review serves as a crucial resource for clinicians and researchers involved in the multifaceted domains of prostate cancer diagnosis, treatment, and management.

In-target production of [11C]CH4 from a nitrogen/hydrogen gas target as a function of beam current, irradiation time, and target temperature.

BACKGROUND: Production of [11C]CH4 from gas targets is notorious for weak performance with respect to yield, especially when using high beam currents. Post-target conversion of [11C]CO2 to [11C]CH4 is a widely used roundabout method in 11C-radiochemistry, but the added complexity increase the challenge to control carrier carbon. Thus in-target-produced [11C]CH4 is superior with respect to molar activity. We studied the in-target production of [11C]CO2 and [11C]CH4 from nitrogen gas targets as a function of beam current, irradiation time, and target temperature. RESULTS: [11C]CO2 production was practically unchanged across the range of varied parameters, but the [11C]CH4 yield, presented in terms of saturation yield YSAT(11CH4), had a negative correlation with beam current and a positive correlation with target chamber temperature. A formulated model equation indicates behavior where the [11C]CH4 formation follows a parabolic graph as a function of beam current. The negative square term, i.e., the yield loss, is postulated to arise from Haber-Bosch-like NH3 formation: N2 + 3H2 → 2NH3. The studied conditions suggest that the NH3 (liq.) would be condensed on the target chamber walls, thus depleting the hydrogen reserve needed for the conversion of nascent 11C to [11C]CH4. CONCLUSIONS: [11C]CH4 production can be improved by increasing the target chamber temperature, which is presented in a mathematical formula. Our observations have implications for targetry design (geometry, gas volume and composition, pressure) and irradiation conditions, providing specific knowledge to enhance [11C]CH4 production at high beam currents. Increased [11C]CH4 radioactivity is an obvious benefit in radiosynthesis in terms of product yield and molar radioactivity.

Radiosynthesis and In Vitro Evaluation of [11C]tozadenant as Adenosine A2A Receptor Radioligand.

Tozadenant (4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide) is a highly selective adenosine A2A receptor (A2AR) antagonist and a promising lead structure for the development of A2AR-selective positron emission tomography (PET) probes. Although several 18F-labelled tozadenant derivatives showed favorable in vitro properties, recent in vivo PET studies observed poor brain penetration and lower specific binding than anticipated from the in vitro data. While these findings might be attributable to the structural modification associated with 18F-labelling, they could also reflect inherent properties of the parent compound. However, PET studies with radioisotopologues of tozadenant to evaluate its cerebral pharmacokinetics and brain distribution are still lacking. In the present work, we applied N-Boc-O-desmethyltozadenant as a suitable precursor for the preparation of [O-methyl-11C]tozadenant ([11C]tozadenant) by O-methylation with [11C]methyl iodide followed by acidic deprotection. This approach afforded [11C]tozadenant in radiochemical yields of 18 ± 2%, with molar activities of 50-60 GBq/µmol (1300-1600 mCi/µmol) and radiochemical purities of 95 ± 3%. In addition, in vitro autoradiography in pig and rat brain slices demonstrated the expected striatal accumulation pattern and confirmed the A2AR specificity of the radioligand, making it a promising tool for in vivo PET studies on the cerebral pharmacokinetics and brain distribution of tozadenant.

Gas Phase Transformations in Carbon-11 Chemistry.

The short-lived positron-emitter carbon-11 (t1/2 = 20.4 min; ß+, 99.8%) is prominent for labeling tracers for use in biomedical research with positron emission tomography (PET). Carbon-11 is produced for this purpose with a cyclotron, nowadays almost exclusively by the 14N(p,α)11C nuclear reaction, either on nitrogen containing a low concentration of oxygen (0.1-0.5%) or hydrogen (~5%) to produce [11C]carbon dioxide or [11C]methane, respectively. These primary radioactive products can be produced in high yields and with high molar activities. However, only [11C]carbon dioxide has some utility for directly labeling PET tracers. Primary products are required to be converted rapidly and efficiently into secondary labeling synthons to provide versatile radiochemistry for labeling diverse tracer chemotypes at molecular positions of choice. This review surveys known gas phase transformations of carbon-11 and summarizes the important roles that many of these transformations now play for producing a broad range of labeling synthons in carbon-11 chemistry.

