The use of 3'-deoxy-3'-18F-fluorothymidine (FLT) PET in the assessment of long-term survival in breast cancer patients treated with neoadjuvant chemotherapy.

OBJECTIVE: To assess the role of serial FLT-PET scans during early neoadjuvant treatment as a prognostic marker of response to treatment and survival. METHODS: This study is a prospective cohort study which draws from a larger original study which examined the utility of FLT-PET imaging across multiple cancers. Our cohort consisted of patients who had biopsy-confirmed breast cancer amenable to surgical resection. These patients underwent serial FLT-PET scans: the first scan prior to starting neoadjuvant chemotherapy (NAC), and a second scan shortly after starting NAC. SUVmean was derived using an isocontour ROI drawn approximately half way between the SUVmax and background on three planes for each scan. The change in mean standardized uptake value (SUVmean) for the primary tumor between these two scans was then calculated, and patients were stratified into "responder" and "non-responder" groups based on a cut-off of 20% arithmetic decrease in SUVmean between the two scans. The rates of pathologic complete response (pCR) on subsequent surgical excision, overall survival (OS), and progression-free survival (PFS) were then compared between the two groups to assess for significant difference between responders and non-responders. RESULTS: 16 patients (n = 16) met criteria for inclusion and successfully underwent FLT-PET scans in the prescribed sequence of events. Seven of these patients had a decrease of 20% or larger between the two serial PET scans, making them "responders". The remaining nine patients were "non-responders" to NAC based on PET imaging. Between responders and non-responders, there was no significant difference in median PFS (7.9 years versus 3.7 years; p = 0.425) and median OS (7.5 years versus 5.0 years; p = 0.944). In the 14 patients who underwent surgical resection (n = 14), there was no significant difference in the rate of achieving pCR (33% vs. 14%; p = 0.5846) between responders and non-responders. CONCLUSION: Further study of a larger sample size is needed to examine the potential role for FLT-PET in predicting response to neoadjuvant treatment, particularly in correlating with long-term overall and progression-free survival. Our study is limited by small sample size, but does suggest that FLT-PET has a role in the long-term prognosis of breast cancer treated with NAC and surgical resection which is worthy of further study.

Biomarkers and Bone Imaging Dynamics Associated with Clinical Outcomes of Oral Cabozantinib Therapy in Metastatic Castrate-Resistant Prostate Cancer.

PURPOSE: Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.Experimental Design: Eligibility included patients with metastatic castrate-resistant prostate cancer with normal organ function and performance status 0-2. Cabozantinib 60 mg orally was administered daily. Pretherapy and 2 weeks post, 99mTc-labeled bone scans, positron emission tomography with 18F-sodium fluoride (NaF-PET) and 18F-(1-(2'-deoxy-2'-fluoro-ß-D-arabinofuranosyl) thymine (FMAU PET) scans were conducted. Pretherapy and posttherapy tumor biopsies were conducted, and serum and urine bone markers were measured. RESULTS: Twenty evaluable patients were treated. Eight patients had a PSA decline, of which 2 had a decline of ≥50%. Median progression-free survival (PFS) and OS were 4.1 and 11.2 months, respectively, and 3 patients were on therapy for 8, 10, and 13 months. The NaF-PET demonstrated a median decline in SUVmax of -56% (range, -85 to -5%, n = 11) and -41% (range, -60 to -25%, n = 9) for patients who were clinically stable and remained on therapy for ≥4 or <4 cycles, respectively. The FMAU PET demonstrated a median decline in SUVmax of -44% (-60 to -14%) and -42% (-63% to -23%) for these groups. The changes in bone markers and mesenchymal epithelial transition/MET testing did not correlate with clinical benefit. CONCLUSIONS: Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.

