Hyperostosis frontalis interna on fluorine-18 sodium fluoride PET/computed tomography of obese cancer patients: a potential mimicker of metastasis.

OBJECTIVE: The objective of this retrospective study was to identify the uptake patterns and suggest a quantitative method to detect hyperostosis frontalis interna (HFI) on fluorine-18 sodium fluoride ([18F]NaF) PET/computed tomography (CT). METHODS: Between January 2019 and December 2021, patients who underwent [18F]NaF PET/CT with a BMI of 30 and above, were included. Three nuclear medicine consultants reviewed the studies to determine the presence and identify the uptake patterns of HFI. Quantitative evaluation was performed on PET images using the total number of counts over the frontal bone and the ratio of counts between the frontal bone and iliac crest. RESULTS: A total of 105 out of 249 cases were included in this study. Among these scans, there were 67 positive HFI in [18F]NaF PET scans representing 64% of the studied population. As for the [18F]NaF PET uptake pattern, there were 53 with uniformly diffused and 14 with heterogeneous uptake pattern. There were 17 out of 67 with positive HFI in [18F]NaF PET scans but negative CT scans. CONCLUSION: HFI is a common finding on [18F]NaF PET in obese patients and is probably underdiagnosed. HFI may present with a heterogeneous and diffuse pattern of uptake on [18F]NaF PET. The proposed quantitative analysis using the count ratios is in agreement with the visual evaluation of [18F]NaF PET images regardless of the CT findings. Awareness of this condition and its scintigraphic patterns is warranted since it can have clinical significance and may mimic other pathologies including metastasis in cancer patients.

Glucose intolerance induces anxiety-like behaviors independent of obesity and insulin resistance in a novel model of nutritional metabolic stress.

OBJECTIVES: Type 2 diabetes (T2D) is a metabolic disease of major public health concern. It impacts peripheral tissues and the central nervous system, leading to systemic dysmetabolism and neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we sought to address this question by developing a proprietary (P-) high-fat diet (HFD), in which glucose intolerance precedes weight gain and insulin resistance. METHODS: The P-HFD model was nutritionally characterized, and tested in vivo in mice that underwent behavioral and metabolic testing. The diet was benchmarked against reference models. . RESULTS: P-HFD has 42% kcal from fat, high monounsaturated/polyunsaturated fatty acid ratio, and 10% (w/v) sucrose in drinking water. When administered, from the early stages of glucose intolerance alone, animals exhibit anxiety-like behavior, without depression nor recognition memory deficits. Long-term P-HFD feeding leads to weight gain, brain glucose hypometabolism as well as impaired recognition memory. Using an established genetic model of T2D (db/db) and of diet-induced obesity (60% kcal from fat) we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. DISCUSSION: Our findings demonstrate that glucose intolerance alone can elicit anxiety-like behavior. Through this study, we also provide a novel nutritional model (P-HFD) to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.

Potential Pitfalls of Steatopygia on Bone Scintigraphy and the Added Value of SPECT and SPECT/CT.

OBJECTIVES: A retrospective study of bone scintigraphy to assess the prevalence of steatopygia on bone scintigraphy of obese patients and evaluate its effect on the appearance of the lumbar spine, and the added benefit of SPECT and SPECT/CT in overcoming possible artifacts. METHODS: Between 2016 and 2019, patients who underwent bone scintigraphy, BMI ≥ 30, were included. Three nuclear medicine consultants reviewed the studies to determine whether significant steatopygia is present, if it resulted in attenuation of underlying lumber spine and crease edge artifact. SPECT or SPECT/CT images were reviewed to evaluate their impact in diagnosis. RESULTS: 56 patients out of the 100 were noted with steatopygia on planar images. Among the group of 80 obese patients, 50% patients showed steatopygia, while in the group of 20 morbidly obese patients, 80% patients showed steatopygia. 32 patients of the 56 with steatopygia, had significant attenuation at the lower lumber vertebrae. Nine of these patients showed crease edge artifact. SPECT and SPECT/CT clarified the scintigraphic abnormalities noted in all patients including patients with edge artifact alleviating diagnostic difficulty. Among the nine patients with edge artifact, six patients showed normal appearance on SPECT/CT images while three showed true abnormalities. CONCLUSIONS: Steatopygia is common on bone scintigraphy of obese patients, higher in females and morbidly obese patients. Obesity related artifacts in bone scintigraphy, including attenuation effect and edge artifact, are common in this patient group. SPECT or SPECT/CT improves the diagnostic accuracy by overcoming the steatopygia effects seen on planar images.

