- Email: [email protected]
PET microdosing - promises and limitations
Abstracts of the AMI Annual Meeting 2004 89
and bone regions. In the comparison between PET/CT and CT, PET/CT showed true-positive findings in 60 regions. CT showed true-positive findings in 39 (65.0 %) of the 60 regions, and the remaining 21 regions (35.0 %) had inconclusive or negative findings. PET/CT appeared to be useful in evaluating small-sized lymph nodes and bone lesions. Conclusion: PET/CT was demonstrated to add incremental value to PET alone in many patients and regions with increased FDG uptake and exhibit more true-positive findings than CT did at the same location. PET/CT appears preferable to PET or CT in the diagnosis of breast cancer in this initial evaluation. No. 74 ULTRAHIGH RESOLUTION CLINICAL POSITRON EMISSION TOMOGRAPHY - PRELIMINARY RESULTS I. N. Weinberg1, L. P. Adler2, D. Beylin1, E. Anashkin1, P. Stepanov1, D. Narayanan2, M. Doss2, K. Lauckner3; 1Naviscan PET Systems, Inc., Rockville, MD, 2Fox Chase Cancer Center, Philadelphia, PA, 3seleon GMBH, Freiburg, GERMANY. Purpose: To evaluate clinical images using ultrahigh resolution positron emission tomography (PET). Materials and Methods: Directed examination of specific body parts were taken with a novel portable compact clinical PET scanner (PEM FlexTM, Naviscan PET Systems, Rockville, MD), with 1.5 mm intrinsic spatial resolution. When possible, these images were compared with those taken using a state-of-the-art combined PET/CT scanner. Results: Delayed 2-deoxy-2-[18F]fluoro-D-glucose (FDG) images with the PEM Flex device appear to reveal anatomic details not previously visible with PET: Breast images demonstrate individual ducts and other ductal patterns. Extremity images clearly show exercised-induced increased FDG accumulation in intra-osseous muscles, and insertions of individual muscle groups. Direct sagittal images display anatomic features (e.g., optic nerve) and intra-articular structures (e.g., cruciate ligament) typically seen on magnetic resonance imaging (MRI). Conclusion: Ultrahigh spatial resolution PET provides functional detail unprecedented in a clinical PET scanner. Further work will be needed to determine whether high resolution imaging findings in pathological states (e.g., multifocal breast cancer, musculoskeletal pain) would complement conventional imaging evaluations (e.g., MRI). No. 75 11C-METHIONINE UPTAKE MEASURED BY POSITRON EMISSION TOMOGRAPHY (PET) IS AN INDEPENDENT PREDICTOR OF SURVIVAL IN PATIENTS WITH BONE AND SOFT TISSUE SARCOMAS TREATED BY CARBON ION RADIOTHERAPY H. Zhang, K. Yoshikawa, M. Tian, S. Tanada, H. Tsujii, T. Suhara; National Institute of Radiological Sciences, Chiba, JAPAN. Purpose: We evaluated whether C-11-methionine (MET) uptake and its change after carbon ion radiotherapy (CIRT) were the early survival predicators in patients with bone and soft tissue sarcomas. Methods: MET-PET was prospectively performed in 62 patients with bone and soft tissue sarcomas before and within one month after CIRT. Tumor MET uptake was measured with the semiquantitative tumor-to-nontumor ratio (T/N ratio). The MET uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analysis. Results: The overall median survival time was 20 months. Patients with a baseline T/N ratio of ≤ 6 had a significant better survival than patients with a baseline T/N ratio > 6 (2-year survival rate: 69.4% versus 32.3%, P=0.01). Patients with a post CIRT ratio of ≤ 4.4 had a better survival than that with a post CIRT ratio > 4.4 (2-year survival rate: 63.7% versus 41.3%, P=0.01). A significant higher survival rate was observed in patients with posttherapeutic MET uptake change of > 30% than patients in lower change group (2-year survival rate: 74.6% versus 41.6%, P=0.049). The multivariate analysis showed that both baseline and postCIRT T/N ratio
were statistically significant independent predictors of patient survival. Tumors with larger T/N ratio had a significantly poorer prognosis. Conclusions: MET uptake as measured by either baseline or postCIRT T/N ratio was an independent predictor of survival in patients with bone and soft tissue sarcomas treated by CIRT, while posttherapeutic MET uptake change might have potential value for the same purpose.
