Radiotracers For Imaging Research Articles

Recent Advances in Cancer Imaging with 64CuCl2 PET/CT.

Copper is required for cancer cell proliferation and tumor angiogenesis. Radioactive copper-64 chloride (64CuCl2) is a useful radiotracer for cancer imaging with position emission tomography (PET) based on increased cellular uptake of copper mediated by human copper transporter 1 (hCtr1) expressed on cancer cell membrane. Significant progress has been made in research of using 64CuCl2 as a radiotracer for cancer imaging with PET. Radiation dosimetry study in humans demonstrated radiation safety of 64CuCl2. Recently, 64CuCl2 was successfully used for PET imaging of prostate cancer, bladder cancer, glioblastoma multiforme (GBM), and non-small cell lung carcinoma in humans. Based on the findings from the preclinical research studies, 64CuCl2 PET/CT also holds potential for diagnostic imaging of human hepatocellular carcinoma (HCC), malignant melanoma, and detection of intracranial metastasis of copper-avid tumors based on low physiological background of radioactive copper uptake in the brain. Copper-64 radionuclide emits both β+ and β- particles, suggesting therapeutic potential of 64CuCl2 for radionuclide cancer therapy of copper-avid tumors. Recent progress in production of therapeutic copper-67 radionuclide invites clinical research in use of theranostic pair of 64CuCl2 and 67CuCl2 for cancer imaging and radionuclide therapy.

Technetium-99m Radiopharmaceuticals for Ideal Myocardial Perfusion Imaging: Lost and Found Opportunities.

The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [99mTc]Tc-Sestamibi, [99mTc]Tc-Tetrofosmin, and [99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals for myocardial perfusion imaging in nuclear cardiology. Despite its peculiar properties, the clinical use of [99mTc]Tc-Teboroxime was quickly abandoned due to its rapid myocardial washout. Despite their widespread clinical applications, both [99mTc]Tc-Sestamibi and [99mTc]Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent due to their relatively low first-pass extraction fraction and high liver absorption. An ideal radiotracer for myocardial perfusion imaging should have a high myocardial uptake; a high and stable target-to-background ratio with low uptake in the lungs, liver, stomach during the image acquisition period; a high first-pass myocardial extraction fraction and very rapid blood clearance; and a linear relationship between radiotracer myocardial uptake and coronary blood flow. Although it is difficult to reconcile all these properties in a single tracer, scientific research in the field has always channeled its efforts in the development of molecules that are able to meet the characteristics of ideality as much as possible. This short review summarizes the developments in 99mTc myocardial perfusion tracers, which are able to fulfill hitherto unmet medical needs and serve a large population of patients with heart disease, and underlines their strengths and weaknesses, the lost and found opportunities thanks to the developments of the new ultrafast SPECT technologies.

Galectin expression detected by 68Ga-galectracer PET as a predictive biomarker of radiotherapy resistance

Hypoxia is a hallmark of solid tumors that is related to radiotherapy resistance. As galectin members, such as galectin-1 and galectin-3, are associated with tumor hypoxia, herein we aimed to investigate whether positron emission tomography (PET) imaging of galectin expression can be employed to effectively pinpoint tumor hypoxia, and to predict radiotherapy resistance. We synthesized a galectin-targeting radiotracer, designated 68Ga-galectracer, by radiolabeling a thiodigalactoside derivative. The properties of 68Ga-galectracer for PET imaging of tumor hypoxia were characterized in three tumor hypoxia mouse models. Additionally, preliminary PET/CT was performed in two patients with lung cancer to investigate the potential application of 68Ga-galectracer for clinical imaging. High-contrast imaging was achieved in the murine acute hypoxia tumor model, A549 natural hypoxia model, and sorafenib treatment-induced hypoxic 4T1 tumor model by PET using 68Ga-galectracer. In fact, 68Ga-galectracer exhibited superior hypoxia detection to that of 18F-misonidazole in the 4T1 tumors. Moreover, tumors with high galectin expression levels, as detected by 68Ga-galectracer PET, exhibited significantly lower responses to subsequent radiotherapy compared to those with low galectin expression levels. In patients with lung cancer, PET imaging using 68Ga-galectracer provided data that were complementary to that of the glucose metabolic PET radiotracer 18F-fluorodeoxyglucose. 68Ga-galectracer is a promising radiotracer for PET-based imaging of tumor hypoxia in vivo. Thus, hypoxia PET with 68Ga-galectracer could provide a noninvasive approach to proactively predict radiotherapy efficacy. Chictr.org.cn (ChiCTR2000029522). Registered 03 February 2020.