Reducing Radiation Exposure from PET Patients.

This study measured the typical emitted radiation rate from the urinary bladder of PET patients after their scan and investigated simple methods for reducing the emitted radiation before discharge. Methods: The study included 83 patients (63 18F-FDG and 20 18F-NaF patients). Emitted radiation from the patients' urinary bladder was measured with an ionization survey meter at a 1-m distance, presuming the urinary bladder to be the primary source of radiation. The measurements were taken at different time points after PET image acquisition: immediate (prevoid 1), voided (postvoid 1), after waiting 30 min in the uptake room while drinking 500 mL of water (prevoid 2), and voided again (postvoid 2). Results: For 18F-FDG patients, the reduction of emitted radiation due to drinking water and voiding alone from prevoid 1 to decay-corrected postvoid 2 was an average of 22.49% ± 7.48% (13.65 ± 3.42 µSv/h to 10.48 ± 2.37 µSv/h, P < 0.001). For 18F-NaF patients, the reduction was an average of 25.80% ± 10.03% (9.83 ± 2.01 µSv/h to 7.23 ± 1.49 µSv/h, P < 0.001). Conclusion: In addition to the physical decay of the radiotracers, using the biologic clearance properties resulted in a significant decrease of the emitted radiation in this study. Implementing additional water consumption to facilitate voiding with 30 min of wait time before discharging certain 18F-FDG and 18F-NaF patients who need to be in close contact with others, such as elderly, caregivers, and inpatients, might facilitate lowering their emitted radiation by an average of 22%-25% due to voiding, not counting in the physical decay that should add an additional 17% reduction.

Effect of brown adipose tissue activation on myocardial fluorine-18-fluorodeoxyglucose uptake.

The aim of this study is to investigate the relationship between brown adipose tissue (BAT) activation and myocardial fluorine-18-fluorodeoxyglucose ([18F] FDG) uptake in terms of intensity and patterns. The patients were divided into two groups as follows: BAT and control groups. The BAT group consists of 34 cases that showed BAT uptake. The control group, with no BAT uptake, included 68 patients who were matched for body mass index, gender, and season. The scans were retrospectively reviewed by two nuclear medicine physicians who visually evaluated the intensity of myocardial [18F] FDG uptake. The myocardial [18F] FDG uptake was visually classified into the following three patterns: diffuse, heterogeneous, and focal. The regions of activated BAT distribution were noted. The mean myocardial [18F] FDG uptake was 2.50 ± 0.75 for the BAT group and 2.13 ± 0.88 for the control group with a statistically significant difference (P = 0.031). The myocardial [18F] FDG uptake pattern was similar in the BAT and control groups with the diffuse pattern being the most common, followed by the heterogeneous and less commonly focal. In the BAT group, the anatomical distribution of BAT was mainly in supraclavicular, paravertebral, and axillary and to a lesser extent in cervical regions. BAT group had a significantly higher intensity of [18F] FDG myocardial uptake compared to that of the control group. The presence of activated BAT did not affect the pattern of myocardial uptake. Knowledge of these findings may help in understanding the variability of myocardial [18F] FDG uptake and consequently in avoiding misinterpretation of cardiac findings in positron-emission tomography/computed tomography studies.

Effect of Causative Micro-organisms on Patterns of Labeled White Blood Cells in Osteomyelitis.