Validation of a good manufacturing practice procedure for the production of [11C]AZD4747, a CNS penetrant KRASG12c inhibitor.

AZD4747 is a KRASG12C inhibitor recently shown to cross the non-human primate blood-brain barrier efficiently. In the current study, a GMP-compliant production of [11C]AZD4747 was developed to enable PET studies in human subjects. The validated procedure afforded [11C]AZD4747 as an injectable solution in good radioactivity yield (1656 ± 532 MBq), excellent radiochemical purity (100%), and a molar activity of 77 ± 13 GBq/µmol at the end of the synthesis, which took 46 ± 1 min from the end of the bombardment. Quality control on the final product was performed satisfactorily and met all acceptance criteria.

OMNI: Gas Chromatograph Captures Seven Common PET Radiotracer Analytes in under 5 Minutes.

A novel gas chromatography method was developed using automatic injections to identify and quantify the amount of residual solvents or analytes in samples of fluorine-18 and carbon-11 radiopharmaceuticals. This approach evaluates seven analytes in less than 5 versus 13 min of acquisition time. The method additionally includes a 3 min bakeout to aid in the removal and carry-over of higher-boiling impurities. Chromatographic parameters such as column temperature, hold time, column pressure, flow rate, and split ratios were adjusted and optimized to analyze radioactive drug samples containing analytes which include methanol, ethanol, acetone, acetonitrile, triethylamine, N,N-dimethylformamide, and dimethyl sulfoxide. The relative standard deviation for each solvent was determined to be no greater than 1.6%. The method limit of detection (LOD) and limit of quantification (LOQ) were between 0.053 and 0.163 and 0.000 (5.791 × 10-6) and 0.520 mg/mL, respectively. This GC technique, using flame ionization detection (FID), was validated and is currently employed for the routine quality control of all approved IND and RDRC PET radiopharmaceuticals at our center.

Radiocarbon Flux Measurements Reveal Mechanistic Insight into Heat-Stress Induction of Nicotine Biosynthesis in Nicotiana attenuata.

The effect of high-temperature (HT) stress on nicotine biosynthesis in Nicotiana attenuata was examined. Nicotine content was measured in mature leaves, young sink leaves, and in roots from well-watered plants grown at 25 °C as controls and from plants exposed to 38 °C and 43 °C temperatures applied for 24, 48, 72, and 96 h duration. At 38 °C, all leaf nicotine levels were significantly less than control plants for up to 72 h exposure but rose sharply thereafter to levels significantly greater than controls with 96 h exposure. In contrast, plants exposed to 43 °C never exhibited a reduction in leaf nicotine content and showed an increase in content with just 48 h exposure. Using radioactive 11CO2 and 13NO3-, we found that HT stress reduced both CO2 fixation and nitrate uptake. Furthermore, radiocarbon flux analysis revealed that 'new' carbon partitioning (as 11C) into the 11C-radiolabeled amino acid (AA) pool was significantly reduced with HT stress as were yields of [11C]-aspartic acid, an important AA in nicotine biosynthesis, and its beta-amido counterpart [11C]-asparagine. In contrast, [12C]-aspartic acid levels appeared unaffected at 38 °C but were elevated at 43 °C relative to controls. [12C]-Asparagine levels were noted to be elevated at both stress temperatures. Since HT reductions in carbon input and nitrogen uptake were noted to impede de novo AA biosynthesis, protein degradation at HT was examined as a source of AAs. Here, leaf total soluble protein (TSP) content was reduced 39% with long exposures to both stress temperatures. However, Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) which was 41% TSP appeared unaffected. Altogether, these results support the theory that plant proteins other than Rubisco degrade at elevated temperatures freeing up essential AAs in support of nicotine biosynthesis.

Preliminary PET imaging of [11 C]evobrutinib in mouse models of colorectal cancer, SARS-CoV-2, and lung damage: Radiosynthesis via base-aided palladium-NiXantphos-mediated 11 C-carbonylation.

