Misfolded superoxide dismutase-1 (mSOD1) is an abnormal protein observed in amyotrophic lateral sclerosis (ALS) and constitutes a therapeutic target. The present study evaluated the biodistribution, dosimetry, and safety of a new antibody-based radiopharmaceutical, [89Zr]Zr-DFO-AP-101, targeting mSOD1. Seven control participants and one patient with ALS received 41 ± 3 MBq of [89Zr]Zr-DFO-AP-101. They were followed up with five whole-body positron emission tomography (PET) scans over 10 days. Semi-automatic segmentation was performed on the images to derive time-activity curves, radiotracer effective half-life and dose exposure. Total elimination of the radiotracer (urinary and hepatobiliary) was 25–30

PET is the modality of choice for studying the biochemistry and physiology of the human brain in vivo, although its low spatial resolution, attributable to inherent physical and technical constraints, has limited its ability to resolve small cerebral structures. Here, we report PET images of the human brain obtained at a volumetric resolution of nearly 2 µL. Methods: A dedicated ultra-high-resolution (UHR) PET scanner featuring 1.2-mm true pixelated detectors was developed to achieve microvolumetric spatial resolution. A partially assembled UHR PET scanner with an axial field of view of 143 mm was used to obtain 18F-FDG PET images of the human brain. Patients who had a clinical PET/CT scan subsequently underwent UHR PET on completion of their medical examination. UHR PET images were reconstructed using a 3-dimensional ordered-subset expectation maximization iterative algorithm with analytic coincidence function modeling. Reconstructed images were normalized to the Montreal Neurological Institute 152 brain template and analyzed using atlases for region identification. Relative SUVs to the cerebellum were extracted for selected small brain structures. Results: All major brain regions were easily identifiable in UHR PET images, including details of the primary motor and somatosensory cortices, caudate nucleus, putamen, thalamus, inferior colliculi, and dentate nuclei. Notably, regions rarely seen so distinctly with 18F-FDG PET, such as the subthalamic areas and brainstem nuclei, were successfully resolved, suggesting that UHR PET has the potential to provide enhanced quantification of these tiny cerebral structures. This was further confirmed by higher SUV ratios in the UHR PET images compared with the PET/CT images. The UHR PET image of 1 patient revealed hypermetabolic foci in the cerebellum that were not discernible on the PET/CT and MR images. Conclusion: UHR PET images of the human brain at nearly 2-µL volumetric spatial resolution were obtained. Previously indistinguishable, small, highly relevant regions of the brain were resolved, paving the way for more accurate and detailed studies with the potential for greater insight in neuropsychiatry, neurooncology, and neurodegenerative diseases.

Radiosynoviorthesis is approved in several European countries and the United States to treat refractory synovitis in many inflammatory joint diseases, such as rheumatoid arthritis, spondyloarthropathies, and other arthritic joint diseases. No radiopharmaceuticals for radiosynoviorthesis are currently approved in Canada. The aim of this Health Canada-approved trial was to demonstrate the safety and efficacy of radiosynoviorthesis. Methods: Between July 2012 and November 2017, we conducted a multicenter, prospective, interventional Canadian trial. Patients (n = 360) with synovitis refractory to standard treatments after failing 2 intraarticular glucocorticoid injections were included. They were followed up at 3, 6, and 12 mo. Outcome measures included adverse events (AEs) and clinical signs of synovitis (pain, swelling, and joint effusion) measured with the Health Assessment Questionnaire Disability Index, the Disease Activity Score, and the Visual Analog Scale. Results: In total, 392 joints were treated, including those reinjected after 6 mo (n = 34). Of these, 83.4% (327/392) were injected with [90Y]Y-citrate for the knees and 9.9% (39/392) with [186Re]Re-sulfide for medium-sized joints. Of the joints treated, 82.7% (324/392) were knees. Fifty-five AEs, most of them of mild grade, occurred and resolved without sequelae and were not life-threatening. The incidence of radiosynoviorthesis-related AEs was 9.4% (34/360). The proportion of patients showing an improvement in synovitis symptoms after radiosynoviorthesis was significant at 3 mo and was maintained up to 12 mo (P < 0.001). Conclusion: This study confirmed the safety of radiosynoviorthesis in the treatment of patients with synovitis refractory to standard treatments. There is evidence of sustained clinical efficacy at 12 mo, suggesting that radiosynoviorthesis is an effective treatment for improving synovitis symptoms.