Characterization in nonhuman primates of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 for imaging the GluN2B subunits of the NMDA receptor

PurposeGluN2B containing N-methyl-D-aspartate receptors (NMDARs) play an essential role in neurotransmission and are a potential treatment target for multiple neurological and neurodegenerative diseases, including stroke, Alzheimer’s disease, and Parkinson’s disease. (R)-[18F]OF-Me-NB1 was reported to be more specific and selective than (S)-[18F]OF-Me-NB1 for the GluN2B subunits of the NMDAR based on their binding affinity to GluN2B and sigma-1 receptors. Here we report a comprehensive evaluation of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF–Me-NB1 in nonhuman primates.MethodsThe radiosynthesis of (R)-[18F]OF-Me-NB1 and (S)-[18F]OF-Me-NB1 started from 18F-fluorination of the boronic ester precursor, followed by removal of the acetyl protecting group. PET scans in two rhesus monkeys were conducted on the Focus 220 scanner. Blocking studies were performed after treatment of the animals with the GluN2B antagonist Co101,244 or the sigma-1 receptor antagonist FTC-146. One-tissue compartment (1TC) model and multilinear analysis-1 (MA1) method with arterial input function were used to obtain the regional volume of distribution (VT, mL/cm3). Occupancy values by the two blockers were obtained by the Lassen plot. Regional non-displaceable binding potential (BPND) was calculated from the corresponding baseline VT and the VND derived from the occupancy plot of the Co101,244 blocking scans.Results(R)- and (S)-[18F]OF-Me-NB1 were produced in > 99% radiochemical and enantiomeric purity, with molar activity of 224.22 ± 161.69 MBq/nmol at the end of synthesis (n = 10). Metabolism was moderate, with ~ 30% parent compound remaining for (R)-[18F]OF-Me-NB1 and 20% for (S)-[18F]OF-Me-NB1 at 30 min postinjection. Plasma free fraction was 1–2%. In brain regions, both (R)- and (S)-[18F]OF-Me-NB1 displayed fast uptake with slower clearance for the (R)- than (S)-enantiomer. For (R)-[18F]OF-Me-NB1, both the 1TC model and MA1 method gave reliable estimates of regional VT values, with MA1 VT (mL/cm3) values ranging from 8.9 in the cerebellum to 12.8 in the cingulate cortex. Blocking with 0.25 mg/kg of Co101,244 greatly reduced the uptake of (R)-[18F]OF-Me-NB1 across all brain regions, resulting in occupancy of 77% and VND of 6.36, while 0.027 mg/kg of FTC-146 reduced specific binding by 30%. Regional BPND, as a measure of specific binding signals, ranged from 0.40 in the cerebellum to 1.01 in the cingulate cortex.ConclusionsIn rhesus monkeys, (R)-[18F]OF-Me-NB1 exhibited fast kinetics and heterogeneous uptake across brain regions, while the (S)-enantiomer displayed a narrower dynamic range of uptake across regions. A Blocking study with a GluN2B antagonist indicated binding specificity. The value of BPND was > 0.5 in most brain regions, suggesting good in vivo specific binding signals. Taken together, results from the current study demonstrated the potential of (R)-[18F]OF-Me-NB1 as a useful radiotracer for imaging the GluN2B receptors.

A Convenient Route to New (Radio)Fluorinated and (Radio)Iodinated Cyclic Tyrosine Analogs.

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [123I]IMT, [18F]FET, [18F]FDOPA, [123I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [123I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [123I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [125I]5-iodo-L-TIC(OH), [125I]6-iodo-L-TIC(OH) and [125I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51–78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5–2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [18F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [18F]F− with 19–28% RCY d.c., high RCP (>98.9%), Am (20–107 GBq/µmol) and e.e. (>99%).

Radioiodination of balsalazide, bioevaluation, and characterization as a highly selective radiotracer for imaging of ulcerative colitis in mice.

