Dose rate conversion coefficients for ocular contamination in nuclear medicine: A Monte Carlo simulation with experimental validation.

BACKGROUND: Since 2011, the International Commission on Radiological Protection (ICRP) has recommended an annual eye lens dose limit of 20 mSv for radiation workers, averaged over 5 years, with no year exceeding 50 mSv. However, limited research has been conducted on dose rate conversion coefficients (DCCs) for direct contamination of the eye. PURPOSE: This study aimed to accurately determine DCCs for the eye lens and cornea for ocular contamination with radionuclides used in nuclear medicine. METHODS: DCCs for 37 radionuclides used in nuclear medicine were determined using two different methods. Method 1 involved conducting Monte Carlo (MC) simulations of an ICRU cylinder to determine the absorbed dose at a depth of 3 mm resulting from a point source. The accuracy of this simulation approach was validated by experimental thermoluminescent dosimeter (TLD) measurements for 18F, 68Ga, 99mTc, and 177Lu. In method 2, average DCCs were calculated for the eye lens (complete and radiosensitive parts) and the cornea for both a point source and thin surface contamination centered on the cornea using MC simulations on the adult mesh-type reference computational phantom of the eye from the ICRP (MRCP). RESULTS: DCCs determined from TLD measurements showed excellent agreement (deviations: +1.4%, +4.7%, -3.1%, and -2.5% for 18F, 68Ga, 99mTc, and 177Lu, respectively) compared to MC simulations of the experimental set-up. For the 37 radionuclides, DCCs of the complete eye-lens for a point source ranged from 2.53 × 10-7 to 4.15 × 10-2 mGy MBq-1 s-1 for the adult MRCPs, being substantially smaller compared to DCCs determined via MC simulations of a ICRU cylinder. In general, point source and surface contamination showed comparable DCCs for the eye lens. Radionuclides emitting low-energy beta radiation or conversion electrons (e.g., 177Lu, 99mTc) showed low DCCs as the radiation does not penetrate to the depth of the eye lens, while radionuclides emitting high-energy beta radiation (e.g., 90Y) showed high DCCs. Overall, DCCs for the radiosensitive part of the eye lens were larger (up to a factor of 3) compared to the complete eye lens. DCCs for the cornea were larger than for the eye lens with a factor that strongly depended on the emitted radiation type. Especially alpha emitters (e.g., 211At, 223Ra) showed high DCCs for the cornea because of the short range of alpha radiation, leading to local maxima in the cornea and not reaching the eye lens. CONCLUSION: DCCs at a depth of 3 mm in an ICRU cylinder and adult MRCP DCCs for both the complete and sensitive parts of the eye lens and cornea were determined for 37 radionuclides having applications in nuclear medicine. These DCCs are highly useful in radiation safety assessments and radiation dose calculations in ocular contamination incidents.

Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions.

By clearing GABA from the synaptic cleft, GABA transporters (GATs) play an essential role in inhibitory neurotransmission. Consequently, in vivo visualization of GATs can be a valuable diagnostic tool and biomarker for various psychiatric and neurological disorders. Not surprisingly, in recent years several research attempts to develop a radioligand have been conducted, but so far none have led to suitable radioligands that allow imaging of GATs. Here, we provide an overview of the radioligands that were developed with a focus on GAT1, since this is the most abundant transporter and most of the research concerns this GAT subtype. Initially, we focus on the field of GAT1 inhibitors, after which we discuss the development of GAT1 radioligands based on these inhibitors. We hypothesize that the radioligands developed so far have been unsuccessful due to the zwitterionic nature of their nipecotic acid moiety. To overcome this problem, the use of non-classical GAT inhibitors as basis for GAT1 radioligands or the use of carboxylic acid bioisosteres may be considered. As the latter structural modification has already been used in the field of GAT1 inhibitors, this option seems particularly viable and could lead to the development of more successful GAT1 radioligands in the future.

Correction: Sankaranarayanan et al. Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study. Cancers 2022, 14, 230.