Using Radiolabeled 3'-Deoxy-3'-18F-Fluorothymidine with PET to Monitor the Effect of Dexamethasone on Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality in the United States, and pemetrexed-based therapies are regularly used to treat nonsquamous NSCLC. Despite widespread use, pemetrexed has a modest effect on progression-free survival, with varying efficacy between individuals. Recent work has indicated that dexamethasone, given to prevent pemetrexed toxicity, is able to protect a subset of NSCLC cells from pemetrexed cytotoxicity by temporarily suppressing the S phase of the cell cycle. Therefore, dexamethasone might block treatment efficacy in a subpopulation of patients and might be contributing to the variable response to pemetrexed. Methods: Differences in retention of the experimental PET tracer 3'-deoxy-3'-fluorothymidine (FLT) were used to monitor S-phase suppression by dexamethasone in NSCLC cell models, animals with tumor xenografts, and patients with advanced cancer. Results: Significant reductions in tracer uptake were observed after 24 h of dexamethasone treatment in NSCLC cell lines and xenograft models expressing high levels of glucocorticoid receptor α, coincident with pemetrexed resistance visualized by attenuation of the flare effect associated with pemetrexed activity. Two of 4 patients imaged in a pilot study with 18F-FLT PET after dexamethasone treatment demonstrated reductions in tracer uptake from baseline, with a variable response between individual tumor lesions. Conclusion:18F-FLT PET represents a useful method for the noninvasive monitoring of dexamethasone-mediated S-phase suppression in NSCLC and might provide a way to individualize chemotherapy in patients receiving pemetrexed-based regimens.

A Pilot Trial Evaluating Zoledronic Acid Induced Changes in [18F]FMAU-Positron Emission Tomography Imaging of Bone Metastases in Prostate Cancer.

PURPOSE: We conducted a pilot trial utilizing [18F]FMAU [1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl thymine] as a tumor tracer in positron emission tomography (PET) and evaluated its reproducibility, and changes in maximum and peak standardized uptake value (SUVmax and SUVpeak) with zoledronic acid treatment in castrate resistant prostate cancer (CRPC) patients with bone metastases (BM). PROCEDURES: Eligible patients had CRPC with radiographic evidence of BM and creatinine clearance >30 ml/min. Two baseline [18F]FMAU-PET scans (about 1 week apart, range 2-12 days) were obtained for testing reproducibility. Zoledronic acid 4 mg was infused over 15 min within 1 week after second scan and a third PET scan was obtained 7 days later. The bony lesion with the highest uptake on the first scan was compared with later scans. Bone turnover markers and prostate-specific antigen (PSA) were obtained pre- and post-therapy. PET response was defined as decline in SUVmean of ≥15 % after zoledronic acid. RESULTS: Eleven patients were evaluated, median age was 65 years, five were African-American and six were Caucasian, and median PSA level was 36.3 ng/ml (range 1.0-1209.3). Notably, the range of absolute percent SUVmax changes varied between 0.77 and 54.7, and only nine measurements were greater than one (1.09-2.19). Zoledronic acid did not appreciably change FMAU uptake. No clinical response was noted. Urine N-telopeptide (NTx) was markedly decreased in all patients after zoledronic acid and serum bone-specific alkaline phosphatase (BSAP) registered a modest change. Urine NTx correlated more closely with SUV max than serum BSAP. CONCLUSIONS: FMAU tracer was able to detect bone metastases in CRPC patients but uptake was highly variable in bony lesions. Zoledronic acid did not produce an appreciable change in scans. Future investigations of FMAU tracer as a marker of early response in CRPC is recommended.

Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: 18F-FAU, 18F-FMAU, and 18F-FLT.

BACKGROUND: A principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT), 1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl) thymidine (18F-FMAU), and 1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl) uracil (18F-FAU) in patients with advanced cancer. METHODS: Fifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUVmean) and using kinetic analysis. RESULTS: Patients imaged with 18F-FLT showed variable changes in retention and two patients exhibited an increase in SUVmean of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in 18F-FMAU retention was 0.2 % (range -24.4 to 23.1) and 18F-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUVmax but not kinetic measurements. CONCLUSIONS: This pilot study demonstrates that patients treated with capecitabine can produce a marked increase in 18F-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. 18F-FAU and 18F-FMAU showed little change, on average, after treatment.

Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase.