Abstract Disclosure: S. Cote: None. K. Fathy: None. S. Lenet: None. O. Espinosa-Bentancourt: None. E. Lavallee: None. E. Croteau: None. D. Rottembourg: None. J. Lepage: None. K. Whittingstall: None. There is increasing demand for gender-affirming hormonal therapy (GAHT) in recent years, with increased access to GAHT for transgender teenagers. While it is well documented that psychological outcomes and quality of life improve after GAHT, it remains unclear how cerebrovascular physiology changes with GAHT. Therefore, this study aimed to investigate the effects of testosterone GAHT on cerebral microvascular and macrovascular physiology in teenage transgender men receiving GAHT. Six teenage transgender men were referred by their endocrinologist prior to the start of GAHT. Participants visited the research center before GAHT (session 1) and between 3 to 9 months into their GHAT (session 2). At each visit, participants completed a non-contrast-enhanced magnetic resonance imaging (MRI) protocol. This protocol assessed the macrovasculature using time-of-flight magnetic resonance angiography to visualize cerebral arteries and estimate diameters of the Circle of Willis and 2D-Phase Contrast to estimate large artery blood velocity. The microvasculature was assessed using pseudo-Continuous Arterial Spin Labelling, which estimates cerebral blood flow (CBF). Paired-sample t-tests were performed between sessions to determine if arterial diameters, CBF and blood velocity change with GAHT. Whole-brain CBF significantly decreased with GAHT between session 1 and session 2 (CBFS1=69.15 +/- 5.85 ml/100g/min; CBFS2=59.30 +/- 8.11 ml/100g/min; t=3.19, p=0.02, df=5). The average percent change in CBF was -9.85%, and the largest decrease experienced by a participant was -20.44%. Note that even though CBF decreased, average whole-brain CBF for all participants remained in a healthy range. We observed no significant change in large artery blood velocity or arterial lumen diameters of the Circle of Willis after starting GAHT. Our results suggest that GAHT influences the brain’s microvasculature. As women tend to have higher CBF than men, the reduction in CBF likely reflects a masculinization of the brain with GAHT. Without EEG to probe neuronal activity, it is difficult to determine if the change is due to decreased neuronal activity or a structural and/or functional change in the microvasculature. Considering that little is known about the long-term effects of GAHT on the brain, these results highlight the need to better understand how hormonal states impact human cerebrovascular physiology and how it may relate to risk for cerebrovascular disease and neurological disorders. Presentation: Sunday, June 18, 2023

