Lessons learned in application driven imaging agent design for image-guided surgery.

To meet the growing demand for intraoperative molecular imaging, the development of compatible imaging agents plays a crucial role. Given the unique requirements of surgical applications compared to diagnostics and therapy, maximizing translational potential necessitates distinctive imaging agent designs. For effective surgical guidance, exogenous signatures are essential and are achievable through a diverse range of imaging labels such as (radio)isotopes, fluorescent dyes, or combinations thereof. To achieve optimal in vivo utility a balanced molecular design of the tracer as a whole is required, which ensures a harmonious effect of the imaging label with the affinity and specificity (e.g., pharmacokinetics) of a pharmacophore/targeting moiety. This review outlines common design strategies and the effects of refinements in the molecular imaging agent design on the agent's pharmacological profile. This includes the optimization of affinity, pharmacokinetics (including serum binding and target mediated background), biological clearance route, the achievable signal intensity, and the effect of dosing hereon.

Bifunctional Hexadentate Pyclen-based Chelating Agent for Mild Radiofluorination in Aqueous Solution at Room Temperature with a Ga-18F Ternary Complex.

Positron Emission Tomography (PET) is used in oncology for tumor diagnosis, commonly relying on fluorine-18 (18F) emission detection. The conventional method of 18F incorporation on to probes by covalent bonding is harsh for sensitive biomolecules, which are nonetheless compounds of choice for the development of targeted probes. This study explores gallium-18F (Ga18F) coordination, a milder alternative method occurring in aqueous media at the final stage of radiosyntheses. Pyclen-based chelating agents were proposed to capture (GaF) species at room temperature and pH ≥ 5 making the radiofluorination process compatible with heat- and acid-sensitive biomolecules. Highly promising results were obtained with the PC2A-based chelating agent LH2 derived from the new bifunctional PC2A-OAE-NCS compound. The solid-state structure of GaF(L) was elucidated by X-ray diffraction and revealed an unconventional heptacoordination of Ga(III). A high radiochemical conversion (RCC) of 86% was achieved at room temperature, in water at pH 5 within 20 minutes. Stability studies showed the robustness of the GaF(L) complex in aqueous media for at least one day and at least one hour for the radiolabeled analog Ga18F(L). These findings demonstrated that PC2A-based compounds are chelating agents of choice for (Ga18F) species, suggesting a real technological breakthrough for PET imaging and precision medicine.

Preparation and bioevaluation of a novel 99mTc-labelled propylene amine oxime (PnAO) containing two 4-methyl-2-nitroimidazole groups as a promising tumor hypoxia imaging agent.

Hypoxia is a common phenomenon in solid tumors, and its presence inhibits the efficacy of tumor chemotherapy and radiotherapy. Accurate measurement of hypoxia before tumor treatment is essential. Three propylene amine oxime (PnAO) derivatives with different substituents attached to 2-nitroimidazole were synthesized in the work, they are 3,3,9,9-tetramethyl-1,11-bis(4-bromo-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (Br2P2), 3,3,9,9-tetramethyl-1,11-bis(4-methyl-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (Me2P2) and 3,3,9,9-tetramethyl-1,11-bis(4,5-dimethyl-2-nitro-1H-imidazol-1-yl)-4,8-diazaundecane-2,10-dione dioxime (2Me2P2). The three compounds were radiolabeled with 99mTc to give three complexes([99mTc]Tc-Br2P2, [99mTc]Tc-Me2P2 and [99mTc]Tc-2Me2P2) with good in vitro stability. [99mTc]Tc-Me2P2 with a more suitable reduction potential had the highest hypoxic cellular uptake, compared with [99mTc]Tc-2P2 that have been previously reported, [99mTc]Tc-Br2P2 and [99mTc]Tc-2Me2P2. Biodistribution results in S180 tumor-bearing mice demonstrated that [99mTc]Tc-Me2P2 had the highest tumor-to-muscle (T/M) ratio (12.37 ± 1.16) at 2 h in the four complexes. Autoradiography and immunohistochemical staining results revealed that [99mTc]Tc-Me2P2 specifically targeted tumor hypoxic regions. The SPECT/CT imaging results showed that [99mTc]Tc-Me2P2 could target the tumor site. [99mTc]Tc-Me2P2 may become a potential hypoxia imaging agent.

