Novel and simple carbon-11-labeled ammonium salts as PET agents for myocardial perfusion imaging.

BACKGROUND: Positron emission tomography (PET) has clear advantages over single photon emission computed tomography (SPECT) in the field of myocardial perfusion scintigraphy (MPS); however, there are just a small number of efficient PET tracers available today for MPS. We sought to develop and perform a preliminary biological evaluation of novel carbon-11-labeled ammonium salts as potential MPS PET agents. METHODS AND RESULTS: Three potential tracers were labeled and evaluated via biodistribution in mice and PET imaging in both rats and rabbits, and the results obtained were also compared to agents that are routinely used in the clinical practice. CONCLUSIONS: The results designated carbon-11-labeled ammonium salts as having great potential as MPS PET agents. Specifically, carbon-11-labeled trimethyl-phenyl-ammonium iodide ([(11)C]2) and homologues of higher lipophilicity/charge warrant further studies in larger animals and humans such as measurements of myocardial uptake at rest and stress under both normal and pathological coronary flow conditions.

In vivo measurement of brain monoamine oxidase B occupancy by rasagiline, using (11)C-l-deprenyl and PET.

UNLABELLED: In recent years, monoamine oxidase B (MAO-B) inhibitors have become widely used in the treatment of early-stage Parkinson's disease. (11)C-l-deprenyl PET has been used by others to characterize MAO-B ligands in terms of their in vivo potency toward MAO-B and duration of action. In this study, we used (11)C-l-deprenyl PET to demonstrate the specific binding characteristics of the new irreversible selective MAO-B inhibitor rasagiline in 3 healthy volunteers. METHODS: The healthy volunteers received 1 mg of rasagiline daily for 10 d. Dynamic (11)C-l-deprenyl PET brain scans were acquired before the first treatment (scan 1) and immediately (scan 2), 2-3 wk (scan 3), and 4-6 wk (scan 4) after the final treatment. RESULTS: On scan 1, all subjects showed the highest l-deprenyl uptake in the thalamus and basal ganglia, with fairly high activity also in the cortex and cerebellum and much lower activity in the white matter. The areas of high uptake were absent from scan 2, on which activity throughout the brain was comparable to that in white matter, presumably because of blocking of MAO-B binding sites by rasagiline. Gradual recovery toward the baseline state was observed in the weeks after termination of treatment (scans 3 and 4). CONCLUSION: (11)C-l-deprenyl PET showed binding of rasagiline to MAO-B, confirming blocking of MAO-B sites after 10 d of treatment with 1 mg of rasagiline per day, with immediate post-rasagiline treatment tracer uptake and metabolism in the basal ganglia compatible only with nonspecific binding. Subsequent gradual recovery was also seen, with return to near-baseline uptake. This finding is compatible with the known rate of de novo synthesis of MAO-B, confirming the irreversible binding of rasagiline.

Simplified kinetic analysis of tumor 18F-FDG uptake: a dynamic approach.

UNLABELLED: Standardized uptake value (SUV) is often used to quantify (18)F-FDG tumor use. Although useful, SUV suffers from known quantitative inaccuracies. Simplified kinetic analysis (SKA) methods have been proposed to overcome the shortcomings of SUV. Most SKA methods rely on a single time point (SKA-S), not on tumor uptake rate. We describe a hybrid between Patlak analysis and existing SKA-S methods, using multiple time points (SKA-M) but reduced imaging time and without measurement of an input function. We compared SKA-M with a published SKA-S method and with Patlak analysis. METHODS: Twenty-seven dynamic (18)F-FDG scans were performed on 11 cancer patients. A population-based (18)F-FDG input function was generated from an independent patient population. SKA-M was calculated using this population input function and either a short, late, dynamic acquisition over the tumor (starting 25-35 min after injection and ending approximately 55 min after injection) or dynamic imaging 10 or 25 min to approximately 55 min after injection but using only every second or third time point, to permit a 2- or 3-field-of-view study. SKA-S was also calculated. Both SKA-M and SKA-S were compared with the gold standard, Patlak analysis. RESULTS: Both SKA-M (1 field of view) and SKA-S correlated well with Patlak slope (r > 0.99, P < 0.001, and r = 0.96, P < 0.001, respectively), as did multilevel SKA-M (r > 0.99 and P < 0.001 for both). Mean values of SKA-M (25-min start time) and SKA-S were statistically different from Patlak analysis (P < 0.001 and P < 0.04, respectively). One-level SKA-M differed from the Patlak influx constant by only -1.0% +/- 1.4%, whereas SKA-S differed by 15.1% +/- 3.9%. With 1-level SKA-M, only 2 of 27 studies differed from K(i) by more than 20%, whereas with SKA-S, 10 of 27 studies differed by more than 20% from K(i). CONCLUSION: Both SKA-M and SKA-S compared well with Patlak analysis. SKA-M (1 or multiple levels) had lower variability and bias than did SKA-S, compared with Patlak analysis. SKA-M may be preferred over SUV or SKA-S when a large unmetabolized (18)F-FDG fraction is expected and 1-3 fields of view are sufficient.