This article reports the preliminary results of a phase II clinical trial investigating the use of the estrogen receptor (ER)-targeting PET tracer 4-fluoro-11β-methoxy-16α-18F-fluoroestradiol (18F-4FMFES) and 18F-FDG PET in endometrial cancers. In parallel, noninvasive interventions were attempted to slow progression of 18F-4FMFES metabolites in the intestines to reduce abdominal background uptake. Methods: In an ongoing study, 25 patients who received prior pathologic confirmation of an ER-positive endometrial cancer or endometrial intraepithelial neoplasia agreed to participate in the ongoing clinical trial. Patients were scheduled for 18F-FDG and 18F-4FMFES PET/CT imaging in random order and within 2 wk. Patients were administered either 4 mg of loperamide orally before 18F-4FMFES tracer injection or repeated intravenous injection of 20 mg of hyoscine N-butylbromide during 18F-4FMFES PET/CT. Regions of interest covering the whole abdomen and excluding the liver, bladder, and uterus were drawn for the 18F-4FMFES PET images, and an SUV threshold of more than 4 was applied. The volume of the resulting region was compared between the different interventions to estimate the extent of the intestinal background uptake. Results: Repeated injection of hyoscine N-butylbromide substantially reduced the intestinal background volume, whereas loperamide had a significant but moderate effect. 18F-4FMFES tumor SUVmax ranged from 3.0 to 14.4 (9.4 ± 3.2), whereas 18F-FDG SUVmax ranged from 0 to 22.0 (7.5 ± 5.1). Tumor-to-background ratio was significantly higher for 18F-4FMFES (16.4 ± 5.4) than for 18F-FDG (7.4 ± 4.6). Significant differences were observed between grade 1 and higher-grade tumors concerning 18F-4FMFES uptake and contrast, 18F-FDG uptake, and the 18F-FDG/18F-4FMFES uptake ratio. Conclusion: It is possible to improve 18F-4FMFES abdominal background using hyoscine N-butylbromide. Both 18F-FDG and 18F-4FMFES PET are suitable for detection of ER-positive endometrial cancers, although 18F-4FMFES yielded a better tumor contrast than did 18F-FDG.

The calcification of arterial wall is a process linked to osteogenesis, thus, the PET radiotracer Fluorine-18F-NaF (18F-NaF) is capable of identifying micro-calcification in atherosclerotic plaque. In the present work, we assessed the relationship of calcification seen on CT images and 18F-NaF uptake measured in PET image. Calcification was classified based on its intensity (IC), area ratio (RCA) and scores (ACS) and each group was clustered using Hierarchical K-means algorithm (AHK) with the use of silhouette-coefficient. 18F-NaF uptake was quantified as tissue to background ratio by using superior vena cava for blood pool correction. TBR values corresponded to IC clusters were 2.52, IQR (1.70 – 2.76), 2.40, IQR (1.93 – 2.68), 2.11, IQR (1.95 – 2.27) and 1.86, IQR (1.36 – 2.33) for CI1, CI2, CI3 and CI4 respectively and 2.68 IQR (2.14 – 2.73), 2.20 IQR (1.52 – 2.46) and 2.26 IQR (1.40 – 2.43) for RCA1, RCA2 and RCA3 respectively. For ACS clusters, TBR values were 2.53 IQR (1.64 – 2.69), 2.31 IQR (2.13 – 2.55) and 2.25 IQR (1.60 – 2.38) for ACS1, ACS2 and ACS3 respectively. There was a reverse association of 18F-NaF uptake as a function of area, where large area (RCA3) was statistically significantly different (p=0.027) compared to small area (RCA1). No statistical difference was observed among CI and ACS clusters. In conclusion, there is a reverse correlation of calcification area as a function of 18F-NaF uptake. No statistical association of calcification intensity and 18F-NaF uptake. 18F-NaF may be a useful marker for the detection of plaque vulnerability. Multi-spot of calcification (MSCS) has higher 18F-NaF uptake compared to single spot of calcification (SSCS), and the difference was statistically significantly different

Sex hormones estrogen (EST) and progesterone (PROG) have received increased attention for their important physiological action outside of reproduction. While studies have shown that EST and PROG have significant impacts on brain function, their impact on the cerebrovascular system in humans remains largely unknown. To address this, we used a multi-modal magnetic resonance imaging (MRI) approach to investigate the link between serum hormones in the follicular phase and luteal phase of the menstrual cycle (MC) with measures of cerebrovascular function (cerebral blood flow [CBF]) and structure (intracranial artery diameter). Fourteen naturally cycling women were recruited and assessed at two-time points of their MC. CBF was derived from pseudo-continuous arterial spin labeling while diameters of the internal carotid and basilar artery was assessed using time of flight magnetic resonance angiography, blood samples were performed after the MRI. Results show that PROG and EST had opposing and spatially distinct effects on CBF: PROG correlated negatively with CBF in anterior brain regions (r = -.86, p < .01), while EST correlations were positive, yet weak and most prominent in posterior areas (r = .78, p < .01). No significant correlations between either hormone or intracranial artery diameter were observed. These results show that EST and PROG have opposing and regionally distinct effects on CBF and that this relationship is likely not due to interactions with large intracranial arteries. Considering that CBF in healthy women appears tightly linked to their current hormonal state, future studies should consider assessing MC-related hormone fluctuations in the design of functional MRI studies in this population.

