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Purpose: [18F]PR04.MZ is a new PET imaging agent for dopamine transporters, providing excellent image quality and allowing for the evaluation of patients with movement disorders such as Parkinson's disease. The objective of this study was to evaluate the biodistribution and radiation dosimetry of [18F]PR04.MZ by serial PET imaging. Methods: Six healthy subjects (n = 3 males, n = 3 females) were enrolled in this study. A series of 14 whole-body PET/CT scans were acquired until 5.5 h post-injection of 200 ± 11 MBq of [18F]PR04.MZ. After rigid co-registration, volumes of interest were outlined either on CT or PET images. Time-integrated activity coefficients were calculated for selected source organs. Organ absorbed doses, and the effective dose were calculated using IDAC-Dose 2.1. Results: Physiological uptake of [18F]PR04.MZ was mainly observed in the striatum, brain, liver, gall bladder, intestine, red marrow and cortical bone. [18F]PR04.MZ was primarily excreted via hepatobiliary clearance and, to a lower extent, via renal clearance. The normalized absorbed doses were highest in gall bladder wall (32.2 ± 6.4 µGy/MBq), urinary bladder wall (27.2 ± 4.5 µGy/MBq), red marrow (26.5 ± 1.4 µGy/MBq), cortical bone surface (26.3 ± 2.5 µGy/MBq), liver (22.5 ± 1.8 µGy/MBq) and kidneys (21.8 ± 1.1 µGy/MBq). The effective dose according to ICRP 60 and 103 was 16.3 ± 1.1 and 16.6 ± 1.5 µSv/MBq, respectively. Conclusion: [18F]PR04.MZ has a favourable dosimetry profile, comparable to those of other 18F-labelled PET tracers, and is suitable for larger clinical applications. Trial registration CEC SSM Oriente, Santiago, Chile, permit 20140520. [ABSTRACT FROM AUTHOR]

Abstract: Accurate quantification of PET imaging data is required for a useful interpretation of the measured radioactive tracer concentrations. The partial volume effect (PVE) describes signal dilution and mixing due to spatial resolution and sampling limitations, which introduces bias in quantitative results. In the present study we investigated the magnitude of PVE for volumes of interest (VOIs) in the rat brain and the effect of positron range. In simulated 11C-raclopride studies we examined the influence of PVE on time activity curves in striatal and cerebellar VOIs and binding potential estimation. The performance of partial volume correction (PVC) was studied using the region-based geometric transfer matrix (GTM) method including the question of whether a spatially variant point spread function (PSF) is necessary for PVC of a rat brain close to the centre of the field of view. Furthermore, we determined the effect of spillover from activity outside the brain. The results confirmed that PVE is significant in rat brain PET and showed that positron range is an important factor that needs to be included in the PSF. There was considerable bias in time activity curves for the simulated 11C-raclopride studies and significant underestimation of binding potential even for very small centred VOIs. Good activity recovery was achieved with the GTM PVC using a spatially invariant simulated PSF when no activity was present outside the brain. PVC using a simple Gaussian fit point spread function was not sufficiently accurate. Spillover from regions outside the brain had a significant impact on measured activity concentrations and reduced the accuracy of PVC with the GTM method using rat brain regions alone, except for the smallest VOI size but at the cost of increased noise. Voxel-based partial volume correction methods which inherently compensate for spillover from outside the brain might be a more suitable choice. [Copyright &y& Elsevier]

Background: Optimal peptide concentration in treatment with 177Lu-DOTATOC/DOTATATE is amatter of debate. Most of the studies with peptide receptor radionuclide therapy mention peptidedose ranging between 100 and 250 µg. The aim of this is to identify possible differences inradiation-absorbed doses (D/Gy) to tumor and kidney as a function of the peptide mass dose in orderto identify the most suitable peptide dose for treatment. The therapeutic index (Dtumor/Dkidneys) wasassessed as a key parameter for the treatment response. Materials and Methods: Five patients withmetastasized Grade 1 to Grade 2 neuroendocrine tumor were analyzed in this study. Patients (n = 4)received two cycles of treatment with intravenously injected 177Lu-DOTATOC containing peptidemass doses of 200 µg and 90 µg, alternatively; one patient was treated with 90 µg peptide massin both the therapy cycles. Whole-body (head to mid-thigh) three-dimensional single-photonemission computerized tomography (3D SPECT)/CT images were acquired at 1, 4, 24, 48, and72 h following the injection of 177Lu-DOTATOC. Attenuation correction for 3D SPECT images wasperformed using CT data acquired and fused with the SPECT data (SPECT/CT). Results: Overall, 28 target lesions (liver n = 17, lung n = 4, lymph nodes n = 1, and bone n = 2) were analyzed after 1st and 2nd therapy cycles. Tumor normalized absorbed doses varied by a factor of 74 between 0.35 and26 mGy/MBq. Averaged over all patients, a higher normalized mean tumor dose (10.51 mGy/MBq)was achieved for a peptide dose of 200 µg compared to 90 µg (4.58 mGy/MBq). Kidneys dosesvaried by a factor of up to 4 between patients (0.25-1.0 mGy/MBq) (independent of dose cycle andpeptide dose) and by a factor of up to 2 between dose cycles. The mean kidney dose was 13.7%higher for the 90 µg peptide dose compared to 200 µg. Given the higher tumor dose, the meantherapeutic index of a 200 µg mass dose was considerably higher (16.95), compared to a 90 µg massdose (9.63). This coincided with the observation, that lesion volume reduction was more pronouncedafter an initial treatment with a 200 µg mass dose. Biologically effective dose was only 5. 1%-19.3%higher than the absorbed dose for individual dose cycles. Conclusions: Higher peptide dose of 200µg appears to be more suitable than 90 µg in terms of tumor dose, kidney dose, and therapeuticindex for treatment with 177Lu-DOTATOC. [ABSTRACT FROM AUTHOR]