OBJECTIVE: The aim of this study is to investigate the effect of microbiological characteristics of causative organisms on the scintigraphic patterns of labeled-white blood cells (WBC) scan in cases of proven osteomyelitis. MATERIALS AND METHODS: Retrospective analysis of 25 patients referred with suspected osteomyelitis and had both bone and labeled-WBC scans performed and complete records of the microbiological culture of the causative organism. The bone and labeled-WBC scans were retrieved and reviewed by two nuclear medicine physicians. Any definite focal accumulation of labeled WBCs within the bone was considered positive for osteomyelitis. Diagnosis of osteomyelitis in the discharge summary was considered the reference standard and was based on a combination of the clinical scenario, imaging, and laboratory findings including microbiology. Correlation of the pattern of labeled WBC and the type of microorganisms was done. RESULTS: A total of 16 patients were included in this study, seven females and nine males. Of these, seven patients had Gram-positive whereas nine patients had Gram-negative organisms. The majority (85.7%) of Gram-positive organisms showed increased accumulation of labeled WBCs, whereas only one-third (33.3%) of patients with Gram-negative organisms had such finding. CONCLUSION: The pattern observed in this study shows that the false-negative results of labeled-WBC scans were mainly noted in patients with Gram-negative as opposed to Gram-positive infections. This confirms the experimental animal study findings that the secretion of anti-chemotactic factors by Gram-negative organisms, seems to be inhibiting the migration of labeled WBCs to the site of infection. The inhabitation is decreasing the accumulation of labeled WBCs and consequently resulting in a false-negative finding. The study adds to evidence that microbiological characteristics of the causative organisms are another explanation for the false-negative WBC in proven osteomyelitis.

The efficacy of the available peptide receptor radionuclide therapy for neuroendocrine tumors: a meta-analysis.

AIM: This study was carried out to compare the efficacy of Y, Lu, and combination of both radiotracers (tandem) peptide receptor radionuclide therapy (PRRT) in patients with inoperable and metastatic neuroendocrine tumors. MATERIALS AND METHODS: Systematic searches of PubMed and SciVerse Scopus databases were performed till December of 2016. The data were categorized into three groups: Y-PRRT, Lu-PRRT, and tandem-PRRT. Each group was subdivided on the basis of the response criteria used: Response Evaluation Criteria in Solid Tumors (RECIST) or Southwest Oncology Group (SWOG) criteria. Disease response and disease control rates of each group were analyzed. RESULTS: For the RECIST group, Y-PRRT disease response rates ranged from 22.81 to 56.1%, with a pooled random effect of 42.92%, and the disease control rate was 100%. Lu-PRRT disease response rates ranged from 27.63 to 57.35%, with a pooled random effect of 33.41%, and disease control rates ranged between 71.88 and 100%, with a pooled fixed effect of 79.32%. As for tandem-PRRT, disease response rates ranged between 42.11 and 66.67%, with a pooled fixed effect of 50.52%, and the disease control rate ranged between 93.33 and 100%, with a pooled fixed effect of 98.97%.For the SWOG group, Y-PRRT disease response rates ranged from 5.13 to 26.56%, with a pooled random effect of 13.4%, and disease control rates ranged between 76.56 and 85.9%, with a pooled fixed effect of 80.93%. Lu-PRRT disease response rates ranged from 6.06 to 60.29%, with a pooled random effect of 26.4%, and the disease control rates between 48.48 and 85.29%, with a pooled random effect of 74.53%. CONCLUSION: Y-PRRT had the highest disease control rates under both RECIST and SWOG criteria. Tandem-PRRT had the highest disease response rate in the RECIST criteria, indicating that PRRT should be customized to each patient individually for maximum benefit.

Scintigraphic Patterns of Indium-111 Oxine-Labeled White Blood Cell Imaging of Gram-Negative versus Gram-Positive Vertebral Osteomyelitis.