A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11β-methoxy-16α-[18F]-fluoroestradiol (4FMFES) and its comparison with 16α-[18F]-fluoroestradiol (FES) in mice, rats, and humans with a focus on the brain uptake. Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semi-quantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field of view, brain uptake of discernable foci was measured and reported as SUVMax. Regardless of the species studied, 4FMFES and FES uptake were relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates that the signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial preoptic area. Dissection data further confirmed those findings and revealed additional signals corresponding to the arcuate and ventromedial nuclei, along with the medial and cortical amygdala. 4FMFES allowed visualization of ER expression in the pituitary in humans and two different rodent species with better contrast than FES. Improvement in clinical spatial resolution might allow visualization and analysis of other ER-rich brain areas in humans. Further work is now possible to link 4FMFES pituitary uptake to cognitive functions.

Positron Emission Tomography (PET) imaging with 11C-Acetate (ACE) is regularly used in cardiovascular and in cancer imaging. In the earlier stages of ACE developments, it has been mainly used for hepatocellular carcinoma, prostate cancer, and myocardial oxygen consumption. The previous studies compared the advantage of ACE with 18F-Fluorodeoxyglucose (18F-FDG) imaging using Standard Uptake Value (SUV) and the tissue-to-blood ratio (TBR) method. The current study proposes the application of dynamic ACE PET imaging in monitoring the early response to cancer treatment. We conducted two dynamic ACE PET scans on two patients suffering from Head and Neck Cancer (HNC) (Squamous Cell Carcinoma) in the base of the tongue. Pre-treatment dynamic ACE and static 18F-FDG PET were conducted before initiation of the treatment, and the second ACE dynamic scan was performed after four weeks of radiotherapy (after 35 Gy). We applied the two-tissue compartment model to represent the kinetics of ACE in HNC. The results showed a reduction in tumor volume by more than 50% compared to the initial volume in patient-1. Besides, patient-2 has displayed a more reduced tumor volume after 4 weeks of treatment. Compartmental modeling parameter k2 increased after radiotherapy dose in both patients. This increase of k2 could reflect the reoxygenation process inside the tumor, and it can reflect the early treatment response. In conclusion, ACE could predict the early changes in the tumor perfusion and the oxidative metabolism to optimally adjust the treatment.

After encouraging preclinical and human dosimetry results for the novel estrogen receptor (ER) PET radiotracer 4-fluoro-11β-methoxy-16α-18F-fluoroestradiol (18F-4FMFES), a phase II clinical trial was initiated to compare the PET imaging diagnostic potential of 18F-4FMFES with that of 16α-18F-fluoroestradiol (18F-FES) in ER-positive (ER+) breast cancer patients. Methods: Patients diagnosed with ER+ breast cancer (n = 31) were recruited for this study, including 6 who underwent mastectomy or axillary node dissection. For each patient, 18F-FES and 18F-4FMFES PET/CT scans were done sequentially (within a week) and in random order. One hour after injection of either radiotracer, a head-to-thigh static scan with a 2-min acquisition per bed position was obtained. Blood samples were taken at different times after injection to assess each tracer metabolism by reverse-phase thin-layer chromatography. The SUVmean of nonspecific tissues and the SUVmax of the tumor were evaluated for each detected lesion, and tumor-to-nonspecific organ ratios were calculated. Results: Blood metabolite analysis 60 min after injection of the tracer showed a 2.5-fold increase in metabolic stability of 18F-4FMFES over 18F-FES. Although for most foci 18F-4FMFES PET had an SUVmax similar to that of 18F-FES PET, tumor contrast improved substantially in all cases. Lower uptake was consistently observed in nonspecific tissues for 18F-4FMFES, notably a 4-fold decrease in blood-pool activity as compared with 18F-FES. Consequently, image quality was considerably improved using 18F-4FMFES, with lower overall background activity. As a result, 18F-4FMFES successfully identified 9 more lesions than 18F-FES. Conclusion: This phase II study with ER+ breast cancer patients showed that 18F-4FMFES PET achieves a lower nonspecific signal and better tumor contrast than 18F-FES PET, resulting in improved diagnostic confidence and lower false-negative diagnoses.