Background: Internal dosimetry in individual patients is essential for safe and effective radioligand therapy. Multiple time point imaging for accurate dosimetry is time consuming and hence can be demanding for nuclear medicine departments as well as patients. The objectives of this study were (1) to assess absorbed doses to organs at risk and tumor lesions for [177Lu]Lu-PSMA-I&T using whole body SPECT imaging and (2) to investigate possible simplified dosimetry protocols. Methods: This study included 16 patients each treated with 4 cycles of [177Lu]Lu-PSMA-I&T. They underwent quantitative whole body SPECT/CT imaging (3 bed positions) at four time points (TP) comprising 2 h, 24 h, 48 h and 72–168 h post-injection (p.i.). Full 3D dosimetry (reference method) was performed for all patients and dose cycles for organs at risk (kidneys, parotid glands and submandibular glands) and up to ten tumor lesions per patient (resulting in 90 lesions overall). The simplified dosimetry methods (SM) included (1) generating time activity curves for subsequent cycles using a single TP of imaging applying the kinetics of dose cycle 1, and for organs at risk also (2) simple extrapolation from dose cycle 1 and (3) from both, dose cycle 1 and 2. Results: Normalized absorbed doses were 0.71 ± 0.32 mGy/MBq, 0.28 ± 0.12 mGy/MBq and 0.22 ± 0.08 mGy/MBq for kidneys, parotid glands and submandibular glands, respectively. Tumor doses decreased from 3.86 ± 3.38 mGy/MBq in dose cycle 1 to 2.01 ± 2.65 mGy/MBq in dose cycle 4. Compared to the full dosimetry approach the SM 1 using single TP imaging at 48 h p.i. resulted in the most accurate and precise results for the organs at risk in terms of absorbed doses per cycle and total cumulated dose. For tumor lesions better results were achieved using the fourth TP (≥ 72 h p.i.). Conclusion: Simplification of safety dosimetry protocols is possible for [177Lu]Lu-PSMA-I&T therapy. If tumor dosimetry is of interest a later imaging TP (≥ 72 h p.i.) should be used/added to account for the slower kinetics of tumors compared to organs at risk. [ABSTRACT FROM AUTHOR]

Introduction: PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. Methods: Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120–160 μg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. Results: [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. Conclusion: Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer. [ABSTRACT FROM AUTHOR]

A correction to the article "Analytical positron-range modelling in heterogeneous media for PET Monte Carlo simulation" that was published in the June 7, 2012 issue is presented.

Background: The specific binding ratio (SBR) of 123I-FP-CIT in the putamen is widely used to support the interpretation of dopamine transporter (DAT) SPECT. Automatic methods for computation of the putamen SBR often include stereotactical normalization of the individual DAT-SPECT image to an anatomical standard space. This study compared using a single 123I-FP-CIT template image as target for stereotactical normalization versus multiple templates representative of normal and different levels of Parkinson-typical reduction of striatal 123I-FP-CIT uptake. Methods: 1702 clinical 123I-FP-CIT SPECT images were stereotactically normalized (affine) to the anatomical space of the Montreal Neurological Institute (MNI) with SPM12 either using a single custom-made 123I-FP-CIT template representative of normal striatal uptake or using eight different templates representative of normal and different levels of Parkinson-typical reduction of striatal FP-CIT uptake with and without attenuation and scatter correction. In the latter case, SPM finds the linear combination of the multiple templates that best matches the patient's image. The putamen SBR was obtained using hottest voxels analysis in large unilateral regions-of-interest predefined in MNI space. The histogram of the putamen SBR in the whole sample was fitted by the sum of two Gaussians. The power to differentiate between reduced and normal SBR was estimated by the effect size of the distance between the two Gaussians computed as the differences between their mean values scaled to their pooled standard deviation. Results: The effect size of the distance between the two Gaussians was 3.83 with the single template versus 3.96 with multiple templates for stereotactical normalization. Conclusions: Multiple templates representative of normal and different levels of Parkinson-typical reduction for stereotactical normalization of DAT-SPECT might provide improved separation between normal and reduced putamen SBR that could result in slightly improved power for the detection of nigrostriatal degeneration. [ABSTRACT FROM AUTHOR]

