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Sialic acid-binding immunoglubulin-like lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1 (VAP-1). A gallium 68-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-human study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy males underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1–240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to gamma counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM 2.2 software. In addition, a patient with early rheumatoid arthritis was studied with both 68Ga-DOTA-Siglec-9 and 18F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Results:68Ga-DOTA-Siglec-9 was well tolerated by all subjects. 68Ga-DOTA-Siglec-9 was rapidly cleared from blood circulation and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range 0.020–0.024 mSv/MBq). Most importantly, however, 68Ga-DOTA-Siglec-9 was able to detect arthritis comparable to 18F-FDG. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution is favorable for testing of the tracer in larger group of patients with rheumatoid arthritis planned in the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as those of other 68Ga-labeled tracers. Injection of 150 MBq of 68Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of 68Ga-DOTA-Siglec-9, e.g., in trials aiming to elucidate the treatment efficacy of novel drug candidates.

1380 Objectives: The purpose of this study was to investigate how gender, BMI, patient cross-sectional area and heart size affect the influence of time-of-flight (TOF) and point spread function (PSF) modeling in image reconstruction on regional absolute myocardial blood flow (MBF) measured with 82Rb PET in an obese population. Methods: Dynamic rest/stress 82Rb cardiac PET studies were performed for 30 obese subjects on a TOF PET scanner. Subject characteristics were (mean ± SD for continuous variables): gender 9 male, 21 female; weight 138.9 ± 32.8 kg; BMI 47.8 ± 9.5 kg/m2; heart size 92.4 ± 55.3 ml; cross-sectional area in a transaxial slice containing the heart 1133 ± 233 cm2. Images were reconstructed in four ways: (1) OSEM without TOF or PSF modeling (OSEM), (2) OSEM with TOF (TOF), (3) OSEM with PSF modeling (PSF) and (4) OSEM with TOF and PSF modeling (PSFTOF). All were with 3 iterations, 8 subsets and with a post-reconstruction 8mm 3D Gaussian filter. A one tissue compartmental model was used to compute MBF. Average rest and stress flow and myocardial flow reserve were computed in five regions: anterior, septal, inferior, lateral and apical. Results from TOF, PSF and PSFTOF were compared with those from OSEM, with subjects grouped by gender, and by tertiles (10 subjects each) for BMI (I: 32.5-40.5, II: 41.1-52.3, III: 53.3-75.6 (kg/m2)), cross-sectional area (I: 532 - 1086, II: 1089 - 1157, III: 1187 - 1662 (cm2)) and heart size (I: 19 -56, II: 66 - 93, III: 97 - 238 (ml)). The MBF or myocardial flow reserve (MFR) in a given region was compared with the corresponding OSEM value and the change was expressed as a percent. Results: The general trends for all subjects with TOF were similar MBF increases in the apical (+22.0%) and septal walls (+19.4%), and a slightly lower increase in the anterior wall (+11.3 %). Increases were small in the inferior (+4.6%) and lateral (+4.9%) walls. There was little effect of PSF modeling in any region. MBF trends with PSFTOF were similar to those for TOF alone. Rest and stress increases with TOF tended to be matched, so that MFR was little changed. Trends were examined for the groupings by patient characteristics. (1) Gender. MBF showed a greater increase with TOF for females (mean +20.9%) compared to males (mean +14.9%) in the apical, septal and anterior walls. Results with PSFTOF were similar. (2) BMI. The MBF increase with TOF in the apical, anterior and septal walls was greatest for tertile II (mean +26.9%) compared with tertile I (mean +13.6%) and tertile III (mean +16.7%). (3) Cross-sectional area. The MBF increase with TOF in the apical, anterior and septal walls was similar for tertiles II (mean +22.1%) and III (mean +22.6%), and was greater than that for tertile I (mean +12.6%). (4) Heart size. The MBF increase with TOF in the apical, anterior and septal walls was greater for smaller heart sizes: tertile I (mean +21.2%), tertile II (+20.7%) and tertile III (+15.3%). These results are for our patient population and particular hardware, software and processing implementation. Conclusions: Patient gender, BMI, cross-sectional area and heart size affect the degree to which MBF values change with TOF. The largest changes are observed for females, patients with larger BMI, larger cross-sectional area and smaller hearts. The greatest changes are found in the apical, septal and lateral walls. The studied patient characteristics have little effect on flow reserve. It is important to consider these patient-dependent effects when evaluating absolute MBF in a clinical environment, and to recognize that equipment or protocol changes may affect MBF results.

