30 years of [11C]methyl triflate.

Some scientific discoveries are well known only to a core group of researchers working on technical subjects. Nevertheless, they open new research directions, allow existing knowledge to be viewed in entirely new and useful ways, or provide a way to make something that was hard or impossible to make before. Carbon-11 methyl triflate ([11C]MeOTf) is one such advance, facilitating the synthesis of many carbon-11 radio tracers and broadening the range of applications of carbon-11 radiochemistry. The year 2022 marked the 30th anniversary of the original paper in Applied Radiation and Isotopes introducing a simple synthesis of [11C]MeOTf from carbon-11 methyl iodide ([11C]MeI) and it also marked the end of the fruitful career and life of the researcher who developed it, Douglas Jewett. It seems fitting to say a few words on how it came to be and how it has helped advance carbon-11 radiochemistry.

Optimizing the radiosynthesis of [68Ga]DOTA-MLN6907 peptide containing three disulfide cyclization bonds - a GCC specific chelate for clinical radiopharmaceuticals.

In the present study, the effect of radiolabeling conditions on radiolabeling efficiency and achievable specific activity of a DOTA-conjugated highly-lipophilic peptide containing three disulfide cyclization bonds was examined. The peptide is designed to bind specifically (with high affinity) to cell-surface receptor guanylyl cyclase C (GCC), which is universally expressed by colorectal cancer cells. The effect of systematic variation of chemical parameters pH, mass of peptide, acetate buffer concentration (ionic strength), and inclusion of ethanol in the radiolabeling reaction vessel on achievable specific activity and labeling efficiency was examined. In addition, a unique approach to acetone-based elution of 68Ga from an initial cation-exchange pre-concentration column is introduced, which improved radiochemical yield and radiochemical purity. For the evaluation of the acetone-based method, two different post-radiolabeling reverse-phase (C18) approaches to purify the final radiolabeled peptide were tested. These results revealed the potential for peptide degradation via the cleavage of disulfide cyclization bonds to form free thiols when using one of these C18 cartridges. The final optimized procedure enabled radiolabeling efficiency of greater than 99% and specific activity greater than 35 MBq/nmole in less than 30 min. The optimized parameters were amenable to the use of an automated 68Ge/68Ga generator and fluid-handling system for clinical production of the GCC receptor-specific [68Ga]DOTA-MLN6907 peptide. The chemical characteristics of individual peptides govern the most appropriate radiolabeling conditions for the preparation of radiopharmaceuticals.

90Y-DOTATOC Dosimetry-Based Personalized Peptide Receptor Radionuclide Therapy.

Pretherapy PET with 86Y-DOTATOC is considered the ideal dosimetry protocol for 90Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90Y-DOTATOC using 90Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m2; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90Y-DOTATOC PET/CT at 5 h after therapy and 90Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90Y-DOTATOC is feasible using 90Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles.

Localization of Unknown Primary Site with 68Ga-DOTATOC PET/CT in Patients with Metastatic Neuroendocrine Tumor.

Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent 68Ga-DOTATOC PET/CT in a single-site prospective study. The 68Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the 68Ga-DOTATOC-positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if 68Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion:68Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET.

Preliminary Investigation of Cerebral Blood Flow and Amyloid Burden in Veterans With and Without Combat-Related Traumatic Brain Injury.

This study aimed to examine global and regional cerebral blood flow and amyloid burden in combat veterans with and without traumatic brain injury (TBI). Cerebral blood flow (in milliliters per minute per 100 mL) was measured by quantitative [(15)O]water, and amyloid burden was measured by [(11)C]PIB imaging. Mean global cerebral blood flow was significantly lower in veterans with TBI compared with non-TBI veterans. There were essentially no differences between groups for globally normalized regional cerebral blood flow. Amyloid burden did not differ between TBI and non-TBI veterans. Veterans who have suffered a TBI have significantly lower cerebral blood flow than non-TBI controls but did not manifest increased levels of amyloid, globally or regionally.

Repeatability of gallium-68 DOTATOC positron emission tomographic imaging in neuroendocrine tumors.