The authors wish to replace the 'Author Contributions' statement and the affiliation for Jochen Maurer of this article [...].

PARP targeted Auger emitter therapy with [125I]PARPi-01 for triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) lacks biomarkers for targeted therapy. Auger emitters display the best therapeutic effect, if delivered directly into the nucleus proximal to DNA. The nuclear protein Poly (ADP-ribose)-Polymerase 1 (PARP1) is a suitable target against which few inhibitors (PARPi) are clinically approved for treatment of breast cancer with germline BRCA mutation (BRCAmut). In this study, a theranostic approach was investigated in a TNBC xenografted mouse model by radiolabelling a close derivative of a PARPi Olaparib (termed PARPi-01) with the Auger emitters 123/125I. METHODS: TNBC cell line MDA-MB-231 was subcutaneously implanted in female NOD/SCID mice. At a tumour size of ~ 500mm3, [123I]PARPi-01 was administered intravenously, and SPECT/CT images were obtained at 4 h or 24 h post injection (p.i). A therapy study was performed with [125I]PARPi-01 in 4 doses (10 MBq/dose, 10 days apart). Tumour growth was monitored by CT scans longitudinally once per week. Upon reaching study endpoint, tissues were harvested and stained with TUNEL assay for detection of apoptosis induction. RESULTS: SPECT/CT images showed rapid hepatobiliary tracer clearance at 4 h post injection (p.i.). Retention in thyroid at 24 h p.i. suggested tracer deiodination in vivo. The tumour and liver uptake were 0.2%ID/g and 2.5%ID/g, respectively. The tumour: blood ratio was 1.3. Endogenous therapy induced a significant delay in tumour growth (doubling time increased from 8.3 to 14.2 days), but no significant survival advantage. Significantly higher apoptosis ratio was observed in [125I]PARPi-01 treated tumour tissues. No radiotoxicity was detected in the liver and thyroid. CONCLUSION: Considering the radio-cytotoxic effect in the tumour tissue and a delay on tumour doubling time, [125I]PARPi-01 presents a potential radiotherapeutics for treatment of TNBC. Improvements to overcome the suboptimal pharmacokinetics are necessary for its potential clinical application.

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study.

PARP1 inhibitors (PARPi) are currently approved for BRCAmut metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [125I] coupled olaparib derivative: [125I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCAwt/mut). Anchorage independent growth potential was evaluated using soft agar assay. [125I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [125I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCAwt cell lines. The clonogenic survival was significantly reduced after treatment with [125I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [125I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.

Molecular Imaging of Angiogenesis in Oncology: Current Preclinical and Clinical Status.

Angiogenesis is an active process, regulating new vessel growth, and is crucial for the survival and growth of tumours next to other complex factors in the tumour microenvironment. We present possible molecular imaging approaches for tumour vascularisation and vitality, focusing on radiopharmaceuticals (tracers). Molecular imaging in general has become an integrated part of cancer therapy, by bringing relevant insights on tumour angiogenic status. After a structured PubMed search, the resulting publication list was screened for oncology related publications in animals and humans, disregarding any cardiovascular findings. The tracers identified can be subdivided into direct targeting of angiogenesis (i.e., vascular endothelial growth factor, laminin, and fibronectin) and indirect targeting (i.e., glucose metabolism, hypoxia, and matrix metallo-proteases, PSMA). Presenting pre-clinical and clinical data of most tracers proposed in the literature, the indirect targeting agents are not 1:1 correlated with angiogenesis factors but do have a strong prognostic power in a clinical setting, while direct targeting agents show most potential and specificity for assessing tumour vascularisation and vitality. Within the direct agents, the combination of multiple targeting tracers into one agent (multimers) seems most promising. This review demonstrates the present clinical applicability of indirect agents, but also the need for more extensive research in the field of direct targeting of angiogenesis in oncology. Although there is currently no direct tracer that can be singled out, the RGD tracer family seems to show the highest potential therefore we expect one of them to enter the clinical routine.

Off-target effects of oral anticoagulants - vascular effects of vitamin K antagonist and non-vitamin K antagonist oral anticoagulant dabigatran etexilate.