OBJECTIVE: The goal of the study was to investigate whether or not gram-negative organisms that secrete antichemotactic factors cause the nonaccumulation pattern of 111In-oxine-labeled white blood cell (111In-WBC) scans. MATERIALS AND METHODS: Staphylococcus aureus (gram-positive) (group 1) was injected into 25 rabbits and Escherichia coli (gram-negative) (group 2) into another 25 to induce infection in the lumbar vertebrae or left thigh bone (femur). Sixteen successfully infected and surviving rabbits from each group were used for imaging and analysis. Of the 16 rabbits, each group included 8 with vertebral infection and 8 with femur infection. For imaging, each rabbit was injected intravenously with 11.1 MBq (300 µCi) 111In-WBC, and images were acquired 24 h later. Microscopic histopathology was performed after decalcification to confirm osteomyelitis. RESULTS: The 111In-WBC accumulation was observed in 7 (87.5%) of the 8 rabbits infected with S. aureus in the vertebrae and thigh bone. Of the rabbits infected with the gram-negative vertebrae, 1 (12.5%) showed little accumulation of 111In-WBC. Of the 8 rabbits with gram-negative-infected femurs, 1 had high accumulation and another had low accumulation of 111In-WBC, while the rest did not show any uptake. Osteomyelitis was confirmed by histopathology in all the successfully infected rabbits used for imaging. CONCLUSION: In the majority of the gram-positive-infected rabbit vertebrae there was high accumulation of 111In-WBC. However, no accumulation of 111In-WBC was observed in most of the vertebrae infected with gram-negative organisms, which release antichemotactic factors that prevent adequate accumulation of WBC at the infected area.

Ultrastructure of Hyperfunctioning Parathyroid Glands: Does it Explain Various Patterns of 99mTc-sestamibi Uptake.

The aim of this study was to correlate the uptake of 99mTc-methoxy-isobutyl-isonitrile (MIBI) with ultra-structural features of parathyroid adenomas. Twenty patients with proven primary hyperparathyroidism were evaluated prospectively. Preoperative double-phase 99mTc-MIBI scintigraphy was performed in all patients and the degree of tracer uptake by the parathyroid lesions was assessed visually and semi-quantitatively. The excised glands were examined histologically and ultrastructurally, and their features were correlated with the degree of the radiotracer uptake. At surgery, 21 parathyroid adenomas were removed (double adenoma in one patient and a solitary adenoma in each of the remaining 19 patients). 99mTc-MIBI scan detected 18 of the 21 adenomas. There was positive correlation between the degree of 99mTc-MIBI uptake and the mitochondrial contents of the parathyroid adenoma cells. Four adenomas with intense uptake had high content of mitochondria in the cells. The three false-negative scans had low-to-moderate mitochondrial content. 99mTc-MIBI uptake is related to the mitochondrial content of the parathyroid adenoma cells.

Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.

A high-affinity [(18)F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer.

INTRODUCTION: In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated. METHODS: p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [(18)F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(-) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4 h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent. RESULTS: The crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [(18)F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(-) cells (0.08%) at 4 h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4 h. CONCLUSIONS: We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [(18)F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa. ADVANCES IN KNOWLEDGE: The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [(18)F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.

Synthesis and evaluation of constrained phosphoramidate inhibitors of prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA) is a cell-surface enzyme-biomarker that is actively pursued for targeted delivery of imaging and therapeutic agents for prostate cancer. Our lab has developed PSMA inhibitors based on a phosphoramidate scaffold, which has shown both high selectivity for PSMA-positive tumors and rapid clearance in vivo when radiolabeled with (18)F. However, this scaffold exhibits hydrolytic instability under low pH and high temperature conditions, barring the use of other imaging or therapeutic radionuclides such as (68)Ga or (177)Lu. Previous studies in our lab have shown a trend in increasing acid stability as the distance between the phosphoramidate core and the α-carboxylate of the P1 residue is increased. Therefore, a new generation of phosphoramidate inhibitors was developed based on trans-4-hydroxyproline as the P1 residue to restrict the interaction of the α-carboxylate to the phosphoramidate core. These hydroxyproline inhibitors demonstrated comparable IC50 values to earlier generations as well as enhanced thermal and acid stability.

Tumor dosimetry using [124I]m-iodobenzylguanidine microPET/CT for [131I]m-iodobenzylguanidine treatment of neuroblastoma in a murine xenograft model.