OBJECTIVE: To evaluate the repeatability of gallium-68 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic (DOTA)-D-Phe1-Try3-octreotide (68Ga-DOTATOC) positron emission tomography (PET) in neuroendocrine tumors. METHODS: Five patients with neuroendocrine tumors were imaged with 68Ga-DOTATOC PET twice within 5 days. Maximum and mean standardized uptake values (SUVmax and SUVmean) and kinetic parameters (K-Patlak and K-influx) of target lesions were measured. The repeatability of these measurements was investigated. RESULTS: Forty-seven target lesions were identified on whole-body PET and 21 lesions on dynamic images. There was excellent repeatability with intraclass correlation coefficient of 0.99 for SUVmax, SUVmean, and K-Patlak, and 0.85 for K-influx. The median absolute percent differences and the interquartile ranges (IQR) between 2 scans for SUVmax and SUVmean were 7.4% (IQR, 14.1%) and 9.3% (IQR, 10.6%), respectively. The median absolute percent differences for K-Patlak and K-influx were 12.5% (IQR, 12.6%) and 29.9% (IQR, 22.4%), respectively. The SUVmax of target lesions did not differ by more than 25% between the 2 scans. CONCLUSIONS: 68Ga-DOTATOC PET imaging of neuroendocrine tumors is highly reproducible. A difference of more than 25% in SUVmax represents a change that is larger than the measurement error observed on repeated studies and should reflect a significant change in the biological character of the tumor.

Stability of 3'-deoxy-3'-[18F]fluorothymidine standardized uptake values in head and neck cancer over time.

The purpose of this study was to evaluate the consistency of 3'-deoxy-3'[(18)F]fluorothymidine (FLT) standardized uptake values (SUVs) over the time course of imaging in head and neck cancer. Thirteen (13) subjects (all male; age: 56.9 +/- 6.7 years) with squamous cell head and neck cancer, stage III/IV, were administered FLT and imaged dynamically for 1 hour over the tumor and then underwent whole-body (WB) imaging commencing at 74 +/- 6 minutes. Imaging was repeated after 5 days of radiotherapy (10 Gy) and a single course of platinum-based chemotherapy. Volumes-of-interest (VOIs) were created on the last dynamic frame (SUV(60)). The pretherapy WB and midtherapy images were coregistered to the dynamic sequence and VOIs were applied. Mean and maximum SUVs (SUV(60) and SUV(WB)) and the change with treatment were evaluated. The correlations (Spearman's rho) between SUV(60) and SUV(WB) for all VOIs (pre- and midtherapy, n = 108 data pairs) were 0.98 for mean and 0.97 for maximum SUVs (p < 0.0001). Average absolute differences between SUV(60) and SUV(WB) were 0.18 +/- 0.15 and 0.29 +/- 0.32 SUV units, respectively. Correlations (Spearman's rho) between the change in SUV with therapy were 0.90 for mean and 0.89 for maximum SUV (p < 0.0001), with differences in the change values averaging 0.03 +/- 0.36 and -0.17 +/- 0.57 units, respectively. FLT SUVs are stable and comparable for images initiated between 55 and 100 minutes postinjection whether acquired pre- or midtherapy in head and neck cancer.

Investigation of the pharmacokinetics of 3'-deoxy-3'-[18F]fluorothymidine uptake in the bone marrow before and early after initiation of chemoradiation therapy in head and neck cancer.

INTRODUCTION: The kinetics of the bone marrow uptake of 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) before and early after initiation of chemoradiation therapy was investigated in patients with head and neck cancer. METHODS: Fourteen subjects with head and neck cancer underwent FLT positron emission tomography (PET) at baseline and after 10 Gy of radiation therapy. Thirteen subjects also received one cycle of platinum-based chemotherapy before the second FLT PET. Kinetic parameters, including the flux constant based on compartmental analysis (K(FLT)) and the Patlak constant (K(Patlak)) for cervical marrow, were calculated. Standardized uptake values (SUVs) for the cervical marrow (inside the radiation field) and lumbar spine marrow (outside the radiation field) were also determined. RESULTS: There was a significant drop in FLT uptake in the bone marrow inside the radiation field. Mean pretreatment uptake values for the cervical spine were SUV=3.08+/-0.66, K(FLT)=0.045+/-0.016 min(-1) and K(Patlak)=0.039+/-0.013 min(-1). After treatment, these values were SUV=0.74+/-0.19, K(FLT)=0.011+/-0.005 min(-1) and K(Patlak)=0.005+/-0.002 min(-1). Compartmental analysis revealed a significant drop in k(3) in irradiated cervical marrow. FLT uptake in the bone marrow outside the radiation field exhibited a significantly smaller decrease. CONCLUSIONS: There is a marked decrease in FLT uptake in irradiated bone marrow after 10 Gy of radiation therapy to the head and neck. The drop in FLT uptake in irradiated marrow is due to a significant decrease in the net phosphorylation rate of FLT.

Kinetic analysis of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) in head and neck cancer patients before and early after initiation of chemoradiation therapy.