Evobrutinib is a second-generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and lipopolysaccharide (LPS)-induced lung damage. Herein, we report the automated radiosynthesis of [11 C]evobrutinib using a base-aided palladium-NiXantphos-mediated 11 C-carbonylation reaction. [11 C]Evobrutinib was reliably formulated in radiochemical yields of 5.5 ± 1.5% and a molar activity of 34.5 ± 17.3 GBq/µmol (n = 12) with 99% radiochemical purity. Ex vivo autoradiography studies showed high specific binding of [11 C]evobrutinib in HT-29 colorectal cancer mouse xenograft tissues (51.1 ± 7.1%). However, in vivo PET/computed tomography (CT) imaging with [11 C]evobrutinib showed minimal visualization of HT-29 colorectal cancer xenografts and only a slight increase in radioactivity accumulation in the associated time-activity curves. In preliminary PET/CT studies, [11 C]evobrutinib failed to visualize either SARS-CoV-2 pseudovirus infection or LPS-induced injury in mouse models. In conclusion, [11 C]evobrutinib was successfully synthesized by 11 C-carbonylation and based on our preliminary studies does not appear to be a promising BTK-targeted PET radiotracer in the rodent disease models studied herein.

A carbon-11 labeled imidazo[1,2-a]pyridine derivative as a new potential PET probe targeting PI3K/mTOR in cancer.

The PI3K/Akt/mTOR pathway is frequently dysregulated in cancer due to its central role in cell growth, survival, and proliferation. Overactivation of the PI3K/Akt/mTOR pathway may occur through varying mechanisms including mutations, gene amplification, and upstream signaling events, ultimately resulting in cancer. Therefore, PI3K/Akt/mTOR pathway has emerged as an attractive target for cancer therapy and imaging. A promising approach to inhibit this pathway involves a simultaneous inhibition of both PI3K and mTOR using a dual inhibitor. Recently, a potent dual PI3K/mTOR inhibitor, 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (7), was discovered and demonstrated excellent kinase selectivity IC50 (PI3K/mTOR) = 0.20/21 nM; good cellular growth inhibition IC50 (HCT-116 cell) = 10 nM, modest plasma clearance, and acceptable oral bioavailability. Expanding on this discovery, here we present the synthesis of the carbon-11 labeled imidazo[1,2-a]pyridine derivative 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(4-[11C]methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (N-[11C]7) as a new potential radiotracer for the biomedical imaging technique positron emission tomography (PET) imaging of PI3K/mTOR in cancer. The reference standard 7 and its N-demethylated precursor, 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(piperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (11), were synthesized in 7 and 8 steps with 10% and 7% overall chemical yield, respectively. N-[11C]7 was prepared from 11 using [11C]methyl triflate ([11C]CH3OTf) through N-11C-methylation and isolated by high-performance liquid chromatography (HPLC) and solid-phase extraction (SPE) formulation in 40-50% radiochemical yield decay corrected to end of bombardment (EOB) based on [11C]CO2. The radiochemical purity was > 99% and the molar activity (Am) at EOB was in the range of 296-555 GBq/µmol (n = 5).

Radiosynthesis and Preliminary Evaluation of [11C]SSI-4 for the Positron Emission Tomography Imaging of Stearoyl CoA Desaturase 1.

Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme for converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs) and plays a key role in endogenous (de novo) fatty acid metabolism. Given that this pathway is broadly upregulated across many tumor types with an aggressive phenotype, SCD1 has emerged as a compelling target for cancer imaging and therapy. The ligand 2-(4-(2-chlorophenoxy)piperidine-1-carboxamido)-N-methylisonicotinamide (SSI-4) was identified as a potent and highly specific SCD1 inhibitor with a strong binding affinity for SCD1 at our laboratory. We herein report the radiosynthesis of [11C]SSI-4 and the preliminary biological evaluation including in vivo PET imaging of SCD1 in a human tumor xenograft model. Radiotracer [11C]SSI-4 was labeled at the carbamide position via the direct [11C]CO2 fixation on the Synthra MeIplus module in high molar activity and good radiochemical yield. In vitro cell uptake assays were performed with three hepatocellular carcinoma (HCC) cell lines and three renal cell carcinoma (RCC) cell lines. Additionally, in vivo small animal PET/CT imaging with [11C]SSI-4 and the biodistribution were carried out in a mouse model bearing HCC xenografts. Radiotracer [11C]SSI-4 afforded a 4.14 ± 0.44% (decay uncorrected, n = 10) radiochemical yield based on starting [11]CO2 radioactivity. The [11C]SSI-4 radiosynthesis time including HPLC purification and SPE formulation was 25 min from the end of bombardment to the end of synthesis (EOS). The radiochemical purity of [11C]SSI-4 was 98.45 ± 1.43% (n = 10) with a molar activity of 225.82 ± 33.54 GBq/µmol (6.10 ± 0.91 Ci/µmol) at the EOS. In vitro cell uptake study indicated all SSI-4 responsive HCC and RCC cell line uptakes demonstrate specific uptake and are blocked by standard compound SSI-4. Preliminary small animal PET/CT imaging study showed high specific uptake and block of [11C]SSI-4 uptake with co-injection of cold SSI-4 in high SCD1-expressing organs including lacrimal gland, brown fat, liver, and tumor. In summary, novel radiotracer [11C]SSI-4 was rapidly and automatedly radiosynthesized by direct [11C]CO2 fixation. Our preliminary biological evaluation results suggest [11C]SSI-4 could be a promising radiotracer for PET imaging of SCD1 overexpressing tumor tissues.