PURPOSE: [(124)I]m-iodobenzylguanidine ((124)I-mIBG) provides a quantitative tool for pretherapy tumor imaging and dosimetry when performed before [(131)I]m-iodobenzylguanidine ((131)I-mIBG) targeted radionuclide therapy of neuroblastoma. (124)I (T (1/2) = 4.2 days) has a comparable half-life to that of (131)I (T (1/2) = 8.02 days) and can be imaged by positron emission tomography (PET) for accurate quantification of the radiotracer distribution. We estimated expected radiation dose in tumors from (131)I-mIBG therapy using (124)I-mIBG microPET/CT imaging data in a murine xenograft model of neuroblastoma transduced to express high levels of the human norepinephrine transporter (hNET). PROCEDURES: In order to enhance mIBG uptake for in vivo imaging and therapy, NB 1691-luciferase (NB1691) human neuroblastoma cells were engineered to express high levels of hNET protein by lentiviral transduction (NB1691-hNET). Both NB1691 and NB1691-hNET cells were implanted subcutaneously and into renal capsules in athymic mice. (124)I-mIBG (4.2-6.5 MBq) was administered intravenously for microPET/CT imaging at 5 time points over 95 h (0.5, 3-5, 24, 48, and 93-95 h median time points). In vivo biodistribution data in normal organs, tumors, and whole-body were collected from reconstructed PET images corrected for photon attenuation using the CT-based attenuation map. Organ and tumor dosimetry were determined for (124)I-mIBG. Dose estimates for (131)I-mIBG were made, assuming the same in vivo biodistribution as (124)I-mIBG. RESULTS: All NB1691-hNET tumors had significant uptake and retention of (124)I-mIBG, whereas unmodified NB1691 tumors did not demonstrate quantifiable mIBG uptake in vivo, despite in vitro uptake. (124)I-mIBG with microPET/CT provided an accurate three-dimensional tool for estimating the radiation dose that would be delivered with (131)I-mIBG therapy. For example, in our model system, we estimated that the administration of (131)I-mIBG in the range of 52.8-206 MBq would deliver 20 Gy to tumors. CONCLUSIONS: The overexpression of hNET was found to be critical for (124)I-mIBG uptake and retention in vivo. The quantitative (124)I-mIBG PET/CT is a promising new tool to predict tumor radiation doses with (131)I-mIBG therapy of neuroblastoma. This methodology may be applied to tumor dosimetry of (131)I-mIBG therapy in human subjects using (124)I-mIBG pretherapy PET/CT data.

Labeling, stability and biodistribution studies of 99mTc-cyclized Tyr3-octreotate derivatives.

INTRODUCTION: To probe the interplay between radiotracer stability and somatostatin receptor affinity, Tyr(3)-octreotate and six variations of its peptide sequence, for which the Re-cyclized products were previously reported, were radiolabeled with (99m)Tc and investigated for their in vitro stability. METHODS: Radiolabeling of the peptides was effected by ligand exchange from (99m)Tc-glucoheptonate, and the desired products were purified by radio-RP-HPLC. The in vitro stability in phosphate buffered saline, mouse serum and cysteine solutions at physiological temperature and pH for all seven (99m)Tc-cyclized peptides was determined by radio-RP-HPLC and radio-TLC. Normal CF-1 mouse biodistribution studies were performed for three of the (99m)Tc-cyclized peptides. RESULTS: Based on the fully characterized Re-cyclized peptide analogues, four (99m)Tc-coordination motifs were proposed for the (99m)Tc-cyclized peptides. Technetium-99m-cyclized Tyr(3)-octreotate derivatives with N(2)S(2) metal coordination modes and large metal ring sizes were susceptible to oxidation and loss of (99m)Tc in the form of (99m)TcO(4)(-), as evidenced by their instability in the various solutions under physiological conditions (15-58% intact at 24 h). As anticipated, the addition of a third cysteine to the sequence stabilized the (99m)Tc metal coordination, and peptides with NS(3) coordination modes remained >85% intact out to 24 h. No significant differences were observed in the biodistribution studies performed with three peptides of varying stabilities. CONCLUSIONS: Improvements in stability were not sufficient to outweigh the low somatostatin receptor affinity for the peptides in this study. Further improvements in the peptide sequence and/or metal coordination are needed to result in a radiodiagnostic/radiotherapeutic pair for targeting the somatostatin receptor.

Re(V) and Re(III) complexes with sal2phen and triphenylphosphine: rearrangement, oxidation and reduction.

