56 research outputs found
Studies on dosimetry of positron emitting radiopharmaceuticals
Positron emission tomography (PET) is a non-invasive method for studying physiological phenomena in a living subject with radiopharmaceuticals. The physical decay of radioactive radiopharmaceuticals induce ionization in subjects, which results in an absorbed dose. Developing a new radiopharmaceutical always raises the question of how much of this substance can we inject into the patient? Administering radioactive substance to patients should always be justified and the potential benefit should outweigh the risk. Determining radiation doses for new positron emitting radiopharmaceuticals is an important part of the benefit-risk assessment of the use of radioactivity.
In this study, the evaluation of radiation doses was conducted using PET imaging technology. Prior to PET/CT scanners, studies were limited to dynamic imaging of just one part of the body (brain, thorax, abdomen or skeletal muscle). However, developments in the performance of PET scanners enabled producing series of whole body PET scans. With this whole body scanning method, more source organs were evaluated per participant and the number of measurements was increased per timepoint with the same number of participants. This produced more precise temporal time-activity-curves for source organs and more precise radiation dose calculations.
Radiation doses were calculated using computer programs that are commonly used in published dosimetry studies. There were updates in the programs during the course of the study as mathematical models of the human anatomy became more sophisticated and coefficients reflecting the harm caused by radiation to tissues became more accurate.
Dosimetry is only one part in development of a new radiopharmaceutical, and based on the results in this thesis these radiopharmaceuticals can be introduced for clinical use from a radiation safety point of view.---
Positroniemissiotomografia (PET) soveltuu hyvin erilaisten fysiologisten ilmiöiden kajoamattomaan kuvantamiseen elävässä kohteessa radiolääkkeiden avulla. Kun radiolääkkeen radioaktiivisuus hajoaa, syntyy ionisoivaa säteilyä, joka aiheuttaa kohteeseen säteilyrasitusta, absorboitunutta annosta. Uuden radiolääkkeen tuottamisen jälkeen herää kysymys, paljonko kyseistä radiolääkettä voi ihmiseen injektoida, jotta sen käyttö olisi oikeutettua ja radioaktiivisuuden käytöstä saatava hyöty olisi sen mahdollisesti aiheuttamaa haittaa suurempi. Säteilyannosten määrittäminen uusille positroneja emittoiville radiolääkkeille on tärkeä osa radioaktiivisuuden käytön hyöty-haitta arviointia.
Tässä tutkimuksessa säteilyannosten arviointiin käytettiin PET-kuvaustekniikkaa. Aluksi tutkimukset toteutettiin yhden kehon osan (aivot, rintakehä, vatsa tai reisilihakset) dynaamisella kuvaamisella, mutta PET-kameroiden suorituskyvyn kehityksen myötä otettiin käyttöön tutkittavan henkilön koko kehon PET kuvaussarja menetelmä. Tämän kehitysaskeleen johdosta voitiin mitata lukumääräisesti samasta koehenkilöiden joukosta useampia lähde-elimien mittausarvoja kussakin mittapisteessä ja laskettiin tarkempi arvio säteilyannoksesta.
Säteilyannokset laskettiin tietokoneohjelmilla, joita käytetään yleisesti tieteellisissä dosimetriajulkaisuissa. Ohjelmassa tapahtui kehitystä tutkimuksen aikana, koska ihmiskehon anatomian matemaattinen malli muuttui ja säteilyn kudoksille aiheuttamaa haittaa kuvastavat kertoimet tarkentuivat.