UNLABELLED: The purpose of this study was to investigate the kinetic behavior of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) before and early after initiation of chemoradiation therapy in patients with squamous cell head and neck cancer. METHODS: A total of 8 patients with head and neck cancer underwent (18)F-FLT PET scans (7 patients at baseline and after 5 d [10 Gy] of radiation therapy given with concomitant chemotherapy and 1 patient only at baseline). Dynamic PET images were obtained with concurrent arterial or venous blood sampling. Kinetic parameters including the flux constant of (18)F-FLT based on compartmental analysis (K-FLT), the Patlak influx constant (K-Patlak), and standardized uptake value (SUV) were calculated for the primary tumor and (18)F-FLT-avid cervical lymph nodes for all scans. RESULTS: Mean pretreatment values of uptake for the primary tumor and cervical nodes were 0.075 +/- 0.006 min(-1), 0.042 +/- 0.004 min(-1), and 3.4 +/- 0.5 (mean +/- SD) for K-FLT, K-Patlak, and SUV, respectively. After 10 Gy of radiation therapy, these values were 0.040 +/- 0.01 min(-1), 0.018 +/- 0.016 min(-1), and 1.8 +/- 1.1 for K-FLT, K-Patlak, and SUV, respectively. For all lesions seen on pretherapy and midtherapy scans, the correlation was 0.90 between K-FLT and K-Patlak, 0.91 between K-FLT and SUV, and 0.99 between K-Patlak and SUV. CONCLUSION: The initial (18)F-FLT uptake and change early after treatment in squamous head and neck tumors can be adequately characterized with SUV obtained at 45-60 min, which demonstrates excellent correlation with influx parameters obtained from compartmental and Patlak analyses.

Effects of smoking marijuana on focal attention and brain blood flow.

Using an attention task to control cognitive state, we previously found that smoking marijuana changes regional cerebral blood flow (rCBF). The present study measured rCBF during tasks requiring attention to left and right ears in different conditions. Twelve occasional marijuana users (mean age 23.5 years) were imaged with PET using [15O]water after smoking marijuana or placebo cigarettes as they performed a reaction time (RT) baseline task, and a dichotic listening task with attend-right- and attend-left-ear instructions. Smoking marijuana, but not placebo, resulted in increased normalized rCBF in orbital frontal cortex, anterior cingulate, temporal pole, insula, and cerebellum. RCBF was reduced in visual and auditory cortices. These changes occurred in all three tasks and replicated our earlier studies. They appear to reflect the direct effects of marijuana on the brain. Smoking marijuana lowered rCBF in auditory cortices compared to placebo but did not alter the normal pattern of attention-related rCBF asymmetry (i.e., greater rCBF in the temporal lobe contralateral to the direction of attention) that was also observed after placebo. These data indicate that marijuana has dramatic direct effects on rCBF, but causes relatively little change in the normal pattern of task-related rCBF on this auditory focused attention task.

Effect of acute marijuana on cardiovascular function and central nervous system pharmacokinetics of [(15)O]water: effect in occasional and chronic users.

The objective of this study was to evaluate the effect of the acute administration of marijuana (MJ) on cardiovascular (CV) function and CNS pharmacokinetics (PK) of [(15)O]water in occasional (O) versus chronic (C) MJ users. Each subject received four injections of [(15)O]water (one prior and three postsmoking) on two occasions in which they received active or placebo MJ. For each injection, measures of CV function and CNS PK [(15)O]water were made. Postsmoking, MJ influenced all measured CV and [(15)O]water PK parameters. C users reported significantly lower "highness" and smaller heart rate (HR) changes, which resulted in reduced rate pressure product (RPP) changes compared to O users, even though Delta(9)-tetrahydrocannabinol levels were higher, whereas changes in blood pressure (BP), arrival time, and [(15)O]water concentration were not significantly different between the groups. Significant CV changes resulted in changes in the whole-body distribution of cardiac output rather than changes in cerebral blood flow. Chronic MJ use produces tolerance to the HR increases induced by acute MJ smoking compared to changes observed in occasional users, without changing the effects on BP and [(15)O]water PK.

Emotions in unmedicated patients with schizophrenia during evaluation with positron emission tomography.