OP03 Selective extraction of medically-related radionuclides from proton-irradiated thorium targets

A single-site prospective open-label clinical study with cyclotron-produced sodium 99mTc-pertechnetate (99mTc-NaTcO4) was performed in patients with indications for a thyroid scan to demonstrate the clinical safety and diagnostic efficacy of the drug and to confirm its equivalence with conventional 99mTc-NaTcO4 eluted from a generator. Methods: 99mTc-NaTcO4 was produced from enriched 100Mo (99.815%) with a cyclotron (24 MeV; 2 h of irradiation) or supplied by a commercial manufacturer (bulk vial eluted from a generator). Eleven patients received 325 ± 29 (mean ± SD) MBq of the cyclotron-produced 99mTc-NaTcO4, whereas the age- and sex-matched controls received a comparable amount of the generator-derived tracer. Whole-body and thyroid planar images were obtained for each participant. In addition to the standard-energy window (140.5 keV ± 7.5%), data were acquired in lower-energy (117 keV ± 10%) and higher-energy (170 keV ± 10%) windows. Vital signs and hematologic and biochemical parameters were monitored before and after tracer administration. Results: Cyclotron-produced 99mTc-NaTcO4 showed organ and whole-body distributions identical to those of conventional 99mTc-NaTcO4 and was well tolerated. All images led to a clear final diagnosis. The fact that the number of counts in the higher-energy window was significantly higher for cyclotron-produced 99mTc-NaTcO4 did not influence image quality in the standard-energy window. Image definition in the standard-energy window with cyclotron-produced 99mTc was equivalent to that with generator-eluted 99mTc and had no particular features allowing discrimination between the 99mTc production methods. Conclusion: The systemic distribution, clinical safety, and imaging efficacy of cyclotron-produced 99mTc-NaTcO4 in humans provide supporting evidence for the use of this tracer as an equivalent for generator-eluted 99mTc-NaTcO4 in routine clinical practice.

475 Objectives A Phase I prospective open-label single-site clinical study in patients with indication for thyroid scan was initiated to demonstrate the safety and efficacy of sodium pertechnetate 99mTc ([99mTc]NaTcO4) produced using a medium-energy cyclotron, and confirm its equivalence to the tracer eluted from a generator. Methods 99mTc was produced via the 100Mo(p,2n)99mTc nuclear reaction from enriched 100Mo (>99.8%) thick targets irradiated for 2 h at 24→10 MeV. [99mTc]NaTcO4 was purified according to a modified published procedure and subjected to a series of quality control tests. Ten patients received 340 MBq (±10%) of cyclotron-produced [99mTc]NaTcO4 and twenty age/sex matched controls received the same amount of the generator-derived tracer. Both groups underwent standard procedure for the thyroid scan and additional whole-body scan. In addition to the usual 140.5 keV ±7.5% energy window, low and high energy data were also acquired (117 keV ±10% and 170 keV ±10%). Vital signs, hematological and biochemical parameters were monitored for patients receiving cyclotron-produced [99mTc]NaTcO4. Qualitative/quantitative image analysis and comparison were blinded. Results All formulated batches met provisional release specifications and complied with standard requirements for parenteral injections. No adverse effects were observed. For case matches, the biodistribution was identical for cyclotron and generator produced radiotracers. Image definition and contrast were equivalent and without particular features allowing discrimination between 99mTc production methods. Conclusions [99mTc]NaTcO4 manufactured using medium-energy cyclotron at reported conditions is safe for use in humans. Its systemic distribution and image quality were equivalent to 99mTc sourced from a conventional generator.