Molecular Design of Magnetic Resonance Imaging Agents Binding to Amyloid Deposits.

The ability to detect and monitor amyloid deposition in the brain using non-invasive imaging techniques provides valuable insights into the early diagnosis and progression of Alzheimer's disease and helps to evaluate the efficacy of potential treatments. Magnetic resonance imaging (MRI) is a widely available technique offering high-spatial-resolution imaging. It can be used to visualize amyloid deposits with the help of amyloid-binding diagnostic agents injected into the body. In recent years, a number of amyloid-targeted MRI probes have been developed, but none of them has entered clinical practice. We review the advances in the field and deduce the requirements for the molecular structure and properties of a diagnostic probe candidate. These requirements make up the base for the rational design of MRI-active small molecules targeting amyloid deposits. Particular attention is paid to the novel cryo-EM structures of the fibril aggregates and their complexes, with known binders offering the possibility to use computational structure-based design methods. With continued research and development, MRI probes may revolutionize the diagnosis and treatment of neurodegenerative diseases, ultimately improving the lives of millions of people worldwide.

Value of nuclide scintigraphy in the diagnosis and prognosis of cardiac amyloidosis. / æ ¸ç´ æ˜¾åƒåœ¨å¿ƒè„æ·€ç²‰æ ·å˜è¯Šæ–­åŠé¢„åŽè¯„ä¼°ä¸­çš„ä»·å€¼.

Amyloidosis is a local or systemic disease caused by the deposition of misfolded proteins outside the cell, with rapid progression, and dire prognosis. Common types of cardiac amyloidosis are monoclonal immunoglobulin light chain amyloidosis (AL-CA) and transthyretin cardiac amyloidosis (ATTR-CA). Nuclear medicine examinations can be accurate, rapid, and non-invasive to help diagnose diseases and can effectively predict the prognosis of patients with CA. Technetium (99Tcm)-labeled bisphosphonate imaging has been included in the consensus of experts and has become the first-line imaging method for the diagnosis of ATTR-CA. 123I-metaiodoenzylguanidine (MIBG) as a norepinephrine analogue can effectively assess cardiac sympathetic innervation in patients with CA. Aß- amyloid imaging agents such as 11C-pittsburgh compound B and 18F-flubetaben are expected to be new techniques for diagnosing AL-CA and incorporating them into cardiac staging systems for AL-CA patients in the future. New imaging agents such as 18F-NaF has been widely used in the diagnosis, treatment response monitoring, and prognosis assessment of CA. Summarizing the research value of nuclide imaging in CA may provide new ideas for clinical realization of early detection of CA and accurate assessment of disease prognosis.

Polymeric Dendrimers as Nanocarrier Vectors for Neurotheranostics.

Dendrimers are polymers with well-defined 3D branched structures that are vastly utilized in various neurotheranostics and biomedical applications, particularly as nanocarrier vectors. Imaging agents can be loaded into dendrimers to improve the accuracy of diagnostic imaging processes. Likewise, combining pharmaceutical agents and anticancer drugs with dendrimers can enhance their solubility, biocompatibility, and efficiency. Practically, by modifying ligands on the surface of dendrimers, effective therapeutic and diagnostic platforms can be constructed and implemented for targeted delivery. Dendrimer-based nanocarriers also show great potential in gene delivery. Since enzymes can degrade genetic materials during their blood circulation, dendrimers exhibit promising packaging and delivery alternatives, particularly for central nervous system (CNS) treatments. The DNA and RNA encapsulated in dendrimers represented by polyamidoamine that are used for targeted brain delivery, via chemical-structural adjustments and appropriate generation, significantly improve the correlation between transfection efficiency and cytotoxicity. This article reports a comprehensive review of dendrimers' structures, synthesis processes, and biological applications. Recent progress in diagnostic imaging processes and therapeutic applications for cancers and other CNS diseases are presented. Potential challenges and future directions in the development of dendrimers, which provide the theoretical basis for their broader applications in healthcare, are also discussed.