INTRODUCTION: Vitamin K antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup. MATERIAL AND METHODS: Female Apoe-/- mice (age 12 weeks) were fed Western-type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18 F]-NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed. RESULTS: Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran. CONCLUSION: Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

An international multi-center investigation on the accuracy of radionuclide calibrators in nuclear medicine theragnostics.

BACKGROUND: Personalized molecular radiotherapy based on theragnostics requires accurate quantification of the amount of radiopharmaceutical activity administered to patients both in diagnostic and therapeutic applications. This international multi-center study aims to investigate the clinical measurement accuracy of radionuclide calibrators for 7 radionuclides used in theragnostics: 99mTc, 111In, 123I, 124I, 131I, 177Lu, and 90Y. METHODS: In total, 32 radionuclide calibrators from 8 hospitals located in the Netherlands, Belgium, and Germany were tested. For each radionuclide, a set of four samples comprising two clinical containers (10-mL glass vial and 3-mL syringe) with two filling volumes were measured. The reference value of each sample was determined by two certified radioactivity calibration centers (SCK CEN and JRC) using two secondary standard ionization chambers. The deviation in measured activity with respect to the reference value was determined for each radionuclide and each measurement geometry. In addition, the combined systematic deviation of activity measurements in a theragnostic setting was evaluated for 5 clinically relevant theragnostic pairs: 131I/123I, 131I/124I, 177Lu/111In, 90Y/99mTc, and 90Y/111In. RESULTS: For 99mTc, 131I, and 177Lu, a small minority of measurements were not within ± 5% range from the reference activity (percentage of measurements not within range: 99mTc, 6%; 131I, 14%; 177Lu, 24%) and almost none were outside ± 10% range. However, for 111In, 123I, 124I, and 90Y, more than half of all measurements were not accurate within ± 5% range (111In, 51%; 123I, 83%; 124I, 63%; 90Y, 61%) and not all were within ± 10% margin (111In, 22%; 123I, 35%; 124I, 15%; 90Y, 25%). A large variability in measurement accuracy was observed between radionuclide calibrator systems, type of sample container (vial vs syringe), and source-geometry calibration/correction settings used. Consequently, we observed large combined deviations (percentage deviation > ± 10%) for the investigated theragnostic pairs, in particular for 90Y/111In, 131I/123I, and 90Y/99mTc. CONCLUSIONS: Our study shows that substantial over- or underestimation of therapeutic patient doses is likely to occur in a theragnostic setting due to errors in the assessment of radioactivity with radionuclide calibrators. These findings underline the importance of thorough validation of radionuclide calibrator systems for each clinically relevant radionuclide and sample geometry.

Radionuclide tumor necrosis factor-alpha activity in herniated lumbar disc correlates with severe leg pain.

BACKGROUND: Lumbar disc herniation is often associated with an inflammatory process. In this context, inflammation has been considered a key factor in the modulation of pain. Here, we present a case of inflammatory activity directly documented in a patient with a lumbar disc herniation. CASE DESCRIPTION: A 49-year-old male presented with progressive low back pain and left-sided S1 radiculopathy, without a focal neurological deficit. The lumbar MR revealed a prominent herniated disc at the L5-S1 level, with compression of the left S1 root. The patient underwent a L5-S1 discectomy using a standard interlaminar approach. Although initially he was pain free, he required three additional operations to address recurrent pain complaints. As research indicates that local inflammation contributes to neuropathic pain, we had the patient undergoes single-photon emission computed tomography (SPECT) imaging using technetium-99m-labeled-infliximab (an anti-tumor necrosis factor [TNF]-alpha monoclonal antibody) before a proposed fourth operation. The SPECT study documented a strong signal at the site of the herniated disc, thus confirming the diagnosis of a pro-inflammatory process involving the S1 nerve root. Nine months after the fourth operation, the patient was pain free. Of interest, the second SPECT study in the now asymptomatic patient demonstrated no detectable/ residual signal at the operative/disc site. CONCLUSION: Absence of a SPECT TNF-alpha signal in a pain-free patient following a lumbar discectomy correlates with the reduction/resolution of the local preoperative inflammatory response.