Drug Development Oral Presentations No. 76 PET MICRODOSING – PROMISES AND LIMITATIONS M. Bergström1, A. Grahnen2, B. Långström1; 1Uppsala Imanet, Uppsala, SWEDEN, 2Quintiles AB, Uppsala, SWEDEN. PET-microdosing compose a package of safety, radiation exposure, technical feasibility, and validation for a proper interpretation of the results. PET-microdosing is utilized for two different purposes; to gain information on a tentative drug candidate in humans, and to ensure adequate properties of a tentative PET-tracer. For a drug candidate, the organ and plasma pharmacokinetics must be assessed properly. A concern in PET-microdosing is that the radioactivity represents intact drug and not metabolites. This necessitates pre-clinical analyses, including plasma metabolite studies and studies of organ radioactivity. Dose linearity studies in animal models are essential for extrapolation to therapeutic concentrations. Full dose-linearity is not required if the plasma-to-tissue exchange is linear with dose. Lack of dose linearity occurs when transport or metabolic systems come close to saturation. For a PET-tracer under development the relative uptake and kinetics in a tissue must be interpreted and quantified in terms of interaction with the target system. We suggest a set of criteria, to be met by a PET-tracer trusted for the characterization of target system expression or interaction of a drug with this system. Of major concern is specificity. A range of pre-clinical studies is needed for the understanding of the in vivo behavior. For dose-occupancy studies of a new drug, this agent’s dose-dependent effect on the tracer is evaluated, starting with in vitro binding studies and including animal evaluations. With proper pre-clinical validations, PET-microdosing can be a very effective means for obtaining human data early. No. 77 PET WITH 11C-ZOLMITRIPTAN AS NASAL SPRAY DEMONSTRATES A RAPID PLASMA AVAILABILITY VIA NASAL MUCOSA AND ENTRY INTO BRAIN M. Bergström1, M. Kågedahl2, A. Wall1, R. Yates3, J. Sörensen1, G. Antoni1, S. Gustavsson1, B. Långström1; 1Uppsala Imanet, Uppsala, SWEDEN, 2AstraZeneca, Södertälje, SWEDEN, 3AstraZeneca, Alderley Park, UNITED KINGDOM. A nasal spray formulation has been developed for the anti-migraine medicine Zolmitriptan, and clinical trials have shown rapid onset of action as compared to oral administration. Zolmitriptan after nasal administration partly enters the circulation through absorption across the nasal mucosa. Zolmitriptan might have central effects in combination with effects on the vascular endothelium, giving this triptan a special therapeutic feature. Two positron emission tomography (PET)-trials were initiated to demonstrate the pharmacokinetics of zolmitriptan with respect to absorption via the nasal mucosa and brain kinetics. 11C-zolmitriptan was co-administered with the nasal therapeutic dose and the amounts of zolmitriptan characterized with respect to site of deposition and rates of disposition via the oralgastrointestinal tracts. This was in correlated with appearance and kinetics in plasma.
and bone regions. In the comparison between PET/CT and CT, PET/CT showed true-positive findings in 60 regions. CT showed true-positive findings in 39 (65.0 %) of the 60 regions, and the remaining 21 regions (35.0 %) had inconclusive or negative findings. PET/CT appeared to be useful in evaluating small-sized lymph nodes and bone lesions. Conclusion: PET/CT was demonstrated to add incremental value to PET alone in many patients and regions with increased FDG uptake and exhibit more true-positive findings than CT did at the same location. PET/CT appears preferable to PET or CT in the diagnosis of breast cancer in this initial evaluation. No. 74 ULTRAHIGH RESOLUTION CLINICAL POSITRON EMISSION TOMOGRAPHY - PRELIMINARY RESULTS I. N. Weinberg1, L. P. Adler2, D. Beylin1, E. Anashkin1, P. Stepanov1, D. Narayanan2, M. Doss2, K. Lauckner3; 1Naviscan PET Systems, Inc., Rockville, MD, 2Fox Chase Cancer Center, Philadelphia, PA, 3seleon GMBH, Freiburg, GERMANY. Purpose: To evaluate clinical images using ultrahigh resolution positron emission tomography (PET). Materials and Methods: Directed examination of specific body parts were taken with a novel portable compact clinical PET scanner (PEM FlexTM, Naviscan PET Systems, Rockville, MD), with 1.5 mm intrinsic spatial resolution. When possible, these images were compared with those taken using a state-of-the-art combined PET/CT scanner. Results: Delayed 2-deoxy-2-[18F]fluoro-D-glucose (FDG) images with the PEM Flex device appear to reveal anatomic details not previously visible with PET: Breast images demonstrate individual ducts and other ductal patterns. Extremity images clearly show exercised-induced increased FDG accumulation in intra-osseous muscles, and insertions of individual muscle groups. Direct sagittal images display anatomic features (e.g., optic nerve) and intra-articular structures (e.g., cruciate ligament) typically seen on magnetic resonance imaging (MRI). Conclusion: Ultrahigh spatial resolution PET provides functional detail unprecedented in a clinical PET scanner. Further work will be needed to determine whether high