This work focuses on tracking ulcerative colitis in mice. High labeling yield and radiochemical purity were achieved for the formation of a [125/131 I]balsalazide radiotracer at optimum conditions of oxidizing agent content (chloramines-T [Ch-T], 75 μg), substrate amount (100 μg), pH of reaction mixture (6), reaction time (30 min), and temperature (37°C), using radioactive iodine-125 (200-450 MBq). The radiolabeled compound, [125/131 I]balsalazide, was stable in serum and saline solution during 24 h. Balsalazide is acting as a peroxisome proliferator-activated receptor (PPARγ). Biodistribution studies were carried in normal and ulcerated colon mice. High uptake of 75 ± 1.90% injected dose/g organ (ID/g) observed in ulcerated mice confirmed the suitability of [131 I]balsalazide as a novel radiotracer for ulcerative colitis imaging in mice.

Preclinical and exploratory human studies of novel 68Ga-labeled D-peptide antagonist for PET imaging of TIGIT expression in cancers.

PurposeWhile TIGIT has been propelled as a next-generation target in cancer immunotherapy, anti-TIGIT therapy seems to be promising for a fraction of patients in clinical trials. Therefore, patient stratification is critical for this therapy, which could benefit from a whole-body, non-invasive, and quantitative evaluation of TIGIT expression in cancers. In this study, a 68Ga-labeled D-peptide antagonist, 68Ga-GP12, was developed and validated for PET imaging of TIGIT expression in vitro, in vivo, and in an exploratory human study.MethodsThe D-enantiomer peptide antagonists were modified and radiolabeled with 68Ga. In vitro binding assays were performed in human peripheral blood mononuclear cells (PBMCs) to assess their affinity and specificity. The imaging capacity, biodistribution, pharmacokinetics, and radiation dosimetry were investigated. Flow cytometry, autoradiography, and immunohistochemical staining were used to confirm the expression of TIGIT. The safety and potential of 68Ga-GP12 for PET/CT imaging of TIGIT expression were evaluated in NSCLC patients.Results68Ga-labeled D-peptides were conveniently produced with high radiochemical yields, radiochemical purities and molar activities. In vitro binding assays demonstrated 68Ga-GP12 has high affinity and specificity for TIGIT with a KD of 37.28 nM. In vivo and ex vivo studies demonstrated the capacity of 68Ga-GP12 for PET imaging of TIGIT expression with high tumor uptake of 4.22 ± 0.68 %ID/g and the tumor-to-muscle ratio of 12.94 ± 2.64 at 60 min post-injection. In NSCLC patients, primary and metastatic lesions found in 68Ga-GP12 PET images were comparable to that in 18F-FDG PET images. Moreover, tracer uptake in primary and metastatic lesions and intra-tumoral distribution in the large tumor were inhomogenous, indicating the heterogeneity of TIGIT expression.Conclusion68Ga-GP12 is a promising radiotracer for PET imaging of TIGIT expression in cancers, indicating its potential as a potential companion diagnostic for anti-TIGIT therapies.Graphical abstract Supplementary InformationThe online version contains supplementary material available at 10.1007/s00259-021-05672-x.

Preclinical evaluation of [99mTc]Tc-labeled anti-EpCAM nanobody for EpCAM receptor expression imaging by immuno-SPECT/CT.

Overexpression of epithelial cell adhesion molecule (EpCAM) plays essential roles in tumorigenesis and tumor progression in almost all epithelium-derived cancer. Monitoring EpCAM expression in tumors can be used for the diagnosis, staging, and prognosis of cancer patients, as well as guiding the individualized treatment of EpCAM-targeted drugs. In this study, we described the synthesis and evaluation of a site-specifically [99mTc]Tc-labeled EpCAM-targeted nanobody for the SPECT/CT imaging of EpCAM expression. We first prepared the [99mTc]Tc-HYNIC-G4K; then, it was site-specifically connected to EpCAM-targeted nanobody NB4. The in vitro characteristics of [99mTc]Tc-NB4 were investigated in HT-29 (EpCAM positive) and HL-60 (EpCAM negative) cells, while the in vivo studies were performed using small-animal SPECT/CT in the subcutaneous tumor models and the lymph node metastasis model to verify the specific targeting capacity as well as the potential applications of [99mTc]Tc-NB4. [99mTc]Tc-NB4 displayed a high EpCAM specificity both in vitro and in vivo. SPECT/CT imaging revealed that [99mTc]Tc-NB4 was cleared rapidly from the blood and normal organs except for the kidneys, and HT-29 tumors were clearly visualized in contrast with HL-60 tumors. The uptake value of [99mTc]Tc-NB4 in HT-29 tumors was increased continuously from 3.77 ± 0.39%ID/g at 0.5h to 5.53 ± 0.82%ID/g at 12h after injection. Moreover, the [99mTc]Tc-NB4 SPECT/CT could clearly image tumor-draining lymph nodes. [99mTc]Tc-NB4 is a broad-spectrum, specific, and sensitive SPECT radiotracer for the noninvasive imaging of EpCAM expression in the epithelium-derived cancer and revealed a great potential for the clinical translation.