In vivo detection of hydrogen sulfide in the brain of live mouse: application in neuroinflammation models.

PURPOSE: Hydrogen sulfide (H2S) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain H2S in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous H2S in the brain of live mice. METHODS: Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for H2S. The same ATSM-FITC ligand was quantitatively labeled with [64Cu]CuCl2 to obtain a radioactive [64Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models. RESULTS: The Cu(ATSM-FITC) complex reacts instantly with H2S to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to H2S. Endogenous H2S levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [64Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain H2S concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased H2S levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging. CONCLUSION: Our biosensor can be readily utilized to study brain H2S function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.

The potential utility of [68 Ga]Ga-DOTA-FAPI-04 as a novel broad-spectrum oncological and non-oncological imaging agent-comparison with [18F]FDG.

PURPOSE: This study aimed to compare the detection performance of [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in the patients with various oncological and non-oncological lesions. METHODS: A total of 123 patients underwent contemporaneous [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT were included in this prospective study. The maximum standard uptake value (SUVmax) was measured to compare oncological and non-oncological lesion uptake. The sensitivity, specificity, predictive values, and accuracy of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT for detecting primary, metastatic, and non-oncological lesions were calculated and compared to evaluate the detection efficacy. RESULTS: The study subjects consisted of 123 patients (69 men and 54 women; mean age 56.11 ± 11.94 years). Among the 102 patients with either newly diagnosed (82 patients) or previously treated solid tumor (20 patients), a total of 88 solid primary malignant tumors in 84/102 patients were detected. Two patients had two primary tumors each and 1 patient had three primary tumors. Among them, 58/102 and 43/102 patients had nodal (376 lesions) and distant metastases (406 lesions), respectively. Eight patients had hematological neoplasm. No malignant oncological diseases were detected in the remaining 13 patients. A total of 145 non-oncological lesions and benign tumors in 52/123 patients were detected incidentally. [68 Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated a significantly higher uptake and detection rate for the primary (SUVmax 10.98 ± 5.83 vs. 8.36 ± 6.43, p < 0.001; sensitivity 97.67 vs. 84.89%; and accuracy 96.59 vs. 82.95%, X2 = 0.538, p = 0.021), nodal (SUVmax 10.50 ± 5.98 vs. 8.20 ± 6.29, p = 0.011; sensitivity 97.59 vs. 84.72%; and accuracy 97.34 vs. 84.31%, X2 = 2.067, p < 0.001), and distant metastatic lesions (SUVmax 9.64 ± 6.45 vs. 6.74 ± 4.83; p < 0.001; sensitivity 98.01 vs. 65.59%; and accuracy 97.04 vs. 65.51%, X2 = 4.897, p < 0.001) of solid tumor than did [18F]FDG PET/CT. [68 Ga]Ga-DOTA-FAPI-04 PET/CT demonstrated a lower activity (SUVmax: 6.84 ± 4.67 vs. 13.09 ± 7.29, p < 0.001) and detection rate (sensitivity 50.65 vs. 96.75%, and accuracy 51.28 vs. 95.51%, X2 = 5.166, p < 0.001) for multiple myeloma and lymphoma compared to [18F]FDG PET/CT. [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT PET/CT demonstrated a comparative activity (SUVmax 6.40 ± 3.95 vs. 5.74 ± 15.78, p = 0.729) and detection efficacy (sensitivity 86.52 vs. 72.34%, and accuracy 84.83 vs. 72.41%, X2 = 9.460, p = 0.007) for non-oncological lesion and benign tumor detection. CONCLUSIONS: Except for myeloma and lymphoma, [68 Ga]Ga-DOTA-FAPI-04 PET/CT showed a superior detection efficacy for detecting various primary and metastatic lesions than [18F]FDG PET/CT. A comparative detection utility for non-oncological lesion was obtained with both tracers. [68 Ga]Ga-DOTA-FAPI-04 could be used as a broad-spectrum tumor and inflammatory imaging agent in the clinical especially for various solid tumors and non-oncological lesions.