Säteilyannosten määrittäminen uudelle radiolääkkeelle on yksi osa radiolääkekehitystä. Tässä tutkimuksessa julkaistujen tulosten perusteella säteilyturvallisuuden näkökulmasta nämä radiolääkkeet voitiin ottaa kliiniseen käyttöön
Myocardial perfusion reserve of kidney transplant patients is well preserved
Background: Chronic kidney disease (CKD) is associated with endothelial dysfunction and increased cardiovascular mortality. Endothelial dysfunction can be studied measuring myocardial perfusion reserve (MPR). MPR is the ratio of stress and rest myocardial perfusion (MP) and reflects the capacity of vascular bed to increase perfusion and microvascular responsiveness. In this pilot study, our aim was to assess MPR of 19 patients with kidney transplant (CKD stages 2–3) and of ten healthy controls with quantitative [15O]H2O positron emission tomography (PET) method.Results: Basal MP was statistically significantly higher at rest in the kidney transplant patients than in the healthy controls [1.3 (0.4) ml/min/g and 1.0 (0.2) ml/min/g, respectively, p = 0.0015]. After correction of basal MP by cardiac workload [MPcorr = basal MP/individual rate pressure product (RPP) × average RPP of the healthy controls], the difference between the groups disappeared [0.9 (0.2) ml/min/g and 1.0 (0.3) ml/min/g, respectively, p = 0.55)]. There was no difference in stress MP between the kidney transplant patients and the healthy subjects [3.8 (1.0) ml/min/g and 4.0 (0.9) ml/min/g, respectively, p = 0.53]. Although MPR was reduced, MPRcorr (stress MP/basal MPcorr) did not differ between the kidney transplant patients and the healthy controls [4.1 (1.1) and 4.3 (1.6), respectively, p = 0.8].Conclusions: MP during stress is preserved in kidney transplant patients with CKD stage 2–3. The reduced MPR appears to be explained by increased resting MP. This is likely linked with increased cardiac workload due to sympathetic overactivation in kidney transplant patients.</p
Development of [18F]AmBF3 Tetrazine for Radiolabeling of Peptides : Preclinical Evaluation and PET Imaging of [18F]AmBF3-PEG7-Tyr3-Octreotide in an AR42J Pancreatic Carcinoma Model
Radiolabeled peptides have emerged as highly specific agents for targeting receptors expressed in tumors for therapeutic and diagnostic purposes. Peptides developed for positron emission tomography (PET) are typically radiolabeled using prosthetic groups or bifunctional chelators for fast "kit-like" incorporation of the radionuclide into the structure. A novel [18F]alkylammoniomethyltrifluoroborate ([18F]AmBF3) tetrazine (Tz), [18F]AmBF3-Tz, was developed for the [18F]fluorination of trans-cyclooctene (TCO)-modified biomolecules using Tyr3-octreotides (TOCs) as model peptides. [18F]AmBF3-Tz (Am = 15.4 +/- 9.2 GBq/µmol, n = 14) was evaluated in healthy mice by ex vivo biodistribution and PET/computed tomography (CT), where the radiolabel in the prosthetic group was found stable in vivo, indicated by the low bone uptake in tibia (0.4 +/- 0.1% ID/g, t = 270 min). TCO-TOCs tailored with polyethylene glycol (PEG) linkers were radiolabeled with [18F]AmBF3-Tz, forming two new tracers, [18F]AmBF3-PEG4-TOC (Am = 2.8 +/- 1.8 GBq/µmol, n = 3) and [18F]AmBF3-PEG7-TOC (Am of 6.0 +/- 3.4 GBq/µmol, n = 13), which were evaluated by cell uptake studies and ex vivo biodistribution in subcutaneous AR42J rat pancreatic carcinoma tumor-bearing nude mice. The tracer demonstrating superior behavior ex vivo, the [18F]AmBF3-PEG7-TOC, was further evaluated with PET/CT, where the tracer provided dear tumor visualization (SUVbaseline = 1.01 +/- 0.07, vs SUVblocked = 0.76 +/- 0.04) at 25 min post injection. The novel AmBF3-Tz demonstrated that it offers potential as a prosthetic group for rapid radiolabeling of biomolecules in mild conditions using bioorthogonal chemistry.Peer reviewe
Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naïve metastatic prostate cancer patients
Purpose Short-term androgen deprivation therapy (ADT) is known to increase heterogeneously prostate-specific membrane antigen (PSMA) expression. This phenomenon might indicate the potential of cancer lesions to respond to ADT. In this prospective study, we evaluated the flare on [F-18]PSMA-1007 PET/CT after ADT in metastatic prostate cancer (PCa). Given that aggressive PCa tends to display FDG uptake, we particularly investigated whether the changes in PSMA uptake might correlate with glucose metabolism.Methods Twenty-five men with newly diagnosed treatment-naive metastatic PCa were enrolled in this prospective registered clinical trial. All the patients underwent [F-18]PSMA-1007 PET/CT immediately before and 3-4 weeks after ADT initiation (degarelix). Before ADT, [F-18]FDG PET/CT was also performed. Standardized uptake values (SUV)max of primary and metastatic lesions were calculated in all PET scans. Serum