resolution imaging findings in pathological states (e.g., multifocal breast cancer, musculoskeletal pain) would complement conventional imaging evaluations (e.g., MRI). No. 75 11C-METHIONINE UPTAKE MEASURED BY POSITRON EMISSION TOMOGRAPHY (PET) IS AN INDEPENDENT PREDICTOR OF SURVIVAL IN PATIENTS WITH BONE AND SOFT TISSUE SARCOMAS TREATED BY CARBON ION RADIOTHERAPY H. Zhang, K. Yoshikawa, M. Tian, S. Tanada, H. Tsujii, T. Suhara; National Institute of Radiological Sciences, Chiba, JAPAN. Purpose: We evaluated whether C-11-methionine (MET) uptake and its change after carbon ion radiotherapy (CIRT) were the early survival predicators in patients with bone and soft tissue sarcomas. Methods: MET-PET was prospectively performed in 62 patients with bone and soft tissue sarcomas before and within one month after CIRT. Tumor MET uptake was measured with the semiquantitative tumor-to-nontumor ratio (T/N ratio). The MET uptake in the tumor and relevant clinical parameters were entered into univariate and multivariate survival analysis. Results: The overall median survival time was 20 months. Patients with a baseline T/N ratio of ≤ 6 had a significant better survival than patients with a baseline T/N ratio > 6 (2-year survival rate: 69.4% versus 32.3%, P=0.01). Patients with a post CIRT ratio of ≤ 4.4 had a better survival than that with a post CIRT ratio > 4.4 (2-year survival rate: 63.7% versus 41.3%, P=0.01). A significant higher survival rate was observed in patients with posttherapeutic MET uptake change of > 30% than patients in lower change group (2-year survival rate: 74.6% versus 41.6%, P=0.049). The multivariate analysis showed that both baseline and postCIRT T/N ratio
were statistically significant independent predictors of patient survival. Tumors with larger T/N ratio had a significantly poorer prognosis. Conclusions: MET uptake as measured by either baseline or postCIRT T/N ratio was an independent predictor of survival in patients with bone and soft tissue sarcomas treated by CIRT, while posttherapeutic MET uptake change might have potential value for the same purpose.
Drug Development Oral Presentations No. 76 PET MICRODOSING – PROMISES AND LIMITATIONS M. Bergström1, A. Grahnen2, B. Långström1; 1Uppsala Imanet, Uppsala, SWEDEN, 2Quintiles AB, Uppsala, SWEDEN. PET-microdosing compose a package of safety, radiation exposure, technical feasibility, and validation for a proper interpretation of the results. PET-microdosing is utilized for two different purposes; to gain information on a tentative drug candidate in humans, and to ensure adequate properties of a tentative PET-tracer. For a drug candidate, the organ and plasma pharmacokinetics must be assessed properly. A concern in PET-microdosing is that the radioactivity represents intact drug and not metabolites. This necessitates pre-clinical analyses, including plasma metabolite studies and studies of organ radioactivity. Dose linearity studies in animal models are essential for extrapolation to therapeutic concentrations. Full dose-linearity is not required if the plasma-to-tissue exchange is linear with dose. Lack of dose linearity occurs when transport or metabolic systems come close to saturation. For a PET-tracer under development the relative uptake and kinetics in a tissue must be interpreted and quantified in terms of interaction with the target system. We suggest a set of criteria, to be met by a PET-tracer trusted for the characterization of target system expression or interaction of a drug with this system. Of major concern is specificity. A range of pre-clinical studies is needed for the understanding of the in vivo behavior. For dose-occupancy studies of a new drug, this agent’s dose-dependent effect on the tracer is evaluated, starting with in vitro binding studies and including animal evaluations. With proper pre-clinical validations, PET-microdosing can be a very effective means for obtaining human data early. No. 77 PET WITH 11C-ZOLMITRIPTAN AS NASAL SPRAY DEMONSTRATES A RAPID PLASMA AVAILABILITY VIA NASAL MUCOSA AND ENTRY INTO BRAIN M. Bergström1, M. Kågedahl2, A. Wall1, R. Yates3, J. Sörensen1, G. Antoni1, S. Gustavsson1, B. Långström1; 1Uppsala Imanet, Uppsala, SWEDEN, 2AstraZeneca, Södertälje, SWEDEN, 3AstraZeneca, Alderley Park, UNITED KINGDOM. A nasal spray formulation has been developed for the anti-migraine medicine Zolmitriptan, and clinical trials have shown rapid onset of action as compared to oral administration. Zolmitriptan after nasal administration partly enters the circulation through absorption across the nasal mucosa. Zolmitriptan might have central effects in combination with effects on the vascular endothelium, giving this triptan a special therapeutic feature. Two positron emission tomography (PET)-trials were initiated to demonstrate the pharmacokinetics of zolmitriptan with respect to absorption via the nasal mucosa and brain kinetics. 11C-zolmitriptan was co-administered with the nasal therapeutic dose and the amounts of zolmitriptan characterized with respect to site of deposition and rates of disposition via the oralgastrointestinal tracts. This was in correlated with appearance and kinetics in plasma.