Intraoperative 5-ALA fluorescence-guided resection of high-grade glioma leads to greater extent of resection with better outcomes: a systematic review.

IMPORTANCE: High-grade gliomas (HGG) are the most aggressive and common malignant brain tumors in adults. They have a dismally fatal prognosis. Even if gross total resection of the enhancing tumor is achieved, inevitably, invading tumor cells that are indistinguishable to the un-aided eye are left behind, which eventually leads to tumor recurrence. 5-aminolevulinic acid (5-ALA) is an increasingly utilized intraoperative fluorescent imaging agent for patients with HGG. It enhances visualization of HGG tissue. Despite early promising randomized clinical trial data suggesting a survival benefit for 5-ALA-guided surgery, the growing body of literature must be analyzed to confirm efficacy on patient outcomes. OBJECTIVE: To perform a systematic review of the literature to evaluate whether there is a beneficial effect upon survival and extent of resection due to the utilization of 5-ALA in HGG surgery. EVIDENCE REVIEW: Literature regarding 5-ALA usage in HGG surgery was reviewed according to the PRISMA guidelines. Two databases, PubMed and SCOPUS, were searched for assorted combinations of the keywords "5-ALA," "high-grade glioma," "5-aminolevulinic acid," and "resection" in July 2020 for case reports and retrospective, prospective, and randomized clinical trials assessing and analyzing 5-ALA intraoperative use in patients with HGG. Entailed studies on PubMed and SCOPUS were found for screening using a snowball search technique upon the initially searched papers. Systematic reviews and meta-analyses were excluded from our PRISMA table. FINDINGS: 3756 previously published studies were screened, 536 of which were further evaluated, and ultimately 45 were included in our systematic review. There were no date restrictions on the screened publications. Our literature search was finalized on July 16, 2020. We found an observed increase in the overall survival (OS) and progression-free survival (PFS) of the 5-ALA group compared to the white light group, as well as an observed increase in the OS and PFS of complete resections compared to incomplete resections. Of the studies that directly compared the use of 5-ALA to white light (13 of the total analyzed 45, or 28.9%), 5-ALA lead to a better PFS and OS in 88.4 and 67.5% of patients, respectively. When the studies that reported postoperative neurologic outcomes of surgeries using 5-ALA vs. white light were analyzed, 42.2% of subjects demonstrated 5-ALA use was associated with less post-op neurological deficits, whereas 34.5% demonstrated no difference between 5-ALA and without. 23.3% of studies showed that intraoperative 5-ALA guided surgeries lead to more post-op neurological deficits. CONCLUSIONS AND RELEVANCE: Utilization of 5-ALA was found to be associated with a greater extent of resection in HGG surgeries, as well as longer OS and PFS. Postop neurologic deficit rates were mixed and inconclusive when comparing 5-ALA groups to white light groups. 5-ALA is a useful surgical adjunct for resection of HGG when patient safety is preserved.

Novel Drug and Gene Delivery System and Imaging Agent Based on Marine Diatom Biosilica Nanoparticles.

Mesoporous silica nanoparticles (MSNs) have great potential for applications as a drug delivery system (DDS) due to their unique properties such as large pore size, high surface area, biocompatibility, biodegradability, and stable aqueous dispersion. The MSN-mediated DDS can carry chemotherapeutic agents, optical sensors, photothermal agents, short interfering RNA (siRNA), and gene therapeutic agents. The MSN-assisted imaging techniques are applicable in cancer diagnosis. However, their synthesis via a chemical route requires toxic chemicals and is challenging, time-consuming, and energy-intensive, making the process expensive and non-viable. Fortunately, nature has provided a viable alternative material in the form of biosilica from marine resources. In this review, the applications of biosilica nanoparticles synthesized from marine diatoms in the field of drug delivery, biosensing, imaging agents, and regenerative medicine, are highlighted. Insights into the use of biosilica in the field of DDSs are elaborated, with a focus on different strategies to improve the physico-chemical properties with regards to drug loading and release efficiency, targeted delivery, and site-specific binding capacity by surface functionalization. The limitations, as well as the future scope to develop them as potential drug delivery vehicles and imaging agents, in the overall therapeutic management, are discussed.