PSA and testosterone blood samples were collected before the two PSMA PET scans. The changes in PSMA uptake after ADT were represented as Delta SUVmax.Results All the patients reached castration levels of testosterone at the time of the second [F-18]PSMA-1007 PET/CT. Overall, 57 prostate, 314 lymph nodes (LN), and 406 bone lesions were analyzed. After ADT, 104 (26%) bone, 33 (11%) LN, and 6 (11%) prostate lesions showed an increase (>= 20%) in PSMA uptake, with a median Delta SUVmax of + 50%, + 60%, and + 45%, respectively. Among the lesions detected at the baseline [F-18]PSMA-1007 PET/CT, 63% bone and 46% LN were FDG-positive. In these metastases, a negative correlation was observed between the PSMA Delta SUVmax and FDG SUVmax (p Conclusions A heterogeneous increase in PSMA uptake after ADT was detected, most evidently in bone metastases. We observed a negative correlation between the PSMA flare and the intensity of glucose uptake as well as the decrease of serum PSA, suggesting that lesions presenting with such flare might potentially be less aggressive.</p
PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease
Nephrin is a core component of podocyte (glomerular epithelial cell) slit diaphragm and is required for kidney ultrafiltration. Down-regulation or mislocalization of nephrin has been observed in diabetic kidney disease (DKD), characterized by albuminuria. Here, we investigate the role of protein kinase C and casein kinase 2 substrate in neurons 2 (PACSIN2), a regulator of endocytosis and recycling, in the trafficking of nephrin and development of DKD. We observe that PACSIN2 is up-regulated and nephrin mislocalized in podocytes of obese Zucker Diabetic Fatty (ZDF) rats that have altered renal function. In cultured podocytes, PACSIN2 and nephrin colocalize and interact. We show that nephrin is endocytosed in PACSIN2-positive membrane regions and that PACSIN2 overexpression increases both nephrin endocytosis and recycling. We identify rabenosyn-5, which is involved in early endosome maturation and endosomal sorting, as a novel interaction partner of PACSIN2. Interestingly, rabenosyn-5 expression is increased in podocytes in obese ZDF rats, and, in vitro, its overexpression enhances the association of PACSIN2 and nephrin. We also show that palmitate, which is elevated in diabetes, enhances this association. Collectively, PACSIN2 is up-regulated and nephrin is abnormally localized in podocytes of diabetic ZDF rats. In vitro, PACSIN2 enhances nephrin turnover apparently via a mechanism involving rabenosyn-5. The data suggest that elevated PACSIN2 expression accelerates nephrin trafficking and associates with albuminuria.Peer reviewe
Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, F-18-labeled [Nle(14),Lys(40)]exendin-4 analog, shows promise for clinical imaging
Background: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for beta cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label beta cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. F-18-labeled [Nle(14), Lys(40)] exendin-4 analog ([F-18] exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [F-18] exendin-4 was assessed with ex vivo organ.-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of F-18 radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats. Results: [F-18] exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [F-18] exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [F-18] exendin-4. Conclusions: [F-18] exendin-4 showed promise as a tracer for clinical imaging of pancreatic beta cells, due to its high specific uptake in native beta cells and its concomitant low kidney radioactivity uptake.Peer reviewe
Change in brain amyloid load and cognition in patients with amnestic mild cognitive impairment: a 3-year follow-up study
Background Our aim was to investigate the discriminative value of F-18-Flutemetamol PET in longitudinal assessment of amyloid beta accumulation in amnestic mild cognitive impairment (aMCI) patients, in relation to longitudinal cognitive changes. Methods We investigated the change in F-18-Flutemetamol uptake and cognitive impairment in aMCI patients over time up to 3 years which enabled us to investigate possible association between changes in brain amyloid load and cognition over time. Thirty-four patients with aMCI (mean age 73.4 years, SD 6.6) were examined with F-18-Flutemetamol PET scan, brain MRI and cognitive tests at baseline and after 3-year follow-up or earlier if the patient had converted to Alzheimer ' s disease (AD). F-18-Flutemetamol data were analyzed both with automated region-of-interest analysis and voxel-based statistical parametric mapping. Results F-18-flutemetamol uptake increased during the follow-up, and the increase was significantly higher in patients who were amyloid positive at baseline as compared to the