On the Road towards Small-Molecule Programmed Cell Death 1 Ligand 1 Positron Emission Tomography Tracers: A Ligand-Based Drug Design Approach.

PD-1/PD-L1 immune checkpoint blockade for cancer therapy showed promising results in clinical studies. Further endeavors are required to enhance patient stratification, as, at present, only a small portion of patients with PD-L1-positive tumors (as determined by PD-L1 targeted immunohistochemistry; IHC) benefit from anti-PD-1/PD-L1 immunotherapy. This can be explained by the heterogeneity of tumor lesions and the intrinsic limitation of multiple biopsies. Consequently, non-invasive in vivo quantification of PD-L1 on tumors and metastases throughout the entire body using positron emission tomography (PET) imaging holds the potential to augment patient stratification. Within the scope of this work, six new small molecules were synthesized by following a ligand-based drug design approach supported by computational docking utilizing lead structures based on the (2-methyl-[1,1'-biphenyl]-3-yl)methanol scaffold and evaluated in vitro for potential future use as PD-L1 PET tracers. The results demonstrated binding affinities in the nanomolar to micromolar range for lead structures and newly prepared molecules, respectively. Carbon-11 labeling was successfully and selectively established and optimized with very good radiochemical conversions of up to 57%. The obtained insights into the significance of polar intermolecular interactions, along with the successful radiosyntheses, could contribute substantially to the future development of small-molecule PD-L1 PET tracers.

Imaging the TGFß type I receptor in pulmonary arterial hypertension.

Transforming growth factor ß (TGFß) activity is perturbed in remodelled pulmonary vasculature of patients with pulmonary arterial hypertension (PAH), cancer, vascular diseases and developmental disorders. Inhibition of TGFß, which signals via activin receptor-like kinase 5 (ALK5), prevents progression and development of experimental PAH. The purpose of this study was to assess two ALK5 targeting positron emission tomography (PET) tracers ([11C]LR111 and [18F]EW-7197) for imaging ALK5 in monocrotaline (MCT)- and Sugen/hypoxia (SuHx)-induced PAH. Both tracers were subjected to extensive in vitro and in vivo studies. [11C]LR111 showed the highest metabolic stability, as 46 ± 2% of intact tracer was still present in rat blood plasma after 60 min. In autoradiography experiments, [11C]LR111 showed high ALK5 binding in vitro compared with controls, 3.2 and 1.5 times higher in SuHx and MCT, respectively. In addition, its binding could be blocked by SB431542, an adenosine triphosphate competitive ALK5 kinase inhibitor. However, [18F]EW-7197 showed the best in vivo results. 15 min after injection, uptake was 2.5 and 1.4 times higher in the SuHx and MCT lungs, compared with controls. Therefore, [18F]EW-7197 is a promising PET tracer for ALK5 imaging in PAH.

Radiosynthesis and preclinical evaluation of [11C]SNX-ab as an Hsp90α,ß isoform-selective PET probe for in vivo brain and tumour imaging.