Recent Updates on PET Imaging in Neurodegenerative Diseases

양전자방출단층촬영(PET)을 이용한 단백질병리의 생체영상기술은 퇴행성 치매의 질병 기전을 이해하는데 필요한 정보를 제공할 뿐 아니라, 질병의 조기 발견과 치료법 개발에서 중요한 역할을 수행하고 있다. 베타아밀로이드와 타우 PET 영상은 인체 뇌병리에 기반한 알츠하이머병 연속체에 대한 진단 바이오마커로 확립되어 조기진단과 감별진단을 용이하게 하고, 질병 예후를 예측하고 있다. 또한, 치매치료제 개발에서 예후 및 대리 바이오마커로의 역할이 커지고 있다. 이 종설에서는 치매를 유발하는 알츠하이머병 및 기타 퇴행성 뇌질환에서 베타아밀로이드와 타우 단백질의 뇌축적을 영상화하는 PET의 최근 임상적 적용과 최근 동향을 살펴보고, 잠재적 유용성을 소개하고자 한다.

A prodrug strategy for the in vivo imaging of aldehyde dehydrogenase activity.

Therapy resistance is one of the biggest challenges facing clinical oncology. Despite a revolution in new anti-cancer drugs targeting multiple components of the tumour microenvironment, acquired or innate resistance frequently blunts the efficacy of these treatments. Non-invasive identification of drug-resistant tumours will enable modification of the patient treatment pathway through the selection of appropriate second-line treatments. Here, we have designed a prodrug radiotracer for the non-invasive imaging of aldehyde dehydrogenase 1A1 (ALDH1A1) activity. Elevated ALDH1A1 activity is a marker of drug-resistant cancer cells, modelled here with matched cisplatin-sensitive and -resistant human SKOV3 ovarian cancer cells. The aromatic aldehyde of our prodrug radiotracer was intracellularly liberated by esterase cleavage of the geminal diacetate and specifically trapped by ALDH through its conversion to the charged carboxylic acid. Through this mechanism of action, ALDH-specific retention of our prodrug radiotracer in the drug-resistant tumour cells was twice as high as the drug-sensitive cells. Acylal masking of the aldehyde afforded a modest protection from oxidation in the blood, which was substantially improved in carrier-added experiments. In vivo positron emission tomography imaging of tumour-bearing mice produced high tumour-to-background images and radiotracer uptake in high ALDH-expressing organs but was unable to differentiate between drug-sensitive and drug-resistant tumours. Alternative strategies to protect the labile aldehyde are currently under investigation.

HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking.

Rationale: The decreased HER2-accessibility by epitope masking is a primary trastuzumab-resistance mechanism. In this study, we developed a HER2-targeted dual radiotracer approach to predict the HER2-trastuzumab engagement noninvasively.Methods: Two novel HER2-specific VHHs, MIRC208 and MIRC213, were acquired by immunizing alpaca with human HER2 protein, and were site-specifically labeled with 99mTc. Biodistribution and SPECT/CT imaging studies were performed in mice bearing HER2-positive and HER2-negative tumors. The HER2 binding sites of 99mTc-MIRC208 and 99mTc-MIRC213 were investigated by cell binding and SPECT/CT imaging studies. We evaluated the therapeutic predictive ability of our dual-radiotracer imaging approach for trastuzumab treatment in mice bearing MUC4-positive tumors (trastuzumab-resistant JIMT-1 and 87MUC4) and MUC4-negative tumors (trastuzumab-sensitive 7HER2 and NCI-N87). The preliminary clinical studies of 99mTc-MIRC208 were performed in two patients with HER2-positive breast tumors.Results: 99mTc-MIRC208 and 99mTc-MIRC213 clearly visualized HER2-positive tumors, but not HER2-negative tumors. 99mTc-MIRC208 competes with trastuzumab for HER2-binding while 99mTc-MIRC213 recognizes HER2 on an epitope that is not masked by MUC4. The SPECT/CT studies with 99mTc-MIRC208 and 99mTc-MIRC213 clearly showed that the MUC4-negative and trastuzumab-sensitive 7HER2 and NCI-N87 tumors had very similar tumor uptake with the SUV208/SUV213 (2 h) ratios of 1.11 ± 0.17 in 7HER2 and 1.25 ± 0.22 in NCI-N87. However, the MUC4-positive JIMT-1 tumors showed the decreased SUV208/SUV213 (2 h) ratio (0.63 ± 0.07), which correlated well with the low response rate to trastuzumab therapy. The SUV208/SUV213 (2 h) ratio was reduced to 0.72 ± 0.02 in MUC4-expressing NCI-N87 cells, and resulting in the decreased trastuzumab sensitivity, further supporting the correlation between the SUV208/SUV213 (2 h) ratio and trastuzumab-sensitivity. The primary and metastatic HER2-positive lesions of patients were clearly visualized by 99mTc-MIRC208 SPECT at 2 h post injection.Conclusion: Overall, we demonstrated that the dual radiotracer imaging strategy is a valid noninvasive approach for the cancer patient selection before trastuzumab therapy. 99mTc-MIRC213 SPECT is utilized to quantify the tumor HER2 expression and screen HER2-positive cancer patients, while 99mTc-MIRC208 SPECT is used to determine the HER2-accessibility of trastuzumab. The SUV208/SUV213 (2 h) ratio is an important biomarker to determine the responsiveness of trastuzumab therapy.

Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics.

Rationale: Fibroblast activation protein (FAP) targeted molecular imaging radiotracers have shown promising preclinical and clinical results in tumor diagnosis. However, rapid clearance and inadequate tumor retention of these molecules have hindered them for further clinical translation in cancer therapy. In this study, we aimed to develop a series of albumin binder-truncated Evans blue (EB) modified FAP targeted radiotracers, and optimize the pharmacokinetic (PK) characteristics to overcome the existing limitations in order to apply in the radionuclide therapy of cancer.Methods: A series of compounds with the general structure of EB-FAPI-Bn were synthesized based on a FAP inhibitor (FAPI) variant (FAPI-02) and radiolabeled with 177LuCl3. To verify the binding affinity and FAP targeting specificity of these tracers in vitro, U87MG cell uptake and competition assays were performed. Preclinical PK was evaluated in U87MG tumor-bearing mice using SPECT imaging and biodistribution studies. The lead compound EB-FAPI-B1 was selected and cancer therapeutic efficacy of 177Lu-EB-FAPI-B1 was assessed in U87MG tumor-bearing mice.Results: 177Lu-EB-FAPI-B1, B2, B3, B4 were stable in PBS (pH 7.4) and saline for at least 24 h. EB-FAPI-B1 showed high binding affinity (IC50 = 16.5 nM) to FAP in vitro, which was comparable with that of FAPI-02 (IC50 = 10.9 nM). SPECT imaging and biodistribution studies of 177Lu-EB-FAPI-B1, B2, B3, B4 have proved their prominently improved tumor accumulation and retention at 96 h post-injection, especially for 177Lu-EB-FAPI-B1, high tumor uptake and low background signal make it the optimal compound. Compared to the saline group, noteworthy tumor growth inhibitions of 177Lu-EB-FAPI-B1 have been observed after administration of different dosages.Conclusion: In this study, several EB modified FAPI-02 related radiopharmaceuticals have been synthesized successfully and evaluated. High binding affinity and FAP targeting specificity were identified in vitro and in vivo. Remarkably enhanced tumor uptake and retention of EB-FAPI-B1 were found over the unmodified FAPI-02. 177Lu-EB-FAPI-B1 showed remarkable tumor growth suppression in U87MG tumor model with negligible side effects, indicating that 177Lu-EB-FAPI-B1 is promising for clinical application and transformation.

The development of [18F]ACI‐12589, a high affinity and selective alpha‐synuclein radiotracer, as a biomarker for Parkinson’s disease and other synucleinopathies