OBJECTIVE: Schizophrenia is currently conceptualized as a disease of functional neural connectivity, leading to symptoms that affect aspects of mental activity, including perception, attention, memory, and emotion. The neural substrates of its emotional components have not been extensively studied with functional neuroimaging. Previous neuroimaging studies have examined medicated patients with schizophrenia. The authors measured regional cerebral blood flow (rCBF) during performance of a task that required unmedicated patients to recognize the emotional valence of visual images and to determine whether they were pleasant or unpleasant. METHOD: The authors examined rCBF in 17 healthy volunteers and 18 schizophrenia patients who had not received antipsychotic medications for at least 3 weeks during responses to pleasant and unpleasant visual stimuli. Areas of relative increases or decreases in rCBF were measured by using the [(15)O]H(2)O method. RESULTS: When patients consciously evaluated the unpleasant images, they did not activate the phylogenetically older fear-danger recognition circuit (e.g., the amygdala) used by the healthy volunteers, although they correctly rated them as unpleasant. Likewise, the patients showed no activation in areas of the prefrontal cortex normally used to recognize the images as pleasant and were unable to recognize them as such. Areas of decreased CBF were widely distributed and comprised subcortical regions such as the thalamus and cerebellum. CONCLUSIONS: This failure of the neural systems used to support emotional attribution is consistent with pervasive problems in experiencing emotions by schizophrenia patients. The widely distributed nature of the abnormalities suggests the importance of subcortical nodes in overall dysfunctional connectivity.

Residual naming after damage to the left temporal pole: a PET activation study.

Normal subjects activate the left temporal polar cortex when they name persons, and subjects with damage to the left temporal pole due to left anterior temporal lobectomy are impaired in the retrieval of the proper names of persons. Eight such subjects were studied in a PET activation experiment to address the neural systems supporting their residual naming. We hypothesized that there would be increased activity, relative to normal controls, in the surround of the damaged region, the homologous right temporal pole, or both. Neither the group nor individual target subjects showed significantly increased activity in the lesion surround or in the right temporal pole. Several other regions that are activated by normals during the retrieval of the proper names of persons and which were undamaged in the target subjects (left anterior superior temporal sulcus, mesial frontal cortex, and anterior cingulate) were nevertheless significantly less activated by the target subjects, a finding that suggests that damage to the left temporal pole alters the function of a large-scale system needed for the retrieval of proper nouns. There was increased activity in early visual cortices, suggesting intensification of visual processing to compensate for the defective preferred name retrieval processing.

Marijuana alters the human cerebellar clock.

The effects of marijuana on brain perfusion and internal timing were assessed using [15O] water PET in occasional and chronic users. Twelve volunteers who smoked marijuana recreationally about once weekly, and 12 volunteers who smoked daily for a number of years performed a self-paced counting task during PET imaging, before and after smoking marijuana and placebo cigarettes. Smoking marijuana increased rCBF in the ventral forebrain and cerebellar cortex in both groups, but resulted in significantly less frontal lobe activation in chronic users. Counting rate increased after smoking marijuana in both groups, as did a behavioral measure of self-paced tapping, and both increases correlated with rCBF in the cerebellum. Smoking marijuana appears to accelerate a cerebellar clock altering self-paced behaviors.

Regional cerebral blood flow changes during visually induced subjective sadness in healthy elderly persons.

This study examined regional cerebral blood flow (rCBF) changes associated with visually induced sad affect in healthy elderly persons. Subjects viewed sadness-laden, happiness-laden, and emotionally neutral image sets while rCBF was recorded using [(15)O] water PET. The sad image set included human faces and scenery/objects ("scenes"). To control for secondary sensory processing, the neutral and happy comparison sets included exclusively either human faces or scenes. During the sad condition, the ventral prefrontal and temporal cortices were more active compared with happy and neutral scenes conditions and the thalamus was more active compared with happy and neutral faces conditions. Ventral prefrontal cortex and thalamus were associated with processing of sad visual stimuli, whether compared with neutral or happy stimuli. The specific findings associated with sad affect were contingent on the comparison stimuli content (scenes or human faces), not affect (i.e., comparison with neutral or happy conditions).

Global cerebral blood flow after CO2 inhalation in normal subjects and patients with panic disorder determined with [15O]water and PET.

OBJECTIVE: To determine the effect of CO2 inhalation on global cerebral blood flow (gCBF) and pCO2-adjusted gCBF in normal subjects and panic disorder patients. METHOD: Global cerebral blood flow was determined using quantitative [15O] water imaging in normal subjects (n = 12) and panic disorder patients (n = 14) after inhalations of medical grade air and of 35%/65% CO2/O2 mixture, a known inducer of panic. The gCBF was calculated as an area-weighted mean value. The pCO2 -adjusted gCBF values were calculated based on the formula of Reiman et al. [Am. J. Psychiatr. 143 (1986) 469]. Data were analyzed using repeated-measures ANOVA and regression analyses. RESULTS: The pCO2 values did not differ statistically between normals and panic patients. Panic patients exhibited a decrease in gCBF and stable pCO2-adjusted gCBF values in comparisons of AIR and CO2 inhalations, whereas normals exhibited stable gCBF and increasing pCO2-adjusted gCBF values. CONCLUSIONS: Patients with panic disorder, especially when symptomatic, exhibited an abnormal pattern in gCBF response to provocation.