Ceramide analog [18F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer's disease transgenic mice by functioning as a metabolic probe.

The metabolism of ceramides is deregulated in the brain of Alzheimer's disease (AD) patients and is associated with apolipoprotein (APO) APOE4 and amyloid-ß pathology. However, how the ceramide metabolism changes over time in AD, in vivo, remains unknown. Distribution and metabolism of [18F]F-HPA-12, a radio-fluorinated version of the ceramide analog N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide, was investigated in the brain of AD transgenic mouse models (FAD) on an APOE4 or APOE3 genetic background, by positron emission tomography and by gamma counter. We found that FAD mice displayed a higher uptake of [18F]F-HPA-12 in the brain, independently from the APOE4 or APOE3 genetic background. FAD mice could be distinguished from littermate control animals with a sensitivity of 85.7% and a specificity of 87.5%, by gamma counter measurements. Metabolic analysis of [18F]F-HPA-12 in the brain suggested that the tracer is degraded less efficiently in the FAD mice. Furthermore, the radioactive signal registered in the hippocampus correlated with an increase of Cer d18:1/20:2 levels measured in the same brain region by mass spectrometry. Our data gives additional proof that ceramide metabolism is different in FAD mice compared to controls. Ceramide analogs like HPA-12 may function as metabolic probes to study ceramide disbalance in the brain.

Brown adipose tissue uptake of triglyceride-rich lipoprotein-derived fatty acids in diabetic or obese mice under different temperature conditions.

BACKGROUND: In vivo imaging of glucose analogue 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) via positron emission tomography (PET) is the current gold standard to visualize and assess brown adipose tissue (BAT) activity. However, glucose metabolism is only a part of the metabolic activity of BAT. [18F]FDG-PET has been shown in clinical trials to often fail to visualize BAT under insulin-resistant conditions associated with aging and weight gain. We employed a novel developed triglyceride-based tracer to visualize BATs metabolic activity under different temperature conditions as well as under diabetic and obese conditions in preclinical models. RESULTS: [18F]BDP-TG-chylomicron-like particles visualized BAT in control, streptozocin-induced diabetes and obese mice. Increased BAT tracer uptake was found in control mice acutely exposed to cold but not in cold-acclimated animals. Diabetes did not remove BAT tracer uptake, but did limit BAT tracer uptake to levels of control mice housed at 21 °C. In obese animals, BAT tracer uptake was significantly reduced, although the stimulating effect of cold exposure could still be noted. CONCLUSION: BAT was visualized in control, diabetic and obese conditions. Streptozocin-induced diabetes, but not obesity, inhibited the stimulatory effect of cold exposure.

Characterization of BAT activity in rats using invasive and non-invasive techniques.

INTRODUCTION: Brown adipose tissue (BAT) is considered as a potential target for combating obesity in humans where active BAT metabolizes glucose and fatty acids as fuel resulting in heat production. Prospective studies in humans have been set up to further study the presence and metabolic activity of BAT mostly using Positron Emission Tomography (PET) imaging in cold-stimulated conditions with the radiolabeled glucose derivative [18F]FDG. However, radiotracers beyond [18F]FDG have been proposed to investigate BAT activity, targeting various aspects of BAT metabolism. It remains questionable which tracer is best suited to detect metabolic BAT activity and to what extent those results correlate with ex vivo metabolic BAT activity. METHODS: PET and Single Photon Emission Computed Tomography (SPECT) imaging, targeting different aspects of BAT activation such as glucose metabolism, fatty acid metabolism, noradrenergic stimulation, blood perfusion and amino acid transport system, was performed immediately after injection of the tracer in rats under different temperatures: room temperature, acute cold (4 °C for 4 h) or acclimated to cold (4 °C for 6 h per day during 28 days). Furthermore, Magnetic Resonance Spectroscopy (MRS)-derived BAT temperature was measured in control and cold-acclimated rats. RESULTS: At room temperature, only [18F]FDG visualized BAT. Glucose metabolism, fatty acid metabolism, noradrenergic stimulation and blood perfusion showed a clear tracer-dependent twofold increase in BAT uptake upon cold exposure. Only the tracer for the amino acid transport system did not show BAT specific uptake under any of the experimental conditions. MRS demonstrated that cold-acclimated animals had BAT with a stronger heat-production compared to control animals. CONCLUSION: BAT activity following cold exposure in rats was visualized by several tracers, while only [18F]FDG was also able to show BAT activity under non-stimulated conditions (room temperature). The variances in uptake of the different tracers should be taken into account when developing future clinical applications in humans.