BACKGROUND: The molecular chaperone, Hsp90, is a key player in the protein quality control system that maintains homeostasis under cellular stress conditions. It is a homodimer with ATP-dependent activity, and is a prominent member of the chaperone machinery that stabilizes, matures and (re)folds an extensive list of client proteins. Hsp90 occurs as four isoforms, cytosolic Hsp90α and Hsp90ß, mitochondrial TRAP1 and Grp94 present in the endoplasmic reticulum. An aberrant role of Hsp90 has been attributed to several cancers and neurodegenerative disorders. Consequently, Hsp90 has emerged as an attractive therapeutic target. However, pan-Hsp90 inhibition often leads to detrimental dose-limiting toxicities. Novel strategies for Hsp90-targeted therapy intend to avoid this by using isoform-specific Hsp90 inhibition. In this respect, the radiosynthesis of carbon-11 labeled SNX-ab was developed and [11C]SNX-ab was evaluated as a Hsp90α,ß isoform-selective PET probe, which could potentially allow to quantify in vivo Hsp90α,ß expression. RESULTS: [11C]SNX-ab was synthesized with excellent radiochemical yields of 45% and high radiochemical purity (> 98%). In vitro autoradiography studies on tissue slices of healthy mouse brain, mouse B16.F10 melanoma and U87 glioblastoma using homologous (SNX-ab, SNX-0723) and heterologous (Onalespib and PU-H71) Hsp90 inhibitors demonstrated only limited reduction of tracer binding, indicating that the binding of [11C]SNX-ab was not fully Hsp90-specific. Similarly, [11C]SNX-ab binding to U87 cells was not efficiently inhibited by Hsp90 inhibitors. Ex vivo biodistribution studies in healthy mice revealed limited brain exposure of [11C]SNX-ab and predominantly hepatobiliary clearance, which was confirmed by in vivo full-body dynamic µPET studies. CONCLUSION: Our results suggest that [11C]SNX-ab is not an ideal probe for in vivo visualization and quantification of Hsp90α/ß expression levels in tumour and brain. Future research in the development of next-generation Hsp90 isoform-selective PET tracers is warranted to dissect the role played by each isoform towards disease pathology and support the development of subtype-specific Hsp90 therapeutics.

Synthesis and in vivo evaluation of [11C]tucatinib for HER2-targeted PET imaging.

Tucatinib is a selective human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) in April 2020 for HER2-positive lesions in metastatic breast cancer patients, including CNS metastases. In this article, we attempted to develop the first small molecule, blood-brain-barrier (BBB) penetrant HER2 PET imaging probe based on tucatinib. [11C]tucatinib was synthesized via a Stille-coupling from the respective trimethylstannyl precursor and its biodistribution was evaluated in NMRI nude mice bearing HER2-overexpressing human ovarian cancer cells (SKOV-3). No significant tumor accumulation was observed despite its high affinity for HER-2 receptors (IC50 = 6.9 nM). High liver and intestinal uptake indicate that [11C]tucatinib is too lipophilic to be used as a tumor targeting PET tracer. Therefore, chemical modifications of [11C]tucatinib are needed to increase the polarity for tumor imaging. Tucatinib as an FDA approved drug is still an interesting platform to develop the first small molecule HER2-selective PET tracer. The study highlights the differences between a drug, which needs to be effective, and an imaging agent, which is dependent on contrast.

Discovery of a CSF-1R inhibitor and PET tracer for imaging of microglia and macrophages in the brain.

Colony stimulating factor 1 receptor (CSF-1R) is a kinase expressed on macrophages and microglia in the brain. It has been recognized as a potential drug and imaging target in treatment of neuroinflammatory diseases and glioblastoma. Despite several attempts, no validated CSF-1R PET tracer is currently available. The aim of this work was to develop a brain permeable CSF-1R PET tracer for non-invasive imaging of CSF-1R in vivo. Based on fragments of two potent and selective CSF-1R inhibitors, novel hybrid molecules were designed and synthesized. Affinity for human recombinant CSF-1R and selectivity over c-KIT and PDGFR-ß was determined using a FRET based in vitro assay. Radiosynthesis was performed by fully automated [11C]CH3I methylation of the corresponding des-methyl precursor. PET imaging was performed at baseline, efflux transporter blocking and CSF-1R blocking conditions. Moreover, tracer distribution and blood and plasma radiometabolites were determined following injection in healthy mice. The most promising CSF-1R inhibitor, compound 4, showed high selectivity and high affinity for CSF-1R (IC50: 12 ± 3 nM) and no affinity for kinase family members c-KIT and PDGFR-beta. [11C]4 was obtained in good yield (15 ± 0.2 % decay corrected yield, (2.0 ± 0.26 GBq at end of synthesis) and excellent purity. The compound demonstrated high brain penetration and good metabolic stability (>2 %ID/g at 60 min post injection and 79 ± 8 % intact [11C]4 in brain at 60 min post injection) and no strong efflux transporter substrate behavior. Blocking CSF-1R prior to imaging with [11C]4 resulted in significant decrease in brain uptake. In conclusion, [11C]4 shows good potential as a novel PET tracer for imaging of CSF-1R in the CNS and future experiments in relevant animal models are warranted.