FAU, a pyrimidine nucleotide analogue, is a prodrug bioactivated by intracellular thymidylate synthase to form FMAU, which is incorporated into DNA, causing cell death. This study presents a model-based approach to integrating dynamic positron emission tomography (PET) and conventional plasma pharmacokinetic studies to characterize the plasma and tissue pharmacokinetics of FAU and FMAU. Twelve cancer patients were enrolled into a phase 1 study, where conventional plasma pharmacokinetic evaluation of therapeutic FAU (50-1600 mg/m2 ) and dynamic PET assessment of 18 F-FAU were performed. A parent-metabolite population pharmacokinetic model was developed to simultaneously fit PET-derived tissue data and conventional plasma pharmacokinetic data. The developed model enabled separation of PET-derived total tissue concentrations into the parent drug and metabolite components. The model provides quantitative, mechanistic insights into the bioactivation of FAU and retention of FMAU in normal and tumor tissues and has potential utility to predict tumor responsiveness to FAU treatment.

Using 18F-fluorodeoxyglucose positron emission tomography to monitor clinical outcomes in patients treated with neoadjuvant chemo-radiotherapy for locally advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer ranks as the fourth leading cause of cancer death in the United States with 5-year survival ranging from 1% to 5%. Positron emission tomography (PET) is a metabolic imaging system that is widely used for the initial staging of cancer and detecting residual disease after treatment. There are limited data, however, on the use of this molecular imaging technique to assess early tumor response after treatment in pancreatic cancer. METHODS: The objective of the study was to explore the relationship of early treatment response using the F-fluorodeoxyglucose (FDG) PET with surgical outcome and overall survival in patients with locally advanced pancreatic cancer. FDG-PET measurements of maximum standardized uptake value and kinetic parameters were compared with the clinical outcome. RESULTS: Twenty patients were enrolled in the study evaluating neoadjuvant induction chemotherapy followed by concurrent chemoradiotherapy (chemo-RT) for locally advanced pancreatic cancer. All 20 patients had prestudy PET scans and a total of fifty PET scans were performed. Among patients who were PET responders (> or =50% decrease in standardized uptake value after cycle 1), 100% (2/2) had complete surgical resection. Only 6% (1/16) had surgical resection in the PET nonresponders (<50% decrease). Two patients did not have the second PET scan because of clinical progression or treatment toxicity. Mean survival was 23.2 months for PET responders and 11.3 months for nonresponders (P = 0.234). Similar differences in survival were also noted when response was measured using Patlak analysis. CONCLUSIONS: FDG-PET can aid in monitoring the clinical outcome of patients with locally advanced pancreatic cancer treated with neoadjuvant chemo-RT. FDG-PET may be used to aid patients who could have complete surgical resection as well as prognosticate patients' survival.

Herpes simplex virus thymidine kinase imaging in mice with (1-(2'-deoxy-2'-[18F]fluoro-1-ß-D-arabinofuranosyl)-5-iodouracil) and metabolite (1-(2'-deoxy-2'-[18F]fluoro-1-ß-D-arabinofuranosyl)-5-uracil).

PURPOSE: FIAU, (1-(2'-deoxy-2'-fluoro-1-ß-D-arabinofuranosyl)-5-iodouracil) has been used as a substrate for herpes simplex virus thymidine kinases (HSV-TK and HSV-tk, for protein and gene expression, respectively) and other bacterial and viral thymidine kinases for noninvasive imaging applications. Previous studies have reported the formation of a de-iodinated metabolite of 18F-FIAU. This study reports the dynamic tumor uptake, biodistribution, and metabolite contribution to the activity of 18F-FIAU seen in HSV-tk gene expressing tumors and compares the distribution properties with its de-iodinated metabolite 18F-FAU. METHODS: CD-1 nu/nu mice with subcutaneous MH3924A and MH3924A-stb-tk+ xenografts on opposite flanks were used for the biodistribution and imaging studies. Mice were injected IV with either 18F-FIAU or 18F-FAU. Mice underwent dynamic imaging with each tracer for 65 min followed by additional static imaging up to 150 min post-injection for some animals. Animals were sacrificed at 60 or 150 min post-injection. Samples of blood and tissue were collected for biodistribution and metabolite analysis. Regions of interest were drawn over the images obtained from both tumors to calculate the time-activity curves. RESULTS: Biodistribution and imaging studies showed the highest uptake of 18F-FIAU in the MH3924A-stb-tk+ tumors. Dynamic imaging studies revealed a continuous accumulation of 18F-FIAU in HSV-TK expressing tumors over 60 min. The mean biodistribution values (SUV ± SE) for MH3924A-stb-tk+ were 2.07 ± 0.40 and 6.15 ± 1.58 and that of MH3924A tumors were 0.19 ± 0.07 and 0.47 ± 0.06 at 60 and 150 min, respectively. In 18F-FIAU injected mice, at 60 min nearly 63% of blood activity was present as its metabolite 18F-FAU. Imaging and biodistribution studies with 18F-FAU demonstrated no specific accumulation in MH3924A-stb-tk+ tumors and SUVs for both the tumors were similar to those observed with muscle. CONCLUSION: 18F-FIAU shows a continuous accumulation of activity in HSV-TK expressing tumors. 18F-FAU does not show any preferential accumulation in HSV-TK expressing tumors. In the 18F-FIAU treated mice, the 18F-FAU contribution to the total uptake seen in HSV-TK positive tumors is minimal.