A comparison of four radionuclide dose calibrators using various radionuclides and measurement geometries clinically used in nuclear medicine.

PURPOSE: Reliable quantification of radioactivity in nuclear medicine is becoming increasingly important in various therapeutic applications requiring a high accuracy of nuclear medicine measuring equipment, such as radionuclide calibrators. In this study the accuracy of four different radionuclide calibrators was assessed for 99mTc, 111In, 68Ga and 18F for measurement geometries clinically used. METHODS: Syringes and vials were prepared with a reference activity using a stock solution of which the activity concentration was determined using gamma-ray spectroscopy. The accuracy of four different radionuclide calibrator systems, ISOMED 2000, ISOMED 2010, VIK-202 and Capintec CRC-25R, was assessed by comparing the measured activity to the reference activity. RESULTS: Deviations in measured activity from reference values were found up to 12.5%, 32.0%, 29.0% and 12.6% for 99mTc, 111In, 68Ga and 18F, respectively. For 68Ga all radionuclide calibrators systematically overestimated the activity by 10-20%. For 111In, large differences in activity measurements were observed between different source geometries, in particular between syringes and vials. Deviations between radionuclide calibrator systems were found up to 11.8%, 44.4%, 14.4% and 8.7% for 99mTc, 111In, 68Ga and 18F, respectively. When comparing similar syringe types of different brands filled with identical stock solution volume, deviations up to 1.8%, 5.8%, 10.2% and 3.2% were found for 99mTc, 111In, 68Ga and 18F. CONCLUSION: Substantial deviations in measured activity were found for all radionuclides and radionuclide calibrators, which may result in erroneous activity dosing and image quantification. This underlines the importance of thorough validation of radionuclide calibrators for all measurement geometries and radionuclides clinically used.

[18F]BODIPY-triglyceride-containing chylomicron-like particles as an imaging agent for brown adipose tissue in vivo.

Brown adipose tissue (BAT) is present in human adults and the current gold standard to visualize and quantify BAT is [18F]FDG PET-CT. However, this method fails to detect BAT under insulin-resistant conditions associated with ageing and weight gain, such as type 2 diabetes. The aim of this study was to develop a novel triglyceride-based tracer for BAT. For this purpose we designed a dual-modal fluorescent/PET fatty acid tracer based on commercially available BODIPY-FL-C16, which can be esterified to its correspondent triglyceride, radiolabeled and incorporated into pre-synthesized chylomicron-like particles. BODIPY-FL-C16 was coupled to 1,2-diolein with a subsequent radiolabeling step resulting in [18F]BODIPY-C16-triglyceride that was incorporated into chylomicron-like particles. Various quality control steps using fluorescent and radioactive methods were conducted before BAT visualization was tested in mice. Triglyceride synthesis, radiolabeling and subsequent incorporation into chylomicron-like particles was carried out in decent yields. This radiotracer appeared able to visualize BAT in vivo, and the uptake of the radiotracer was stimulated by cold exposure. The here reported method can be used to incorporate radiolabeled triglycerides into pre-synthesized chylomicron-like particles. Our approach is feasible to visualize and quantify the uptake of triglyceride-derived fatty acids by BAT.

Use of Cyclic Backbone NGR-Based SPECT to Increase Efficacy of Postmyocardial Infarction Angiogenesis Imaging.