Reactions of Re(V), tetradentate Schiff base complexes with tertiary phosphines have previously yielded both rearranged Re(V) and reduced Re(III) complexes. To further understand this chemistry, the rigid diiminediphenol (N(2)O(2)) Schiff base ligand sal(2)phen (N,N'-o-phenylenebis(salicylaldimine)) was reacted with (n-Bu(4)N)[ReOCl(4)] to yield trans-[ReOCl(sal(2)phen)] (1). On reaction with triphenylphosphine (PPh(3)), a rearranged Re(V) product cis-[ReO(PPh(3))(sal(2)phen*)]PF(6) (2), in which one of the imines was reduced to an amine during the reaction, and the reduced Re(III) products trans-[ReCl(PPh(3))(sal(2)phen)] (4) and trans-[Re(PPh(3))(2)(sal(2)phen)](+) (5) were isolated. Reaction of sal(2)phen with [ReCl(3)(PPh(3))(2)(CH(3)CN)] resulted in the isolation of [ReCl(2)(PPh(3))(2)(salphen)] (3). The compounds were characterized using standard spectroscopic methods, elemental analyses and single crystal X-ray crystallography.

Radiation dose estimation using preclinical imaging with 124I-metaiodobenzylguanidine (MIBG) PET.

PURPOSE: A pretherapy 124I-metaiodobenzylguanidine (MIBG) positron emission tomography (PET)/computed tomography (CT) provides a potential method to estimate radiation dose to normal organs, as well as tumors prior to 131I-MIBG treatment of neuroblastoma or pheochromocytoma. The aim of this work was to estimate human-equivalent internal radiation dose of 124I-MIBG using PET/CT data in a murine xenograft model. METHODS: Athymic mice subcutaneously implanted with NB1691 cells that express high levels of human norepinephrine transporter (n = 4) were imaged using small animal microPET/CT over 96 h (approximate imaging time points: 0.5, 2, 24, 52, and 96 h) after intravenous administration of 3.07-4.84 MBq of 124I-MIBG via tail vein. The tumors did not accumulate 124I-MIBG to a detectable level. All four animals were considered as control and organ radiation dosimetry was performed. Volumes of interest were drawn on the coregistered CT images for thyroid, heart, lung, liver, kidney, and bladder, and transferred to PET images to obtain pharmacokinetic data. Based on tabulated organ mass distributions for both mice and adult male human, preclinical pharmacokinetic data were extrapolated to their human-equivalent values. Radiation dose estimations for different age groups were performed using the OLINDA/EXM software with modified tissue weighting factors in the recent International Commission on Radiological Protection (ICRP) Publication 103. RESULTS: The mean effective dose from 124I-MIBG using weighting factors from ICRP 103 to the adult male was estimated at 0.25 mSv/MBq. In different age groups, effective doses using values from ICRP 103 were estimated as follows: Adult female: 0.34, 15-yr-old: 0.39 mSv/MBq, 10-yr-old: 0.58 mSv/MBq, 5-yr-old: 1.03 mSv/MBq, 1-yr-old: 1.92 mSv/MBq, and newborn: 3.75 mSv/ MBq. For comparison, the reported effective dose equivalent of 124I-NaI for adult male (25% thyroid uptake, MIRD Dose Estimate Report No. 5) was 6.5 mSv/MBq. CONCLUSIONS: The authors estimated human-equivalent internal radiation dose of 124I-MIBG using preclinical imaging data. As a reference, the effective dose estimation showed that 124I-MIBG would deliver less radiation dose than 124I-NaI, a radiotracer already being used in patients with thyroid cancer.

In vitro structure-activity relationship of Re-cyclized octreotide analogues.

INTRODUCTION: Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor (SSTR)-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. METHODS: Various octreotide analogue sequences and coordination systems (e.g., S(2)N(2) and S(3)N) were synthesized and cyclized with nonradioactive Re. In vitro competitive binding assays with (111)In-DOTA-Tyr(3)-octreotide in AR42J rat pancreatic tumor cells yielded IC(50) values as a measure of SSTR affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr(3)-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogue's pharmacophore. RESULTS: Only two of the 11 Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr(3)-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. CONCLUSIONS: Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal cyclization of octreotide analogues via NS(3) and N(2)S(2) coordination forming five- and six-membered chelate rings. In vivo biodistribution studies are underway of (99m)Tc-cyclized analogue 4.