Background Magnetic resonance imaging (MRI) with Gadolinium 1,4,7,10-tetraazacyclododecane-N′,N″,N′′′,N″″-tetraacetic acid (Gd-DOTA) enables assessment of myocardial perfusion during first-pass of the contrast agent, while increased retention can signify areas of myocardial infarction (MI). We studied whether Gallium-68-labeled analog, 68Ga-DOTA, can be used to assess myocardial perfusion on positron emission tomography/computed tomography (PET/CT) in rats, comparing it with 11C-acetate. Methods Rats were studied with 11C-acetate and 68Ga-DOTA at 24 hours after permanent ligation of the left coronary artery or sham operation. One-tissue compartmental models were used to estimate myocardial perfusion in normal and infarcted myocardium. After the PET scan, hearts were sectioned for autoradiographic detection of 68Ga-DOTA distribution. Results 11C-acetate PET showed perfusion defects and histology showed myocardial necrosis in all animals after coronary ligation. Kinetic modeling of 68Ga-DOTA showed significantly higher k1 values in normal myocardium than in infarcted areas. There was a significant correlation (r = 0.82, P = 0.001) between k1 values obtained with 68Ga-DOTA and 11C-acetate. After 10 minutes of tracer distribution, the 68Ga-DOTA concentration was significantly higher in the infarcted than normal myocardium on PET imaging and autoradiography. Conclusions Our results indicate that acute MI can be detected as reduced perfusion, as well as increased late retention of 68Ga-DOTA. Electronic supplementary material The online version of this article (10.1007/s12350-019-01752-6) contains supplementary material, which is available to authorized users.

There may be some differences in thein vivobehavior of68Ga-chloride and68Ga-citrate leading to different accumulation profiles. This study compared68Ga-citrate and68Ga-chloride PET/CT imaging under standardized experimental models.Methods.DiffuseStaphylococcus aureustibial osteomyelitis and uncomplicated bone healing rat models were used (n=32). Two weeks after surgery, PET/CT imaging was performed on consecutive days using68Ga-citrate or68Ga-chloride, and tissue accumulation was confirmed byex vivoanalysis. In addition, peripheral quantitative computed tomography and conventional radiography were performed. Osteomyelitis was verified by microbiological analysis and specimens were also processed for histomorphometry.Results.In PET/CT imaging, theSUVmaxof68Ga-chloride and68Ga-citrate in the osteomyelitic tibias (3.6 ± 1.4 and 4.7 ± 1.5, resp.) were significantly higher (P=0.0019andP=0.0020, resp.) than in the uncomplicated bone healing (2.7 ± 0.44 and 2.5 ± 0.49, resp.). In osteomyelitic tibias, theSUVmaxof68Ga-citrate was significantly higher than the uptake of68Ga-chloride (P=0.0017). In animals with uncomplicated bone healing, no difference in theSUVmaxof68Ga-chloride or68Ga-citrate was seen in the operated tibias.Conclusions.This study further corroborates the use of68Ga-citrate for PET imaging of osteomyelitis.

Vascular adhesion protein-1 (VAP-1) is an endothelial glycoprotein mediating leukocyte trafficking from blood to sites of inflammation. BTT-1023 is a fully human monoclonal anti-VAP-1 antibody developed to treat inflammatory diseases. In this study, we preclinically evaluated radioiodinated BTT-1023 for inflammation imaging. Methods: Rabbits were intravenously injected with radioiodinated BTT-1023. Distribution and pharmacokinetics were assessed by PET/CT up to 72 h after injection. Human radiation dose estimates for 124I-BTT-1023 were extrapolated. Additionally, rabbits with chemically induced synovitis were imaged with 123I-BTT-1023 SPECT/CT. Results: Radioiodinated BTT-1023 cleared rapidly from blood circulation and distributed to liver and thyroid. Inflamed joints were delineated by SPECT/CT. The estimated human effective dose due to 124I-BTT-1023 was 0.55 mSv/MBq, if blockage of thyroid uptake is assumed. Conclusion: The radioiodinated BTT-1023 was able to detect mild inflammation in vivo. Clinical 124I-BTT-1023 PET studies with injected radioactivity of 0.5–0.7 MBq/kg may be justified.

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared 68Ga-DOTA- and 18F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. Methods. Firstly, we examined 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied 18F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous 68Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. Results. In rats, 68Ga-DOTA-Siglec-9 (SUV, 0.88±0.087) and 18F-FDR-Siglec-9 (SUV, 0.77±0.22) showed comparable (P=0.29) imaging of inflammation. In atherosclerotic mice, 18F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6±0.078) similar to previously tested 68Ga-DOTA-Siglec-9 (P=0.35). Human effective dose estimates for 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. Conclusion. Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of 68Ga-DOTA-Siglec-9 present advantages over 18F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.