AbstractBackgroundParkinson’s disease (PD) and other alpha‐synucleinopathies are characterized by the progressive accumulation of alpha‐synuclein (a‐syn) inclusions in the brain, which start in the pre‐motor stage of the disease and correlates with its severity. An imaging agent for a‐syn could allow differential diagnosis and support interventional trails. AC Immune has developed and is currently testing in a first in human (FiH) clinical trial the recently discovered compound, ACI‐12589, as a PET tracer with high affinity and selectivity for a‐syn.MethodScreening of our conformation‐specific, small‐molecular weight MorphomerTM library was followed by an iterative medicinal chemistry optimization program. The primary screening strategy included the development and use of a proprietary binding assay, that importantly involved aggregates derived from PD brain samples. Autoradiography experiments performed with human tissue samples from different alpha‐synucleinopathies provided target engagement and signal specificity data. Autoradiography techniques were also employed to assess selectivity, using tissue samples from Alzheimer’s disease or Frontotemporal lobar degeneration‐TDP donors. Selected compounds were 18F radiolabeled and evaluated for their pharmacokinetics in non‐human primates (NHPs) before proceeding to clinical studies.ResultRecent optimization efforts have led to the identification of several new, highly promising chemical scaffolds. From these, the compound ACI‐12589, has emerged with highly favorable characteristics including low nanomolar affinity and excellent target occupancy in saturation binding experiments using PD brain homogenates. Using high‐resolution autoradiography, ACI‐12589 illustrates target engagement across multiple alpha‐synucleinopathies including PD, Multiple System Atrophy, and Dementia with Lewy Bodies. In classical autoradiography experiments, ACI‐12589 demonstrates significantly higher specific signal in diseased versus non‐diseased tissue samples. Furthermore, ACI‐12589 has at least 30‐fold selectivity versus Abeta and shows no binding to Tau nor TDP‐43 aggregates. Studying [18F]ACI‐12589 in NHPs reveals rapid brain uptake and quick wash out. ACI‐12589 was considered safe in the IND‐enabling toxicology study allowing advancement into the FiH clinical study.ConclusionBased on experience with other tracers, [18F]ACI‐12589 meets the target product profile deemed necessary of a highly favorable candidate to succeed as a radiotracer for imaging a‐syn inclusions. As such, [18F]ACI‐12589 has advanced into the First in Human clinical trial in patients with Parkinson’s disease to be followed by evaluation in other alpha‐synucleinopathies.

Synthesis and biological evaluation of novel PET tracers [18F]AG120 & [18F]AG135 for imaging mutant isocitrate dehydrogenase 1 expression

Mutations in isocitrate dehydrogenase 1 (IDH1) are commonly found in various human malignancies. Inhibitors of several mutant IDH1 enzymes have entered clinical trials as target therapeutic drugs for the treatment of patients with IDH1 mutations. Herein, we report the synthesis and evaluation of two 18F-labeled tracers, [18F]AG120 and [18F]AG135 for imaging expression of mutated IDH1 in positron emission tomography (PET). [18F]AG120 and [18F]AG135 were synthesized in decay-corrected radiochemical yield of 1 % and 3 %, respectively, high molar activity (52–66 MBq/nmol and 216–339 MBq/nmol, respectively) and high radiochemical purity (>99%). Both tracers showed good in vitro stability, selective uptake into mutated IDH1-expressing cells and good pharmacokinetic profiles with low uptake in most organs/tissues. Furthermore, [18F]AG120 micro-PET/CT imaging displayed significantly greater uptake in IDH1-mutant than in wild-type tumors, Relatively, uptake of [18F]AG135 was observed neither in IDH1-mutant tumor xenografts nor in wild-type tumors. This study suggests that [18F]AG120 is a promising radiotracer for PET imaging of IDH1 mutation, However, further optimization and investigation are necessary for [18F]AG135 due to the limited uptake in mutated IDH1-expressing tumors.

Gallium-68 Labeling of the Cyclin-Dependent Kinase 4/6 Inhibitors as Positron Emission Tomography Radiotracers for Tumor Imaging.