A practical approach to the optimization of positron emission tomography imaging agents for the central nervous system.

The discovery of novel imaging agents for positron emission tomography (PET) relies on medicinal chemistry best practices, including a good understanding of molecular and pharmacological properties required for the acquisition of relevant, high-quality images. This short note reviews the characteristics of a series of clinically successful imaging agents, providing guidance for the optimization of such molecular tools. PET imaging plays an important role in staging disease and in helping clinical dose selection, which is critical for the efficient development of drug candidates.

Side-Chain-Tuned Molecular Packing Allows Concurrently Boosted Photoacoustic Imaging and NIR-II Fluorescence.

It is generally considered that photoacoustic imaging (PAI) and fluorescence imaging (FLI) cannot be enhanced concurrently, as they are dependent on competitive photophysical processes at the single-molecule level. Herein, we reveal that BDTR9-OC8 and BDTR9-C8, which have identical π-conjugated backbones but are substituted by side chains of different rigidity, show distinct phototheranostic properties in the aggregated state. The NIR-II FLI and PAI brightness of BDTR9-C8 nanoparticles are enhanced by 4.6 and 1.4 times compared with BDTR9-OC8 nanoparticles. Theoretical calculations and GIWAXS analysis revealed that BDTR9-C8 with rigid side chains shows a relative amorphous condensed state, which will benefit the efficient transportation of photo-generated excitons and phonons, subsequently enhancing the FLI and PAI signals. Besides, both nanoparticles exhibit excellent photothermal conversion efficiency due to their strong light-harvesting capability and are considered effective photothermal therapy materials. This work provides an illuminating strategy for material design in the future.

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance.

Cardiovascular diseases account for more than 30% of all deaths worldwide and many could be ameliorated with early diagnosis. Current cardiac imaging modalities can assess blood flow, heart anatomy and mechanical function. However, for early diagnosis and improved treatment, further functional biomarkers are needed. One such functional biomarker could be the myocardium pH. Although tissue pH is already determinable via MR techniques, and has been since the early 1990s, it remains elusive to use practically. The objective of this study was to explore the possibility to evaluate cardiac pH noninvasively, using in-cell enzymatic rates of hyperpolarized [1-13 C]pyruvate metabolism (ie, moles of product produced per unit time) determined directly in real time using magnetic resonance spectroscopy in a perfused mouse heart model. As a gold standard for tissue pH we used 31 P spectroscopy and the chemical shift of the inorganic phosphate (Pi) signal. The nonhomogenous pH distribution of the perfused heart was analyzed using a multi-parametric analysis of this signal, thus taking into account the heterogeneous nature of this characteristic. As opposed to the signal ratio of hyperpolarized [13 C]bicarbonate to [13 CO2 ], which has shown correlation to pH in other studies, we investigated here the ratio of two intracellular enzymatic rates: lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), by way of determining the production rates of [1-13 C]lactate and [13 C]bicarbonate, respectively. The enzyme activities determined here are intracellular, while the pH determined using the Pi signal may contain an extracellular component, which could not be ruled out. Nevertheless, we report a strong correlation between the tissue pH and the LDH/PDH activities ratio. This work may pave the way for using the LDH/PDH activities ratio as an indicator of cardiac intracellular pH in vivo, in an MRI examination.

Systematic imaging in medicine: a comprehensive review.