Purpose Positron emission tomography (PET) with 15O-labeled water (H215O) facilitates the visualization and quantification of blood flow in clinical investigations and also in small animals. The quantification of blood flow requires an input function, which is generally obtained by measuring radioactivity in arterial blood withdrawn during PET scanning. However, this approach is not always feasible, because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop and cross-validate two methods, namely, a blood- and an image-based method for obtaining the input function for blood flow studies from rat H215O PET.

Methyl-(11)C-choline ([(11)C]choline) is a radiopharmaceutical used for oncological PET studies. We investigated the biodistribution and biokinetics of [(11)C]choline and provide estimates of radiation doses in humans.The distribution of [(11)C]choline was evaluated ex vivo in healthy rats (n=9) by measuring the radioactivity of excised organs, and in vivo in tumour-bearing rats (n=4) by PET. In addition to estimates of human radiation doses extrapolated from rat data, more accurate human radiation doses were calculated on the basis of PET imaging of patients with rheumatoid arthritis (n=6) primarily participating in a synovitis imaging project with [(11)C]choline. Dynamic data were acquired from the thorax and abdomen after injection of 423+/-11 MBq (mean+/-SD) of tracer. Following PET imaging, the radioactivity in voided urine was measured. The experimental human data were used for residence time estimations. Radiation doses were calculated with OLINDA/EXM.In rats, the radioactivity distributed mainly to the kidneys, lungs, liver and adrenal gland. The effective dose in a human adult of about 70 kg was 0.0044 mSv/MBq, which is equivalent to 2.0 mSv from 460 MBq of [(11)C]choline PET. The highest absorbed doses in humans were 0.021 mGy/MBq in the kidneys, 0.020 mGy/MBq in the liver and 0.029 mGy/MBq in the pancreas. Only 2.0% of injected radioactivity was excreted in the urine during the 1.5 h after injection.The absorbed radiation doses after administration of 460 MBq of [(11)C]choline were low. Except for the pancreas, biodistribution in the rat was in accordance with that in humans, but rat data may underestimate the effective dose, suggesting that clinical measurements are needed for a more detailed estimation. The observed effective doses suggest the feasibility of [(11)C]choline PET for human studies.

Summary Introduction: Expression of vascular adhesion protein-1 (VAP-1) is induced at the sites of inflammation where extravasation of leukocytes from blood to the peripheral tissue occurs. VAP-1 is a potential target for anti-inflammatory therapy and for in vivo imaging of inflammation. Purpose of this study was to preliminarily evaluate a novel VAP-1-targeting peptide as a potential PET imaging agent. Methods: Cyclic 17-amino-acid peptide selected from phage display libraries was 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA) conjugated via 8-amino-3,6-diooxaoctanoyl linker (polyethylene glycol, PEG derivative) and labelled with 68Ga (68Ga-DOTAVAP-PEG-P2). In vitro stability of 68Ga-DOTAVAP-PEG-P2 was determined in saline, rat plasma and human plasma by radio-HLPC. Lipophilicity was measured by calculating octanol-water partition coefficient (logP). Whole-body distribution kinetics and stability after intravenous injection in healthy rats was studied in vivo by PET imaging, ex vivo by measuring radioactivity of excised tissues, and by radio-HPLC. Results: In vitro the 68Ga-DOTAVAP-PEG-P2 remained stable >4 h in saline and rat plasma, but degraded slowly in human plasma after 2 h of incubation. The logP value of 68Ga-DOTAVAP-PEG-P2 was −1·3. In rats, 68Ga-radioactivity cleared rapidly from blood circulation and excreted quickly in urine. At 120 min after injection the fraction of intact 68Ga-DOTAVAP-PEG-P2 were 77 ± 6·0% and 99 ± 1·0% in rat plasma and urine, respectively. Conclusions: These basic and essential in vitro and in vivo studies of the new VAP-1 targeting peptide revealed promising properties for an imaging agent. Further investigations to clarify in vivo VAP-1 targeting are warranted.