Cyclin-dependent kinase 4 and 6 (CDK4/6) have emerged as interesting therapeutic drug targets with many potential applications in anti-tumors, especially in breast cancer. A novel CDK4/6 kinase-derived positron emission tomography (PET) imaging agent was designed based on palbociclib modified with a chelator DOTA. This new compound with a chelator DOTA-palbociclib was radiolabeled with gallium 68 (68Ga). After labeling, the purity and stability were evaluated, and the blood pharmacokinetics were carried out in normal healthy mice. Human breast cancer MCF-7 (ER+/HER2−) cells were used for in vitro cell uptake tests. PET imaging and ex vivo biodistribution were conducted in MCF-7 tumor-bearing mice. Specific binding of tumors was evaluated by the blocking assay. Furthermore, the uptake of 68Ga-DOTA-palbociclib in tumors was studied by autoradiography of tissue sections followed by immunofluorescence evaluation of CDK4 and CDK6. 68Ga-DOTA-palbociclib was synthesized very simply in a high labeling rate and radiochemical purity in 10 min. The labeling compound showed excellent stability both in vitro and in vivo and exhibited good pharmacokinetics, making it suitable for in vivo imaging. Cell uptake studies display that co-incubation with palbociclib can inhibit cellular uptake of 68Ga-DOTA-palbociclib. In vivo imaging and ex vivo biodistribution in mice bearing MCF-7 tumors both showed obvious radioactive uptake in the tumor and higher tumor-to-muscle ratios, while the tumor radioactivity accumulation was significantly decreased when prior administered with an excess of cold palbociclib, confirming CDK4/6 specific binding of 68Ga-DOTA-palbociclib in vivo. Autoradiography of the avid tumor section showed a high correlation between immunofluorescence with the CDK4/6 positive areas of the tumor, further demonstrating that 68Ga-DOTA-palbociclib specifically targeted CDK4/6 positive tumors. We synthesized 68Ga-DOTA-palbociclib, a new CDK4/6 kinase PET imaging agent, and validated its excellent stability, pharmacokinetics, and specific tumor binding. Based on our primary results, 68Ga-DOTA-palbociclib is a promising imaging agent with the potential to tailor a precise treatment program for CDK4/6 inhibitors.

Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging

Background18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades.MethodsThirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters.ResultsA reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation.Conclusions18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake.Clinical Trial RegistrationNCT03036943.

Comparison of Conventional and Radiomic Features between 18F-FBPA PET/CT and PET/MR.

Boron-10-containing positron emission tomography (PET) radio-tracer, 18F-FBPA, has been used to evaluate the feasibility and treatment outcomes of Boron neutron capture therapy (BNCT). The clinical use of PET/MR is increasing and reveals its benefit in certain applications. However, the PET/CT is still the most widely used modality for daily PET practice due to its high quantitative accuracy and relatively low cost. Considering the different attenuation correction maps between PET/CT and PET/MR, comparison of derived image features from these two modalities is critical to identify quantitative imaging biomarkers for diagnosis and prognosis. This study aimed to investigate the comparability of image features extracted from 18F-FBPA PET/CT and PET/MR. A total of 15 patients with malignant brain tumor who underwent 18F-FBPA examinations using both PET/CT and PET/MR on the same day were retrospectively analyzed. Overall, four conventional imaging characteristics and 449 radiomic features were calculated from PET/CT and PET/MR, respectively. A linear regression model and intraclass correlation coefficient (ICC) were estimated to evaluate the comparability of derived features between two modalities. Features were classified into strong, moderate, and weak comparability based on coefficient of determination (r2) and ICC. All of the conventional features, 81.2% of histogram, 37.5% of geometry, 51.5% of texture, and 25% of wavelet-based features, showed strong comparability between PET/CT and PET/MR. With regard to the wavelet filtering, radiomic features without filtering (61.2%) or with low-pass filtering (59.2%) along three axes produced strong comparability between the two modalities. However, only 8.2% of the features with high-pass filtering showed strong comparability. The linear regression models were provided for the features with strong and moderate consensus to interchange the quantitative features between the PET/CT and the PET/MR. All of the conventional and 71% of the radiomic (mostly histogram and texture) features were sufficiently stable and could be interchanged between 18F-FBPA PET with different hybrid modalities using the proposed equations. Our findings suggested that the image features high interchangeability may facilitate future studies in comparing PET/CT and PET/MR.

Preparation, characterization, and bioevaluation of 99mTc-famotidine as a selective radiotracer for peptic ulcer disorder detection in mice

Abstract This work focuses on tracking peptic ulcer localized in mice. The formation of a [99mTc]dithiocarbamate of famotidine complex at optimum conditions of reaction temperature (37 °C), reaction time (30 min), pH of the reaction mixture (5), amount of substrate (100 µg), amount of reducing agent (tin (II) content, 50 µg), was achieved using radioactive Tc-99m (250–400 MBq), with labelling yield of 98% and high radiochemical purity. The in-vitro stability of [99mTc]dithiocarbamate of famotidine complex was shown to be high in rat serum for up to 8 h. Normal and ulcerated mice were used in biodistribution studies. Famotidine works by blocking histamine-2-receptor antagonists (H2RAs). The high absorption of [99mTc]dithiocarbamate of famotidine complex in stomach in amount of 27.15% injected dose/g organ (ID/g) observed in ulcerated mice for up to 24 h demonstrated its usefulness as a novel radiotracer for stomach imaging.