Comparison of SUV and Patlak slope for monitoring of cancer therapy using serial PET scans.

The standardized uptake value (SUV) and the slope of the Patlak plot ( K) have both been proposed as indices to monitor the progress of disease during cancer therapy. Although a good correlation has been reported between SUV and K, they are not equivalent, and may not be equally affected by metabolic changes occurring during disease progression or therapy. We wished to compare changes in tumor SUV with changes in K during serial positron emission tomography (PET) scans for monitoring therapy. Thirteen patients enrolled in a protocol to treat renal cell carcinoma metastases were studied. Serial dynamic fluorodeoxyglucose (FDG) PET scans and computed tomography (CT) and magnetic resonance (MR) scans were performed once prior to treatment, once at 36+/-2 days after the start of treatment, and (in 7/13 subjects, 16/27 lesions) a third time at 92+/-9 days after the start of treatment. This resulted in a total of 33 scans, and 70 tumor Patlak and SUV values (one value for each lesion at each time point). SUV and K were measured over one to four predefined tumors/patient at each time point. The input function was obtained from regions of interest over the heart, combined, if necessary, with late blood samples. Over all tumors and scans, SUV and K correlated well ( r=0.97, P<0.0001). However, change in SUV with treatment over all tumor scan pairs was much less well correlated with the corresponding change in K ( r=0.73, P<0.0001). The absolute difference in % change was outside the 95% confidence limits expected from previous variability studies in 6 of 43 pairs of tumor scans, and greater than 50% in 2 of 43 tumor scan pairs. In four of the six cases, the two indices predicted opposing therapeutic outcomes. Similar results were obtained for SUV normalized by body weight or body surface area and for SUVs using mean or maximum count. Changes in CT and MR tumor cross-product dimensions correlated poorly with each other ( r=0.47, P=NS), and so could not be used to determine the "correct" PET index. Absolute values of SUV and K correlated well over the patient population. However, when monitoring individual patient therapy serially, large differences in the % changes in the two indices were occasionally found, sometimes sufficient to produce opposing conclusions regarding the progression of disease.

Labeled EGFr-TK irreversible inhibitor (ML03): in vitro and in vivo properties, potential as PET biomarker for cancer and feasibility as anticancer drug.

Radiosynthesis of ML03 (N-[4-[(4,5-dichloro-2-fluorophenyl)amino]quinazolin-6-yl]acrylamide), an irreversible EGFr-TK inhibitor, was developed. Its in vitro and in vivo properties, its potential as PET biomarker in cancer and the feasibility of this type of compounds to be used as anticancer drug agents were evaluated. The compound was labeled with carbon-11 at the acryloyl amide group, via automated method with high yield, chemical and radiochemical purities. ELISA carried out with A431 lysate showed high potency of ML03 with an apparent IC(50) of 0.037 nM. The irreversible binding nature of ML03 was studied and 97.5% EGFr-TK autophosphorylation inhibition was observed in intact A431 cells 8 hr post incubation with the inhibitor. Specific binding (67%) of [(11)C]ML03 was obtained in cells. An A431 tumor-bearing rat model was developed and the validity of the model was tested. In biodistribution studies carried out with tumor-bearing rats, moderate uptake was observed in tumor and high uptake in liver, kidney and intestine. In metabolic studies, fast degradation of [(11)C]ML03 was observed in liver and blood indicating a short half-life of the compound in the body. PET scan with tumor-bearing rats confirmed the results obtained in the ex vivo biodistribution studies. Although in vitro experiments may indicate efficacy of ML03, non-specific binding, ligand delivery and degradation in vivo make ML03 ineffective as PET bioprobe. Derivatives of ML03 with lower metabolic clearance rate and higher bioavailability should be synthesized and their potential as anticancer drugs and PET bioprobes evaluated.