Treatments with Liquid Smoke and Certain Chemical Constituents Prevalent in Smoke Reduce Phloem Vascular Sectoriality in the Sunflower with Improvement to Growth.

Many higher plants possess a physiological organization that is based upon the carbon economy of their parts. While photosynthates are partitioned according to the relative strength of the plant's sink tissues, in many species there is also a very close relationship between partitioning, phyllotaxy and vascular connectivity giving rise to sectorial patterns of allocation. Here, we examined the influence of smoke and certain chemical constituents prevalent in smoke including, catechol, resorcinol and hydroquinone on phloem vascular sectoriality in common sunflower (Helianthis annuus L.), as a model plant for sectoriality. By administering radioactive carbon-11 to a single source leaf as 11CO2, 11C-photosynthate allocation patterns were examined using autoradiography. A 1:200 aqueous dilution of liquid smoke treated soil caused 2.6-fold and 2.5-fold reductions in phloem sectoriality in sink leaves and roots, respectively. Treatment with catechol (1,2-d ihydroxybenzene) or resorcinol (1,3-dihydroxybenzene), polyphenolic constituents that are prevalent in smoke, caused similar reductions in phloem sectoriality in the same targeted sink tissues. However, treatment with hydroquinone (1,4-dihydroxybenzene) had no effect. Finally, the longer-term effects of smoke exposure on plant growth and performance were examined using outdoor potted plants grown over the 2022 season. Plants exposed to liquid smoke treatments of the soil on a weekly basis had larger thicker leaves possessing 35% greater lignin content than untreated control plants. They also had thicker stems although the lignin content was the same as controls. Additionally, plants exposed to treatment produced twice the number of flowers with no difference in their disk floret diameters as untreated controls. Altogether, loss of phloem sectoriality from exposure to liquid smoke in the sunflower model benefited plant performance.

Radiosynthesis and First Preclinical Evaluation of the Novel 11C-Labeled FAP Inhibitor 11C-FAPI: A Comparative Study of 11C-FAPIs and (68Ga) Ga-DOTA-FAPI-04 in a High-FAP-Expression Mouse Model.

PURPOSE: 68Ga-labeled fibroblast activation protein inhibitors, such as [68Ga]Ga-DOTA-FAPI-04 and [68Ga]Ga-DOTA-FAPI-46, have been successfully applied in positron emission tomography imaging of various tumor types. To broaden the PET tracers of different positron nuclides for imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of two 11C-labeled FAP inhibitors, 11C-RJ1101 and 11C-RJ1102. METHODS: Two phenolic hydroxyl precursors based on a quinoline amide core coupled with a 2-cyanopyrrolidine moiety were coupled with [11C]CH3I to synthesize 11C-RJ1101 and 11C-RJ1102. In vivo small-animal PET and biological distribution studies of 11C-RJ1101 and 11C-RJ1102 compared to [68Ga]Ga-DOTA-FAPI-04 were conducted in nude mice bearing U87MG tumor xenografts at 30, 60, and 90min, respectively. RESULTS: 11C-RJ1101 and 11C-RJ1102 were synthesized in over 15% radiochemical yields, with specific activities of 67 GBq/µmol and 34 GBq/µmol, respectively, at the end of synthesis and radiochemical purities greater than 99%. In U87MG tumor xenograft PET studies, the three tracers experienced higher specific uptake at the tumor site. However, because of significant differences in metabolism and clearance, [68Ga]Ga-DOTA-FAPI-04 experienced high uptake in the kidney, whereas 11C-RJ1101 and 11C-RJ1102 showed high uptake in the liver and intestine. Biodistribution studies revealed significant hepatobiliary excretion of 11C-RJ1101 and 11C-RJ1102. 11C-RJ1102 showed higher specific tumor uptake in U87MG xenografts (1.71 ± 0.08% injected dose per Gram of tissue [ID/g]) than 11C-RJ1101 (1.34 ± 0.10%ID/g) and [68Ga]Ga-DOTA-FAPI-04 (1.29 ± 0.04%ID/g) after 30 min p. i. In orthotopic glioma models, the uptake values were 0.07 ± 0.03% ([68Ga]Ga-DOTA-FAPI-04) and 0.16 ± 0.03% (11C-RJ1102), respectively. CONCLUSION: 11C-RJ1101 and 11C-RJ1102 are interesting candidates for translation to the clinic, taking advantage of the shorter half-life and physical imaging properties of C-11.