Background: This study investigated the impact of the size of the normal database on the classification performance of the specific binding ratio (SBR) in dopamine transporter (DAT) SPECT with [123I]FP-CIT in different settings. Methods: The first subject sample comprised 645 subjects from the Parkinson's Progression Marker Initiative (PPMI), 207 healthy controls (HC), and 438 Parkinson's disease (PD) patients. The second sample comprised 372 patients from clinical routine patient care, 186 with non-neurodegenerative parkinsonian syndrome (PS) and 186 with neurodegenerative PS. Single-photon emission computed tomography (SPECT) images of the clinical sample were reconstructed with two different reconstruction algorithms (filtered backprojection, iterative ordered subsets expectation maximization (OSEM) reconstruction with resolution recovery). The putaminal specific binding ratio (SBR) was computed using an anatomical region of interest (ROI) predefined in standard (MNI) space in the Automated Anatomic Labeling (AAL) atlas or using hottest voxels (HV) analysis in large predefined ROIs. SBR values were transformed to z-scores using mean and standard deviation of the SBR in a normal database of varying sizes (n = 5, 10, 15,..., 50) randomly selected from the HC subjects (PPMI sample) or the patients with non-neurodegenerative PS (clinical sample). Accuracy, sensitivity, and specificity for identifying patients with PD or neurodegenerative PS were determined as performance measures using a predefined fixed cutoff on the z-score. This was repeated for 10,000 randomly selected normal databases, separately for each size of the normal database. Mean and 5th percentile of the performance measures over the 10,000 realizations were computed. Accuracy, sensitivity, and specificity when using the whole set of HC or non-neurodegenerative PS subjects as normal database were used as benchmark. Results: Mean loss of accuracy of the putamen SBR z-score was below 1% when the normal database included at least 15 subjects, independent of subject sample (PPMI or clinical), reconstruction method (filtered backprojection or OSEM), and ROI method (AAL or HV). However, the variability of the accuracy of the putamen SBR z-score decreased monotonically with increasing size of normal database and was still considerable at size 15. In order to achieve less than 5% "maximum" loss of accuracy (defined by the 5th percentile) in all settings required at least 25 to 30 subjects in the normal database. Reduction of mean and "maximum" loss of accuracy of the putamen SBR z-score by further increasing the size of the normal database was very small beyond size 40. Conclusions: The results of this study suggest that 25 to 30 is the minimum size of the normal database to reliably achieve good performance of semi-quantitative analysis in dopamine transporter (DAT) SPECT, independent of the algorithm used for image reconstruction and the ROI method used to estimate the putaminal SBR. [ABSTRACT FROM AUTHOR]

Purpose: The aims of this study were to develop a prostate-specific membrane antigen (PSMA) ligand for labelling with different radioisotopes of lead and to obtain an approximation of the dosimetry of a simulated 212Pb-based alpha therapy using its 203Pb imaging analogue. Methods: Four novel Glu-urea-based ligands containing the chelators p-SCN-Bn-TCMC or DO3AM were synthesized. Affinity and PSMA-specific internalization were studied in C4-2 cells, and biodistribution in C4-2 tumour-bearing mice. The most promising compound, 203Pb-CA012, was transferred to clinical use. Two patients underwent planar scintigraphy scans at 0.4, 4, 18, 28 and 42 h after injection, together with urine and blood sampling. The time–activity curves of source organs were extrapolated from 203Pb to 212Pb and the calculated residence times of 212Pb were forwarded to its unstable daughter nuclides. QDOSE and OLINDA were used for dosimetry calculations. Results: In vitro, all ligands showed low nanomolar binding affinities for PSMA. CA09 and CA012 additionally showed specific ligand-induced internalization of 27.4 ± 2.4 and 15.6 ± 2.1 %ID/106 cells, respectively. The 203Pb-labelled PSMA ligands were stable in serum for 72 h. In vivo, CA012 showed higher specific uptake in tumours than in other organs, and particularly showed rapid kidney clearance from 5.1 ± 2.5%ID/g at 1 h after injection to 0.9 ± 0.1%ID/g at 24 h. In patients, the estimated effective dose from 250–300 MBq of diagnostic 203Pb-CA012 was 6–7 mSv. Assuming instant decay of daughter nuclides, the equivalent doses projected from a therapeutic activity of 100 MBq of 212Pb-CA012 were 0.6 SvRBE5 to the red marrow, 4.3 SvRBE5 to the salivary glands, 4.9 SvRBE5 to the kidneys, 0.7 SvRBE5 to the liver and 0.2 SvRBE5 to other organs; representative tumour lesions averaged 13.2 SvRBE5 (where RBE5 is relative biological effectiveness factor 5). Compared to clinical experience with 213Bi-PSMA-617 and 225Ac-PSMA-617, the projected maximum tolerable dose was about 150 MBq per cycle. Conclusion: 212Pb-CA012 is a promising candidate for PSMA-targeted alpha therapy of prostate cancer. The dosimetry estimate for radiopharmaceuticals decaying with the release of unstable daughter nuclides has some inherent limitations, thus clinical translation should be done cautiously. [ABSTRACT FROM AUTHOR]