As CD13 is selectively expressed in angiogenesis, it can serve as a target for molecular imaging tracers to noninvasively visualize angiogenic processes in vivo. The CD13-targeting moiety NGR was synthesized and cyclized by native chemical ligation (NCL) instead of disulfide bridging, leading to a cyclic peptide backbone: cyclo(Cys-Asn-Gly-Arg-Gly) (coNGR). Beside this new monomeric coNGR, a tetrameric NGR peptide co(NGR)4 was designed and synthesized. After radiolabeling, their in vitro and in vivo characteristics were determined. Both coNGR-based imaging agents displayed considerably higher standardized uptake values (SUVs) at infarcted areas compared to the previously reported disulfide-cyclized cNGR imaging agent. Uptake patterns of 111In-coNGR and 111In-co(NGR)4 coincided with CD13 immunohistochemistry on excised hearts. Blood stability tests indicated better stability for both novel imaging agents after 50 min blood incubation compared to the disulfide-cyclized cNGR imaging agent. In mice, both coNGR peptides cleared rapidly from the blood mainly via the kidneys. In addition, co(NGR)4 showed a significantly higher specific uptake in infarcted myocardium compared to coNGR and thus is a promising sensitive imaging agent for detection of angiogenesis in infarcted myocardium.

Synthesis, Radiosynthesis, and Preliminary in vitro and in vivo Evaluation of the Fluorinated Ceramide Trafficking Inhibitor (HPA-12) for Brain Applications.

Ceramide levels are increased in blood and brain tissue of Alzheimer's disease (AD) patients. Since the ceramide transporter protein (CERT) is the only known protein able to mediate non-vesicular transfer of ceramide between organelle membranes, the modulation of CERT function may impact on ceramide accumulation. The competitive CERT inhibitor N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12) interferes with ceramide trafficking. To understand the role of ceramide/CERT in AD, HPA-12 can be a useful tool to modulate ceramide trafficking. Here we first report the synthesis and in vitro properties of HPA-12 radiolabeled with fluorine-18 and present preliminary in vitro and in vivo positron emission tomography (PET) imaging and biodistribution data. In vitro results demonstrated that the fluorination did not alter the biological properties of HPA-12 since the [fluorine-19]HPA-12, interferes with 5-DMB-ceramide trafficking in HeLa cells. Radiolabeled HPA-12, [fluorine-18]HPA-12, was obtained with a radiochemical yield of 90% and a specific activity of 73 MBq/µmol. PET imaging on wild-type mice showed hepatobiliary clearance and a brain uptake on the order of 0.3 standard uptake value (SUV) one hour post injection. Furthermore, the biodistribution data showed that after removal of the blood by intracardial perfusion, radioactivity was still measurable in the brain demonstrating that the [fluorine-18]HPA-12 crosses the blood brain barrier and is retained in the brain.

Synthesis, radiosynthesis and in vitro evaluation of 18F-Bodipy-C16/triglyceride as a dual modal imaging agent for brown adipose tissue.

BACKGROUND: Brown adipose tissue research is in the focus in the field of endocrinology. We designed a dual-modal fluorescent/PET fatty acid based tracer on commercially available Bodipy-C16, which can be synthesized to its corresponding triglyceride and which combines the benefits of fluorescent and PET imaging. METHODS: Bodipy-C16 was coupled to 1,3-diolein resulting in Bodipy-triglyceride. Bodipy-C16 and Bodipy-triglyceride compounds were radiolabeled with 18F using an 18F/19F exchange reaction to yield a dual-modal imaging molecule. Uptake of radiolabeled and non-labeled Bodipy-C16 and Bodipy-triglyceride was analyzed by fluorescence imaging and radioactive uptake in cultured adipocytes derived from human brown adipose tissue and white adipose tissue. RESULTS: Bodipy-C16 and Bodipy-triglyceride were successfully radiolabeled and Bodipy-C16 showed high shelf life and blood plasma stability (99% from 0-4 h). The uptake of Bodipy-C16 increased over time in cultured adipocytes, which was further enhanced after beta-adrenergic stimulation with norepinephrine. The uptake of Bodipy-C16 was inhibited by oleic acid and CD36 inhibitor sulfosuccinimidyl-oleate. The poor solubility of Bodipy-triglyceride did not allow stability or in vitro experiments. CONCLUSION: The new developed dual modal fatty acid based tracers Bodipy-C16 and Bodipy-triglyceride showed promising results to stimulate further in vivo evaluation and will help to understand brown adipose tissues role in whole body energy expenditure.