Carbon-11 patents (2012-2022): synthetic methodologies and novel radiotracers for PET imaging.

INTRODUCTION: Carbon-11 is a short-lived radionuclide with versatile applications in synthetic methodologies to develop a variety of novel PET radiotracers. Different primary and secondary carbon-11 precursors are generated from cyclotron produced [11C]CO2 and used to insert carbon-11 radionuclide into the target-specific bioactive molecules. AREAS COVERED: In this review, the patents as well as specific research articles on carbon-11 radiotracer synthesis and PET imaging applications in various diseases are mentioned since 2012 to 2022 through SciFinder database. EXPERT OPINION: Carbon-11 is generally easier to insert into more organic scaffolds as a greater variety of functional groups. Despite the short half-life of carbon-11 radionuclide (t1/2 = 20.4 min), it is widely used in PET radiotracer development due to its direct insertion into bioactive compounds and less isotopic dilution unlike other positron emitters like fluorine-18. Various synthons can be easily generated using the primary and secondary carbon-11 precursors . The carbon-11 radiotracers provide target-oriented information associated with the pharmacology, and physiological conditions of the disease status. Various protocols and automated methods were adapted for easy and convenient synthesis of carbon-11 radiotracers. The PET advances drug development and clinical trials by revealing biological target engagement, proof of mechanism, pharmacokinetic, and pharmacodynamic profiles of new drug candidates using selective radiotracers.

A new concept for the production of 11C-labelled radiotracers.

BACKGROUND: The GMP-compliant production of radiopharmaceuticals has been performed using disposable units (cassettes) with a dedicated synthesis module. To expand this "plug 'n' synthesize" principle to a broader scope of modules we developed a pressure controlled setup that offers an alternative to the usual stepper motor controlled rotary valves. The new concept was successfully applied to the synthesis of N-methyl-[11C]choline, L-S-methyl-[11C]methionine and [11C]acetate. RESULTS: The target gas purification of cyclotron produced [11C]CO2 and subsequent conversion to [11C]MeI was carried out on a TRACERlab Fx C Pro module. The labelling reactions were controlled with a TRACERlab Fx FE module. With the presented modular principle we were able to produce N-methyl-[11C]choline and L-S-methyl-[11C]methionine by loading a reaction loop with neat N,N'-dimethylaminoethanol (DMAE) or an ethanol/water mixture of NaOH and L-homocysteine (L-HC), respectively and a subsequent reaction with [11C]MeI. After 18 min N-methyl-[11C]choline was isolated with 52% decay corrected yield and a radiochemical purity of > 99%. For L-S-methyl-[11C]methionine the total reaction time was 19 min reaction, yielding 25% of pure product (> 97%). The reactor design was used as an exemplary model for the technically challenging [11C]acetate synthesis. The disposable unit was filled with 1 mL MeMgCl (0.75 M) in tetrahydrofuran (THF) bevore [11C]CO2 was passed through. After complete release of [11C]CO2 the reaction mixture was quenched with water and guided through a series of ion exchangers (H+, Ag+ and OH-). The product was retained on a strong anion exchanger, washed with water and finally extracted with saline. The product mixture was acidified and degassed to separate excess [11C]CO2 before dispensing. Under these conditions the total reaction time was 18 ± 2 min and pure [11C]acetate (n = 10) was isolated with a decay corrected yield of 51 ± 5%. CONCLUSION: Herein, we described a novel single use unit for the synthesis of carbon-11 labelled tracers for preclinical and clinical applications of N-methyl-[11C]choline, L-S-methyl-[11C]methionine and [11C]acetate.