amyloid-negative ones. At follow-up, there was a significant association between F-18-Flutemetamol uptake and MMSE, logical memory I (immediate recall), logical memory II (delayed recall) and verbal fluency. An association was seen between the increase in F-18-Flutemetamol uptake and decline in MMSE and logical memory I scores. Conclusions In the early phase of aMCI, presence of amyloid pathology at baseline strongly predicted amyloid accumulation during follow-up, which was further paralleled by cognitive declines. Inversely, some of our patients remained amyloid negative also at the end of the study without significant change in F-18-Flutemetamol uptake or cognition. Future studies with longer follow-up are needed to distinguish whether the underlying pathophysiology of aMCI in such patients is other than AD.</p
Safety, biodistribution and radiation dosimetry of 18 F-rhPSMA-7.3 in healthy adult volunteers
This first-in-human study investigated the safety, biodistribution and radiation dosimetry of the novel 18F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) positron emission tomography (PET) imaging agent, 18F-rhPSMA-7.3. Methods: Six healthy volunteer subjects (3 males, 3 females) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 minutes after the administration of 18F-rhPSMA-7.3 (mean activity 220; range, 210-228 MBq). PET scans were conducted in three separate sessions and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 hours post-injection to assess metabolite-corrected radioactivity in whole blood, plasma and urine. Quantitative measurements of 18F radioactivity in volumes of interest (VOIs) over target organs were determined directly from the PET images at 8 time points and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. Results: 18F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to 18F-rhPSMA-7.3: because of the temporal association with 18F-rhPSMA-7.3 injection, a causal relationship could not be excluded. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-hour voiding interval. The organs with the highest absorbed dose per unit of administered radioactivity were the adrenals (mean absorbed dose, 0.1835 mSv/MBq), the kidneys (mean absorbed dose, 0.1722 mSv/MBq), the submandibular glands (mean absorbed dose, 0.1479 mSv) and the parotid glands (mean absorbed dose, 0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min post-injection), an average of 7.2% (range, 4.4-9.0%) of the injected radioactivity of 18F-rhPSMA-7.3 was excreted into urine. Conclusion: The safety, biodistribution and internal radiation dosimetry 18F-rhPSMA-7.3 are considered favorable for PET imaging
Renal vascular resistance is increased in patients with kidney transplant
Background Despite improvement in short-term outcome of kidney transplants, the long-term survival of kidney transplants has not changed over past decades. Kidney biopsy is the gold standard of transplant pathology but it's invasive. Quantification of transplant blood flow could provide a novel non-invasive method to evaluate transplant pathology. The aim of this retrospective cross-sectional pilot study was to evaluate positron emission tomography (PET) as a method to measure kidney transplant perfusion and find out if there is correlation between transplant perfusion and histopathology. Methods Renal cortical perfusion of 19 kidney transplantation patients [average time from transplantation 33 (17-54) months; eGFR 55 (47-69) ml/min] and 10 healthy controls were studied by [(15) O]H2O PET. Perfusion and Doppler resistance index (RI) of transplants were compared with histology of one-year protocol transplant biopsy. Results Renal cortical perfusion of healthy control subjects and transplant patients were 2.7 (2.4-4.0) ml min(- 1) g(- 1) and 2.2 (2.0-3.0) ml min(- 1) g(- 1), respectively (p = 0.1). Renal vascular resistance (RVR) of the patients was 47.0 (36.7-51.4) mmHg mL(- 1)min(- 1)g(- 1) and that of the healthy 32.4 (24.6-39.6) mmHg mL(- 1)min(-1)g(-1) (p = 0.01). There was a statistically significant correlation between Doppler RI and perfusion of transplants (r = - 0.51, p = 0.026). Transplant Doppler RI of the group of mild fibrotic changes [0.73 (0.70-0.76)] and the group of no fibrotic changes [0.66 (0.61-0.72)] differed statistically significantly (p = 0.03). No statistically significant correlation was found between cortical perfusion and fibrosis of transplants (p = 0.56). Conclusions [(15) O]H2O PET showed its capability as a method in measuring perfusion of kidney transplants. RVR of transplant patients with stage 2-3 chronic kidney disease was higher than that of the healthy, although kidney perfusion values didn't differ between the groups. Doppler based RI correlated with perfusion and fibrosis of transplants.Peer reviewe
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