Effects of smoking marijuana on brain perfusion and cognition.

The effects of smoking marijuana on regional cerebral blood flow (rCBF) and cognitive performance were assessed in 12 recreational users in a double-blinded, placebo-controlled study. PET with [(15)Oxygen]-labeled water ([(15)O]H(2)O) was used to measure rCBF before and after smoking of marijuana and placebo cigarettes, as subjects repeatedly performed an auditory attention task. Smoking marijuana resulted in intoxication, as assessed by a behavioral rating scale, but did not significantly alter mean behavioral performance on the attention task. Heart rate and blood pressure increased dramatically following smoking of marijuana but not placebo cigarettes. However, mean global CBF did not change significantly. Increased rCBF was observed in orbital and mesial frontal lobes, insula, temporal poles, anterior cingulate, as well as in the cerebellum. The increases in rCBF in anterior brain regions were predominantly in "paralimbic" regions and may be related to marijuana's mood-related effects. Reduced rCBF was observed in temporal lobe auditory regions, in visual cortex, and in brain regions that may be part of an attentional network (parietal lobe, frontal lobe and thalamus). These rCBF decreases may be the neural basis of perceptual and cognitive alterations that occur with acute marijuana intoxication. There was no significant rCBF change in the nucleus accumbens or other reward-related brain regions, nor in basal ganglia or hippocampus, which have a high density of cannabinoid receptors.

Effects of frequent marijuana use on memory-related regional cerebral blood flow.

It is uncertain whether frequent marijuana use adversely affects human brain function. Using positron emission tomography (PET), memory-related regional cerebral blood flow was compared in frequent marijuana users and nonusing control subjects after 26+ h of monitored abstention. Memory-related blood flow in marijuana users, relative to control subjects, showed decreases in prefrontal cortex, increases in memory-relevant regions of cerebellum, and altered lateralization in hippocampus. Marijuana users differed most in brain activity related to episodic memory encoding. In learning a word list to criterion over multiple trials, marijuana users, relative to control subjects, required means of 2.7 more presentations during initial learning and 3.1 more presentations during subsequent relearning. In single-trial recall, marijuana users appeared to rely more on short-term memory, recalling 23% more than control subjects from the end of a list, but 19% less from the middle. These findings indicate altered memory-related brain function in marijuana users.

Age and regional cerebral blood flow in schizophrenia: age effects in anterior cingulate, frontal, and parietal cortex.

Positron emission tomography ([(15)O] water PET) was used to examine the relationship between age and regional cerebral blood flow (rCBF) in schizophrenia. Forty-nine unmedicated male patients, ages 20-51, underwent imaging during an eyes-closed resting condition. Negative correlations were observed between age and rCBF in the anterior cingulate, as well as in frontal (Brodmann area 8) and parietal cortex (area 40) bilaterally. The observation of reduced rCBF in the anterior cingulate with increased age is consistent with previous findings in healthy subjects. In contrast, the reduced flow observed in the frontal and parietal regions may be unique to schizophrenia.

Contamination levels in blood samples drawn from the injection intravenous line.

PURPOSE: Securing two intravenous lines, one for injection and one for blood sampling, can be nearly impossible in compromised patients, therefore, a need exists to quantify the potential error when simplified techniques are employed. METHOD: Two venous catheters were placed. 2-deoxy-2-[18F]fluoro-glucose (FDG) was infused through one of the catheters. Venous blood samples were drawn from each line. Triplicate aliquots of plasma were analyzed in duplicate. RESULTS: Concentrations from the infusion line were 2.0% higher than the concentrations from the noninfusion line. The average error was 3.3%, 2.0%, and 0.7% higher for the first, second, and third samples, respectively. CONCLUSIONS: Blood sampling through the infusion catheter is a viable alternative to the placement of separate venous catheters. Sampling from the injection catheter, even with tubing flush and replacement, will potentially incur small (generally < 10%) over-estimations in concentration in initial samples. Subsequent sampling reduces the error to essentially zero by the third sample.