Background This study evaluated the absorption, distribution, and excretion of Gallium-68 (68Ga) radionuclide after a single intravenous (i.v.) injection of 68Ge/68Ga generator eluate in healthy rats. Additionally, human radiation doses were estimated from the rat data. Methods Twenty-one female and 21 male Sprague-Dawley rats were i.v. injected with 47 ± 4 MBq of 68Ge/68Ga generator eluate, and the radioactivity of excised organs was measured using a gamma counter at 5, 30, 60, 120, or 180 min afterwards (n = 3–7 for each time point). The radioactivity concentration and plasma pharmacokinetic parameters were calculated. Subsequently, the estimates for human radiation dosimetry were determined. Additionally, 4 female and 5 male rats were positron emission tomography (PET) imaged for in vivo visualization of biodistribution. Results 68Ga radioactivity was cleared relatively slowly from blood circulation and excreted into the urine, with some retention in the liver and spleen. Notably, the 68Ga radioactivity in female genital organs, i.e., the uterus and ovaries, was considerable higher compared with male genitals. Extrapolating from the female and male rat 68Ga data, the estimated effective dose was 0.0308 mSv/MBq for a 57-kg woman and 0.0191 mSv/MBq for a 70-kg man. Conclusions The estimated human radiation burden of the 68Ge/68Ga generator eluate was slightly higher for females and similar for males as compared with somatostatin receptor ligands 68Ga-DOTANOC, 68Ga-DOTATOC, and 68Ga-DOTATATE, which is probably due to the retention in the liver and spleen. Our results revealed some differences between female and male rat data, which, at least in part, may be explained by the small sample size.

Somatostatin receptor subtype 2 (sstr2) is regarded as a potential target in malignant gliomas for new therapeutic approaches. Therefore, visualizing and quantifying tumor sstr2 expression in vivo would be highly relevant for the future development of sstr2-targeted therapies. The purpose of this study was to evaluate sstr2 status in experimental BT4C malignant gliomas.Methods. Rat BT4C malignant glioma cells were injected into BDIX rat brain or subcutaneously into nude mice. Tumor uptake of [68Ga]DOTA-(Tyr3)-Octreotide ([68Ga]DOTATOC), a somatostatin analog binding to sstr2, was studied by positron emission tomography/computed tomography (PET/CT). Additionally, subcutaneous tumor-bearing mice underwent PET imaging with 5-deoxy-5-[18F]fluororibose-NOC ([18F]FDR-NOC), a novel glycosylated peptide tracer also targeting sstr2. Ex vivo tissue radioactivity measurements, autoradiography and immunohistochemistry were performed to study sstr2 expression.Results. Increased tumor uptake of [68Ga]DOTATOC was detected at autoradiography with mean tumor-to-brain ratio of 68 ± 30 and tumor-to-muscle ratio of 9.2 ± 3.8 for rat glioma. High tumor-to-muscle ratios were also observed in subcutaneous tumor-bearing mice after injection with [68Ga]DOTATOC and [18F]FDR-NOC with both autoradiography (6.7 ± 1.5 and 4.3 ± 0.8, respectively) and tissue radioactivity measurements (6.5 ± 0.8 and 4.8 ± 0.6, respectively). Furthermore, sstr2 immunohistochemistry showed positive staining in both tumor models. However, surprisingly low tumor signal compromised PET imaging. Mean SUVmax for rat gliomas was 0.64 ± 0.28 from 30 to 60 min after [68Ga]DOTATOC injection. The majority of subcutaneous tumors were not visualized by [68Ga]DOTATOC or [18F]FDR-NOC PET.Conclusions. Experimental BT4C gliomas show high expression of sstr2. Weak signal in PET imaging, however, suggests only limited benefit of [68Ga]DOTATOC or [18F]FDR-NOC PET/CT in this tumor model for in vivo imaging of sstr2 status.

The golden standard in nuclear medicine imaging of inflammation is the use of autologous radiolabeled leukocytes. Although their diagnostic accuracy is precise, the preparation of the leukocytes is both laborious and potentially hazardous for laboratory personnel. Molecules involved in leukocyte migration (homing-associated molecules) could serve as targets for the development of imaging agents for inflammation. An excellent target would be a molecule that is absent or expressed at low levels in healthy tissues, but is present or upregulated at the sites of inflammation. In this paper, we will review the literature concerning the use of homing-associated molecules as imaging targets. We will especially concentrate on vascular adhesion protein-1 due to the promising results regarding its use as a target for the imaging of inflammation.