Systematic imaging can be broadly defined as the systematic identification and characterization of biological processes at multiple scales and levels. In contrast to "classical" diagnostic imaging, systematic imaging emphasizes on detecting the overall abnormalities including molecular, functional, and structural alterations occurring during disease course in a systematic manner, rather than just one aspect in a partial manner. Concomitant efforts including improvement of imaging instruments, development of novel imaging agents, and advancement of artificial intelligence are warranted for achievement of systematic imaging. It is undeniable that scientists and radiologists will play a predominant role in directing this burgeoning field. This article introduces several recent developments in imaging modalities and nanoparticles-based imaging agents, and discusses how systematic imaging can be achieved. In the near future, systematic imaging which combines multiple imaging modalities with multimodal imaging agents will pave a new avenue for comprehensive characterization of diseases, successful achievement of image-guided therapy, precise evaluation of therapeutic effects, and rapid development of novel pharmaceuticals, with the final goal of improving human health-related outcomes.

Synthesis and preliminary evaluation of a PET-FI bimodal imaging agent targeting estrogen receptor.

Estrogen receptor is an attractive target for the diagnosis and treatment of breast cancer. This article reports for the first time a dual-modality imaging agent targeting estrogen receptor that can use PET imaging to diagnose breast cancer and utilize fluorescence imaging to achieve intraoperative navigation. Fluorescence experiments show that [natGa] 1 has typical aggregate induced emission characteristics. Above the critical concentration, [natGa] 1 can form biocompatible nanomicelles. [natGa] 1 can quickly light up estrogen receptor positive MCF-7 cells. Cell uptake experiments show that [68Ga] 1 is mediated by estrogen receptor. Therefore, [nat/68Ga] 1 shows the characteristics of highly sensitive diagnosis and visualization of breast cancer, and can be used as a lead compound for the development of a novel PET-FI bimodal imaging agent targeting the estrogen receptor.

Explorations into the Effect of meso-Substituents in Tricarbocyanine Dyes: A Path to Diverse Biomolecular Probes and Materials.

Polymethine cyanine dyes have been widely recognized as promising chemical tools for a range of life science and biomedical applications, such as fluorescent staining of DNA and proteins in gel electrophoresis, fluorescence guided surgery, or as ratiometric probes for probing biochemical pathways. The photophysical properties of such dyes can be tuned through the synthetic modification of the conjugated backbone, for example, by altering aromatic cores or by varying the length of the conjugated polymethine chain. Alternative routes to shaping the absorption, emission, and photostability of dyes of this family are centered around the chemical modifications on the polymethine chain. This Minireview aims to discuss strategies for the introduction of substituents in the meso-position, their effect on the photophysical properties of these dyes and some structure-activity correlations which could help overcome common limitations in the state of the art in the synthesis.

A New [68Ga]Ga-HBED-CC-Bisphosphonate as a Bone Imaging Agent.

Positron emission tomography (PET) imaging using 68Ga-labeled bisphosphonates to target bone metastasis could be a valuable tool in cancer diagnosis and monitoring therapeutic treatment. A 68Ga labeled ligand, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) containing one bisphosphonate group (HBED-CC-BP, 1) was prepared and evaluated. The new ligand, 1, reacted rapidly to form [68Ga]Ga-1, via complexing with [68Ga]GaCl3 eluted from a commercially available 68Ge/68Ga generator (in a sodium acetate buffer at pH 4, reaching >95% labeling yield at room temperature in 5 min). The resulting [68Ga]Ga-1 showed excellent stability in vitro and in vivo. [68Ga]Ga-1 displayed high binding affinity to hydroxyapatite and good uptake in the tibia and femur bone of normal mice. Biodistribution and MicroPET imaging studies of [68Ga]Ga-1 in normal mice and rats showed excellent bone uptake and retention comparable to that of Na[18F]F. The results suggested that [68Ga]Ga-1 might be suitable as a bone imaging agent in humans and it could be useful as a convenient alternative to the current bone imaging PET agent, Na[18F]F, without the need of a near-by cyclotron. Also, an automated synthesis module was developed to produce clinical doses of [68Ga]Ga-1 in a consistent and reproducible manner. Currently, the investigation new drug application (IND) for [68Ga]Ga-HBED-CC-BP, [68Ga]Ga-1, has received FDA approval, and it is currently under clinical trial (IND #129870).

Synthesis and bioevaluation of radioiodinated nitroimidazole hypoxia imaging agents by one-pot click reaction.