Cyclotron production of Tc-99m is a promising route to supply Tc-99m radiopharmaceuticals. Higher Tc-99m yields can be obtained with medium-energy cyclotrons in comparison to those dedicated to PET isotope production. To take advantage of this capability, evaluation of the radioisotopic purity of Tc-99m produced at medium energy (20-24 MeV) and its impact on image quality and dosimetry was required. Methods: Thick Mo-100 (99.03% and 99.815%) targets were irradiated with incident energies of 20, 22, and 24 MeV for 2 or 6 h. The targets were processed to recover an effective thickness corresponding to approximately 5-MeV energy loss, and the resulting sodium pertechnetate Tc-99m was assayed for chemical, radiochemical, and radionuclidic purity. Radioisotopic content in final formulation was quantified using gamma-ray spectrometry. The internal radiation dose for Tc-99m-pertechnetate was calculated on the basis of experimentally measured values and biokinetic data in humans. Planar and SPECT imaging were performed using thin capillary and water-filled Jaszczak phantoms. Results: Extracted sodium pertechnetate Tc-99m met all provisional quality standards. The formulated solution for injection had a pH of 5.0-5.5, contained greater than 98% of radioactivity in the form of pertechnetate ion, and was stable for at least 24 h after formulation. Radioisotopic purity of Tc-99m produced with 99.03% enriched Mo-100 was greater than 99.0% decay corrected to the end of bombardment (EOB). The radioisotopic purity of Tc-99m produced with 99.815% enriched Mo-100 was 99.98% or greater (decay corrected to the EOB). The estimated dose increase relative to Tc-99m without any radionuclidic impurities was below 10% for sodium pertechnetate Tc-99m produced from 99.03% Mo-100 if injected up to 6 h after the EOB. For 99.815% Mo-100, the increase in effective dose was less than 2% at 6 h after the EOB and less than 4% at 15 h after the EOB when the target was irradiated at an incident energy of 24 MeV. Image spatial resolution and contrast with cyclotron-produced Tc-99m were equivalent to those obtained with Tc-99m eluted from a conventional generator. Conclusion: Clinical-grade sodium pertechnetate Tc-99m was produced with a cyclotron at medium energies. Quality control procedures and release specifications were drafted as part of a clinical trial application that received approval from Health Canada. The results of this work are intended to contribute to establishing a regulatory framework for using cyclotron-produced Tc-99m in routine clinical practice.

This paper presents repeated measurements of atherosclerosis using bimodality positron emission tomography and computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) to assess its uptake in aorta, iliac and femoral arteries in three groups of elderly subjects classified as normals (N), hypercholesterolemics (H) and with stable angina (A) in a 12 months follow-up (T0 to T12). The subjects in group H were taking rosuvastatin (20mg/d) for 12 months before the second scan. The calcifications in the arteries were determined by CT imaging and the artery PET images were analyzed slice by slice. The standard uptake values (SUVs) for 18F-FDG uptake were classified in two main groups: calcified and non-calcified arteries and each main group comprises six sub-groups for the three subject groups N, H and A, and for the two measurements 12 months apart. Although the calcifications were present at some portions of the arteries in all subjects (23%, 36% and 44% of calcified sites to total sites analyzed, respectively, in groups N, H and A), the results show the most noticeable SUV changes after 12 months was in group N of non-calcified arteries. In the three groups, the calcified arteries showed no significant differences between T0 and T12 while significant differences were observed for the non-calcified arteries. However, there were no significant changes at T12 between groups N and H following rosuvastatin intake in group H. In conclusion, the quantitative analysis with 18F-FDG-PET/CT could be efficient in the localization of the inflammation and evaluation of its progression in atherosclerosis instead of global evaluations with systemic inflammation biomarkers.