Analysis and reproducibility of 3'-Deoxy-3'-[18F]fluorothymidine positron emission tomography imaging in patients with non-small cell lung cancer.

PURPOSE: Imaging tumor proliferation with 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) and positron emission tomography is being developed with the goal of monitoring antineoplastic therapy. This study assessed the methods to measure FLT retention in patients with non-small cell lung cancer (NSCLC) to measure the reproducibility of this approach. EXPERIMENTAL DESIGN: Nine patients with NSCLC who were untreated or had progressed after previous therapy were imaged twice using FLT and positron emission tomography within 2 to 7 days. Reproducibility (that is, error) was measured as the percent difference between the two patient scans. Dynamic imaging was obtained during the first 60 min after injection. Activity in the blood was assessed from aortic images and the fraction of unmetabolized FLT was measured. Regions of interest were drawn on the plane with the highest activity and the adjacent planes to measure standardized uptake value (SUV(mean)) and kinetic variables of FLT flux. RESULTS: We found that the SUV(mean) obtained from 30 to 60 min had a mean error of 3.6% (range, 0.6-6.9%; SD, 2.3%) and the first and second scans were highly correlated (r(2) = 0.99; P < 0.0001). Using shorter imaging times from 25 to 30 min or from 55 to 60 min postinjection also resulted in small error rates; SUV(mean) mean errors were 8.4% and 5.7%, respectively. Compartmental and graphical kinetic analyses were also fairly reproducible (r(2) = 0.59; P = 0.0152 and r(2) = 0.58; P = 0.0175 respectively). CONCLUSION: FLT imaging of patients with NSCLC was quite reproducible with a worst case SUV(mean) error of 21% when using a short imaging time.

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2.

PURPOSE: Fluoropyrimidines like 1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl)-thymine (FMAU) and 3'-deoxy-3'-fluorothymidine (FLT) accumulate in tumors and are being used as positron emission tomography tumor-imaging tracers. Proliferating tissues with high thymidine kinase 1 (TK1) activity retain FLT; however, the mechanism of selective accumulation of FMAU in tumors and certain other tissues requires further study. METHODS: Retention of [(3)H]FLT and [(3)H]FMAU was measured in prostate cancer cell lines PC3, LNCaP, DU145, and the breast cancer cell line MD-MBA-231, and the tracer metabolites were analyzed by high-performance liquid chromatography (HPLC). FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass were determined in cells stressed by depleted cell culture medium or by treating with oxidative, reductive, and energy stress, or specific adenosine monophosphate-activated protein kinase activator, or eIF2 inhibitor. TK1 and TK2 activities and mitochondrial mass were determined by FLT phosphorylation, 1-beta-D: -arabinofuranosylthymine (Ara-T) phosphorylation, and flow cytometry, respectively. RESULTS: FMAU retention in rapidly proliferating cancer cell lines was five to ten times lower than FLT after 10 min incubation. HPLC analysis of the cellular extracts showed that phosphorylated tracers are the main retained metabolites. Nutritional stress decreased TK1 activity and FLT retention but increased retained FMAU. TK2 inhibition decreased FMAU retention and phosphorylation with negligible effects on FLT. Oxidative, reductive, or energy stress increased FMAU retention and correlated with mitochondrial mass (r (2) = 0.88, p = 0.006). FMAU phosphorylation correlated with increased TK2 activity (r (2) = 0.87, p = 0.0002). CONCLUSION: FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects.