Glycoprotein IIb/IIIa receptor targeted PET/CT imaging: a novel diagnostic tool for detecting bioprosthetic valve thrombosis

Abstract Background/Introduction Bioprosthetic valve thrombosis (BPVT) is an important clinical entity eventually following both bioprosthetic surgical and transcatheter aortic valve replacement. Although dynamic contrast-enhanced 4D-MDCT has improved the diagnosis of BPVT, more sensitive and pathology-specific non-invasive imaging tools are lacking. Recently, the glycoprotein IIb/IIIa receptor targeted, elarofiban-derived PET/CT imaging radiotracer [18F]GP1 has been successfully used for visualization of acute venous and arterial thrombi. Purpose We hypothesized that [18F]GP1 PET/CT imaging is suitable to detect BPVT. Methods In this proof-of-concept study, patients after bioprosthetic aortic valve replacement with symptomatic, severe hemodynamic valve dysfunction and confirmed hypoattenuated leaflet thickening (HALT) in dynamic 4D-MDCT were offered to participate in compassionate use examinations to undergo PET/CT imaging with the investigational [18F]GP1 PET tracer at baseline and after a 12-week course of therapeutic oral anticoagulation. Results This case series reports on three patients after aortic valve replacement. Two patients with symptomatic, obstructive BPVT as confirmed by echocardiography and 4D-MDCT fulfilled specified criteria and underwent [18F]GP1 PET/CT imaging. [18F]GP1 PET/CT clearly distinguished between blood pool activity and thrombotic foci. Clot-to-blood ratios at baseline were 8.2 and 4.5, respectively. A 12-week trial of therapeutic oral anticoagulation was associated with a regression of mean transprosthetic pressure gradient and reversal of HALT. Follow-up 4D-MDCT corroborated thrombus resolution in both patients. Correspondingly, [18F]GP1 PET/CT imaging demonstrated decreased tracer uptake in both patients. Clot-to-blood ratio at follow-up visit decreased to 1.2 and 2.9, respectively. While absent tracer uptake was seen in patient #1, residual tracer uptake was observed in patient #2 suggestive of ongoing platelet aggregation. One asymptomatic SAVR patient was examined with [18F]GP1 PET/CT for a different compassionate use and no thrombotic foci were detected on the leaflets. Conclusions [18F]GP1 PET/CT is a novel imaging technique in patients with obstructive BPVT. In a head-to-head comparison we show that [18F]GP1 PET/CT may have incremental diagnostic value over dynamic contrast-enhanced 4D-MDCT alone by detection of sites of ongoing platelet aggregation at the molecular level. [18F]GP1 PET/CT may serve as a novel, highly sensitive tool to overcome some limitations of current diagnostic imaging modalities for detecting BPVT and may prove useful for the monitoring and guidance of therapeutic interventions. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Life Molecular Imaging provided material for [18F]GP1 radiolabeling free of charge as part of an ongoing research collaboration.

Added value of myocardial blood flow using 18F-flurpiridaz PET to diagnose coronary artery disease: The flurpiridaz 301 trial

Background18F-Flurpiridaz is a promising investigational radiotracer for PET myocardial perfusion imaging with favorable properties for quantification of myocardial blood flow (MBF). We sought to validate the incremental diagnostic value of absolute MBF quantification in a large multicenter trial against quantitative coronary angiography. MethodsWe retrospectively analyzed a subset of patients (N = 231) from the first phase 3 flurpiridaz trial (NCT01347710). Dynamic PET data at rest and pharmacologic stress were fit to a previously validated 2-tissue-compartment model. Absolute MBF and myocardial flow reserve (MFR) were compared with coronary artery disease severity quantified by invasive coronary angiography on a per-patient and per-vessel basis. ResultsStress MBF per-vessel accurately identified obstructive disease (c-index 0.79) and progressively declined with increasing stenosis severity (2.35 ± 0.71 in patients without CAD; 1.92 ± 0.49 in non-obstructed territories of CAD patients; and 1.54 ± 0.50 in diseased territories, P < 0.05). MFR similarly declined with increasing stenosis severity (3.03 ± 0.94; 2.69 ± 0.95; and 2.33 ± 0.86, respectively, P < 0.05). In multivariable logistic regression modeling, stress MBF and MFR provided incremental diagnostic value beyond patient characteristics and relative perfusion analysis. ConclusionsClinical myocardial blood flow measurement with 18F-flurpiridaz cardiac PET shows promise for routine application.