Eight radioiodinated 2-nitroimidazole derivatives for use as hypoxia imaging agents were synthesized by one-pot click reaction using four azides, two alkynes, and [131I]iodide ions and evaluated by hypoxic cellular uptake and biodistribution experiments. The results suggested that radiotracers with suitable partition coefficients (log P: -0.2-1.2) were more likely to have higher hypoxic cellular uptake. Among these eight molecules, [131I]15 ([131I]-(5-iodo-1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl)-4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazole)) had a suitable log P (0.05 ± 0.03) and contained two 2-nitroimidazole groups. The hypoxic/aerobic cellular uptake ratio of [131I]15 was 4.4 ± 0.5, and the tumor/blood (T/B) and tumor/muscle (T/M) ratios were 2.03 ± 0.45 and 6.82 ± 1.70, respectively. These results suggested that [131I]15 was a potential hypoxia imaging agent.

Radiosynthesis and biological evaluation of an fluorine-18 labeled galactose derivative [18F]FPGal for imaging the hepatic asialoglycoprotein receptor.

The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the surface of hepatocytes where it recognizes and endocytoses glycoproteins with galactosyl and N-acetylgalactosamine groups. Given its hepatic distribution, the asialoglycoprotein receptor can be targeted by positron imaging agents to study liver function using PET imaging. In this study, the positron imaging agent [18F]FPGal was designed to specifically target hepatic asialoglycoprotein receptor and its effectiveness was assessed in in vitro and in vivo models. The radiosynthesis of [18F]FPGal required 50 min with total radiochemical yields of [18F]FPGal from [18F]fluoride as 10% (corrected radiochemical yield). The Kd of [18F]FPGal to ASGPR in HepG2 cells was 1.99 ± 0.05 mM. Uptake values of 0.55% were observed within 30 min of incubation with HepG2 cells, which could be blocked by 200 mM d(+)-galactose (<0.1%). In vivo biodistribution analysis showed that the liver accumulation of [18F]FPGal at 30 min was 4.47 ± 0.96% ID/g in normal mice compared to 1.33 ± 0.07% ID/g in hepatic fibrotic mice (P < 0.01). Reduced uptake in the hepatic fibrosis mouse models was confirmed through PET/CT images at 30 min. Compared to normal mice, the standard uptake value (SUV) in the hepatic fibrosis mice was significantly lower when assessed through dynamic data collection for 1 h. Therefore, [18F]FPGal is a feasible PET probe that provide insight into ASGPR related liver disease.

Synthesis and evaluation of 2-(2'-((dimethylamino)methyl)-4'-(2-fluoroethoxy-substituted)phenylthio)benzenamine derivatives as potential positron emission tomography imaging agents for serotonin transporters.

A series of diphenylsulfide derivatives with various substitutions at the 4-position on phenyl ring A and different lengths of the 2-fluoroethoxy-substituted side-chain at the 4'-position on ring B were synthesized and evaluated as potential positron emission tomography (PET) imaging agents for serotonin transporters (SERT). These ligands exhibited high SERT binding affinities (Ki = 0.11-1.3 nM) and the 4-methyl-substituted (4-Me) compounds 7a and 8a displayed excellent selectivity for SERT versus norepinephrine transporters (NET) (392- and 700-fold, respectively). In the parallel artificial membrane permeability assay (PAMPA), these ligands demonstrated moderate to high brain penetration, and the 4-Me analogs showed higher BBB permeability than the corresponding 4-F analogs. The 2-fluoroethoxy-substituted ligands showed higher metabolic stability and lower lipophilicity than 4-F-ADAM. [18F]7a-c were readily prepared using an automatic synthesizer and exhibited significant uptake and slow washout in rat brains. At 120 min after iv injection, [18F]7a exhibited the highest uptake in the midbrain, whereas [18F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [18F]7a in the hypothalamus and striatum was significantly decreased. The potent and highly selective SERT binding and the selective and reversible accumulation in SERT-rich brain regions suggested that [18F]7a is a promising lead for the further development of novel [18F]-labeled PET imaging agents for SERT binding sites in the brain.