Potential of α7 nicotinic acetylcholine receptor PET imaging in atherosclerosis.

Atherosclerotic events are usually acute and often strike otherwise asymptomatic patients. Although multiple clinical risk factors have been associated with atherosclerosis, as of yet no further individual prediction can be made as to who will suffer from its consequences based on biomarker analysis or traditional imaging methods like CT, MRI or angiography. Previously, non-invasive imaging with 18F-fluorodeoxyglucose (18F-FDG) PET was shown to potentially fill this niche as it offers high sensitive detection of metabolic processes associated with inflammatory changes in atherosclerotic plaques. However, 18F-FDG PET imaging of arterial vessels suffers from non-specificity and has still to be proven to reliably identify vulnerable plaques, carrying a high risk of rupture. Therefore, it may be regarded only as a secondary marker for monitoring treatment effects and it does not offer alternative treatment options or direct insight in treatment mechanisms. In this review, an overview is given of the current status and the potential of PET imaging of inflammation and angiogenesis in atherosclerosis in general and special emphasis is given to imaging of α7 nicotinic acetylcholine receptors (α7 nAChRs). Due to the gaps that still exist in our understanding of atherogenesis and the limitations of the available PET tracers, the search continues for a more specific radioligand, able to differentiate between stable atherosclerosis and plaques prone to rupture. The potential role of the α7 nAChR as imaging marker for plaque vulnerability is explored. Today, strong evidence exists that nAChRs are involved in the atherosclerotic disease process. They are suggested to mediate the deleterious effects of the major tobacco component, nicotine, a nAChR agonist. Mainly based on in vitro data, α7 nAChR stimulation might increase plaque burden via increased neovascularization. However, in animal studies, α7 nAChR manipulation appears to reduce plaque size due to its inhibitory effects on inflammatory cells. Thus, reliable identification of α7 nAChRs by in vivo imaging is crucial to investigate the exact role of α7 nAChR in atherosclerosis before any therapeutic approach in the human setting can be justified. In this review, we discuss the first experience with α7 nAChR PET tracers and developmental considerations regarding the "optimal" PET tracer to image vascular nAChRs.

Brown adipose tissue and lipid metabolism imaging.

PURPOSE: Brown adipose tissue (BAT) research has evolved from an underestimated to a fast developing field. Its assumed curing properties for the world wide epidemic obesity, and its related diseases, makes this tissue an interesting target for a broad amount of non-invasive molecular BAT tracers. Apart from 18F-FDG PET/CT there are several methods to detect BAT and measure its metabolism in a more appropriate way. Especially interesting is the measure of lipid turnover, because fatty acids comprise the main fuel for active BAT. This review outlines different imaging modalities suitable for BAT imaging with the overall goal to explain the yet not completely understood mechanism in BAT and its quantitative contribution to whole body lipid and energy metabolism. METHODS: Publications with focus on brown adipose tissue and lipid metabolism imaging are analyzed, different imaging approaches are introduced and promising BAT tracers are presented. RESULTS: Radiolabelled and fluorescent fatty acids, labelled particles, 3H-Triolein and ADIFAB staining can give information about the inflow and therefore about the utilization of fatty acids which represents the activation state in vivo/in vitro. Non-invasive scanning with CT or MRI is a useful addition to those techniques. CONCLUSION: Lipid metabolism imaging offers the opportunity to visualize and quantify yet undiscovered aspects of BAT metabolic activities and is key to completely clarify its role in whole body lipid and energy metabolism.