Tumor imaging using 1-(2'-deoxy-2'-18F-fluoro-beta-D-arabinofuranosyl)thymine and PET.

UNLABELLED: The kinetics of 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU) were studied using PET to determine the most appropriate and simplest approach to image acquisition and analysis. The concept of tumor retention ratio (TRR) is introduced and validated. METHODS: Ten patients with brain (n = 4) or prostate (n = 6) tumors were imaged using (18)F-FMAU PET (mean dose, 369 MBq). Sixty-minute dynamic images were obtained; this was followed by whole-body images. Mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) of each tumor were determined as the mean over 3 planes of each time interval. For kinetic analyses, blood activity was measured in 18 samples over 60 min. Samples were analyzed by high-performance liquid chromatography at 3 selected times to determine tracer metabolites. FMAU kinetics were measured using a 3-compartment model yielding the flux (K1 x k3/(k2 + k3)) (K1, k2, and k3 are rate constants) and compared with TRR measurements. TRR was calculated as the tumor (18)F-FMAU uptake area under the curve divided by the product of blood (18)F-FMAU AUC and time. A similar analysis was performed using muscle to estimate (18)F-FMAU delivery. RESULTS: SUVmean measurements obtained from 5 to 11 min correlated with those obtained from 30 to 60 min (r(2) = 0.92, P < 0.0001) and 50 to 60 min (r(2) = 0.92, P < 0.0001) due to the rapid clearance of (18)F-FMAU. Similar results were obtained using SUVmax measurements (r(2) = 0.93, P < 0.0001; r(2) = 0.88, P < 0.0001, respectively). The measurement of TRR using either blood or muscle activity over 11 min provided results comparable to those of 60-min dynamic imaging and a 3-compartment model. This analysis required only 5 blood samples drawn at 1, 2, 3, 5, and 11 min without metabolite correction to produce comparable results. CONCLUSION: Tissue retention ratio measurements obtained over 11 min can replace flux measurements in (18)F-FMAU imaging. The SUVmean and the SUVmax in 5-11 min images correlated well with those of images obtained at 50-60 min. The quality of the images and tissue kinetics in 11 min of imaging makes it a desirable and shorter tumor imaging option.

Phase II trial of interferon and thalidomide in metastatic renal cell carcinoma.

OBJECTIVES: To evaluate the toxicity and efficacy of interferon and thalidomide combination in a phase II clinical trial. PATIENTS AND METHODS: Eligibility included metastatic renal cancer with a maximum of two prior regimens, performance status of 0-2 and adequate renal, hepatic and bone marrow function. RESULTS: Twenty patients were enrolled on this phase II trial. Median age was 60.5 years (Range: 39-75 years). 17 patients had visceral metastases (lung/liver/both) and 3 patients had lymph node only metastases. A total of 26 cycles of 4 weeks each were administered; median of 1 cycle and range from 0-9 cycles. The therapy was poorly tolerated with grade 3 adverse events noted in 12 (60%) of the 20 patients. No objective responses were noted. Of the 14 response evaluable patients, one had an unconfirmed response (38% decrease in size) and one had prolonged disease stabilization for 10 months. The median time to progression was 1.0 month and median survival was 2.8 months. Pre and post therapy PET scans were performed nine weeks apart on one patient. The mean standardized uptake values (SUV) declined from 1.45 (SUV min-max 0.89-1.76) to 1.12 (SUV min-max 0.55-1.47), denoting anti vascular effect. The patient did not have an objective response but had a disease stabilization sustained for 10 months. CONCLUSION: The combination of interferon and thalidomide has minimal efficacy and considerable toxicity which makes this combination unworthy of future investigation in metastatic renal cancer.

Biodistribution and radiation dosimetry estimates of 1-(2'-deoxy-2'-(18)F-Fluoro-1-beta-D-arabinofuranosyl)-5-bromouracil: PET imaging studies in dogs.