The aim of this study was to evaluate inflammation and tumour imaging with a vascular adhesion protein 1 (VAP-1) targeting peptide (68)Ga-DOTAVAP-P1 in comparison with (18)F-FDG.Rats with both subcutaneous human pancreatic adenocarcinoma xenografts and turpentine oil-induced acute sterile inflammation were evaluated by dynamic positron emission tomography (PET) and by digital autoradiography of tissue cryosections. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections.(68)Ga-DOTAVAP-P1 delineated acute, sterile inflammation comparable with (18)F-FDG. However, the tumour uptake of (68)Ga-DOTAVAP-P1 was low in contrast to prominent (18)F-FDG uptake. The standardised uptake values of inflammation and tumours by PET were 1.1 +/- 0.4 (mean +/- SEM) and 0.4 +/- 0.1 for (68)Ga-DOTAVAP-P1 and 2.0 +/- 0.5 and 1.6 +/- 0.8 for (18)F-FDG, respectively. In addition, PET studies showed inflammation to muscle and tumour to muscle ratios of 5.1 +/- 3.1 and 1.7 +/- 0.3 for (68)Ga-DOTAVAP-P1 and 6.2 +/- 0.7 and 4.6 +/- 2.2 for (18)F-FDG, respectively. Immunohistochemistry revealed increased expression of luminal VAP-1 on the endothelium at the site of inflammation and low expression in the tumourThe (68)Ga-DOTAVAP-P1 PET was able to visualise inflammation better than tumour, which was in accordance with the luminal expression of VAP-1 on vasculature in these experimental models.

Purpose The aim of the study was to compare 68Ga-chloride with 2-[18F]fluoro-2-deoxy-d-glucose (FDG) for the imaging of pancreatic xenografts. Procedures Rats with subcutaneous human pancreatic adenocarcinoma xenografts were evaluated in vivo by dynamic positron emission tomography (PET) and ex vivo by measuring radioactivity of excised tissues and by digital autoradiography of tumor cryosections. Results Both tracers were capable of delineating all subcutaneous tumors from surrounding tissues by PET. The standardized uptake values of tumors by PET were 0.9 ± 0.3 (mean ± SD) for 68Ga-chloride (n = 13) and 1.8 ± 1.2 for FDG (n = 11). Ex vivo studies showed tumor-to-muscle ratio of 4.0 ± 0.3 for 68Ga-chloride (n = 4) and 7.9 ± 3.2 for FDG (n = 4). Conclusions 68Ga-chloride delineated subcutaneously implanted pancreatic adenocarcinoma xenografts by PET, but the uptake was lower than FDG. Further studies to clarify the value of 68Ga-chloride for PET imaging of tumors are warranted.

Background Vascular adhesion protein-1 (VAP-1) is an adhesion molecule that plays a key role in recruiting leucocytes into sites of inflammation. We have previously shown that 68Gallium-labelled VAP-1-targeting peptide (68Ga-DOTAVAP-P1) is a positron emission tomography (PET) imaging agent, capable of visualising inflammation in rats, but disadvantaged by its short metabolic half-life and rapid clearance. We hypothesised that prolonging the metabolic half-life of 68Ga-DOTAVAP-P1 could further improve its imaging characteristics. In this study, we evaluated a new analogue of 68Ga-DOTAVAP-P1 modified with a mini-polyethylene glycol (PEG) spacer (68Ga-DOTAVAP-PEG-P1) for in vivo imaging of inflammation. Methods Whole-body distribution kinetics and visualisation of inflammation in a rat model by the peptides 68Ga-DOTAVAP-P1 and 68Ga-DOTAVAP-PEG-P1 were evaluated in vivo by dynamic PET imaging and ex vivo by measuring the radioactivity of excised tissues. In addition, plasma samples were analysed by radio-HPLC for the in vivo stability of the peptides. Results The peptide with the mini-PEG spacer showed slower renal excretion but similar liver uptake as the original peptide. At 60 min after injection, the standardised uptake value of the inflammation site was 0.33 ± 0.07 for 68Ga-DOTAVAP-P1 and 0.53 ± 0.01 for 68Ga-DOTAVAP-PEG-P1 by PET. In addition, inflammation-to-muscle ratios were 6.7 ± 1.3 and 7.3 ± 2.1 for 68Ga-DOTAVAP-P1 and 68Ga-DOTAVAP-PEG-P1, respectively. The proportion of unchanged peptide in circulation at 60 min after injection was significantly higher for 68Ga-DOTAVAP-PEG-P1 (76%) than for 68Ga-DOTAVAP-P1 (19%). Conclusion The eight-carbon mini-PEG spacer prolonged the metabolic half-life of the 68Ga-DOTAVAP-P1 peptide, leading to higher target-to-background ratios and improved in vivo PET imaging of inflammation.