UNLABELLED: This study reports on the biodistribution and radiation estimates of 1-(2'-deoxy-2'-(18)F-fluoro-1-beta-d-arabinofuranosyl)-5-bromouracil ((18)F-FBAU), a potential tracer for imaging DNA synthesis. METHODS: Three normal dogs were intravenously administered (18)F-FBAU and a dynamic PET scan was performed for 60 min over the upper abdomen followed by a whole-body scan for a total of 150 min. Blood samples were collected at stipulated time intervals to evaluate tracer clearance and metabolism. Tissue samples of various organs were analyzed for tracer uptake and DNA incorporation. Dynamic accumulation of the tracer in different organs was derived from reconstructed PET images. The radiation dosimetry of (18)F-FBAU was evaluated using the MIRD method. RESULTS: At 60 min after injection, blood analysis found >90% of the activity in unmetabolized form. At 2 h after injection, (18)F-FBAU uptake was highest in proliferating tissues (mean SUVs: marrow, 2.6; small intestine, 4.0), whereas nonproliferative tissues showed little uptake (mean SUVs: muscle, 0.75; lung, 0.70; heart, 0.85; liver, 1.28). Dynamic image analysis over 60 min showed progressive uptake of the tracer in marrow. Extraction studies demonstrated that most of the activity in proliferative tissues was in the acid-insoluble fraction (marrow, 83%; small intestine, 73%), consistent with incorporation into DNA. In nonproliferative tissue, most of the activity was not found in the acid-insoluble fraction (>84% for heart, muscle, and liver). CONCLUSION: These results demonstrate that (18)F-FBAU was resistant to metabolism, readily incorporated into DNA in proliferating tissues, and showed good contrast between organs of variable DNA synthesis. These findings indicate that (18)F-FBAU may find use in measuring DNA synthesis with PET.

A simplified analysis of [18F]3'-deoxy-3'-fluorothymidine metabolism and retention.

PURPOSE: [18F]3'-deoxy-3'-fluorothymidine (FLT) is a thymidine analog developed for imaging tumor proliferation with positron emission tomography (PET). To quantitatively assess images, the blood activities of FLT and its glucuronidated metabolite were measured and its kinetics analyzed. This study sought to limit the number of blood samples needed to measure FLT retention. METHODS: Total FLT activity was measured from 18 venous samples obtained over the first hour and dynamic imaging performed on 33 patients (average dose 350 MBq/mmol). The 5-, 10-, 30- and 60-min samples were analyzed to measure the fraction of activity in FLT and its glucuronide. HPLC analysis was compared against a two-step column (Sep-Pak) and metabolic rates measured using full and limited sampling. Probenecid (2 g, oral) was given to two patients to determine whether imaging of the liver improved. RESULTS: At 60 min, 74% of the blood activity was unmetabolized (range 57-85%). HPLC and Sep-Pak gave comparable results (r=0.97; average difference 2.1%). For kinetic analysis, eight venous samples were sufficient to accurately measure total activity; for metabolite analysis, a single sample at 60 min yielded data with mean errors of 2.2%. The metabolic rate correlated with average SUV (r2=0.85; p=0.0002). An aorta input function gave kinetic results comparable to venous blood (r2=0.82). Probenecid did not improve imaging of the liver. CONCLUSION: Dynamic measurements of FLT retention can be used to calculate metabolic rates using a limited set of samples and correction for metabolites measured in a single sample obtained at 60 min.

Kinetics of 3'-deoxy-3'-[F-18]fluorothymidine uptake and retention in dogs.

We have developed 3'-deoxy-3'-[F-18] fluorothymidine ([F-18]FLT) as an agent to image cellular proliferation with PET. Recent work has demonstrated that [F-18]FLT is stable to degradation and produces high contrast images of proliferating tissues and tumors. To increase our understanding for the use of this agent we have explored the kinetics of [F-18]FLT clearance from the blood and uptake into tissues in normal and tumor bearing dogs. The results indicate that [F-18]FLT is readily modeled in canines with a three-compartment model, with parameter k(3) representing phosphorylation by thymidine kinase. During the first 60 minutes, little loss was measured from the phosphorylated compartment, therefore parameter k(4) could not be differentiated from zero. The extraction of marrow from normal dogs was consistent with this model and demonstrated retention of phosphorylated [F-18]FLT. It is concluded that [F-18]FLT produces images of the DNA synthetic pathway by phosphorylation via thymidine kinase. This pathway can be readily modeled using a three-compartment model.