<Superscript>68</Superscript>Ga-DOTANOC: biodistribution and dosimetry in patients affected by neuroendocrine tumors

Objectives The aim of this work was the evaluation of biodistribution and radiation dosimetry of ⁶⁸Ga-DOTANOC in patients affected by neuroendocrine tumors. Materials and methods We enrolled nine patients (six male and three female) affected by different types of neuroendocrine tumors (NETs). Each patient underwent four whole body positron emission tomography (PET) scans, respectively, at 5, 20, 60, and 120 min after the intravenous injection of about 185 MBq of ⁶⁸Ga-DOTANOC. Blood and urine samples were taken at different time points post injection: respectively, at about 5, 18, 40, 60, and 120 min for blood and every 40–50 min from injection time up to 4 h for urine. The organs involved in the dosimetric evaluations were liver, heart, spleen, kidneys, lungs, pituitary gland, and urinary bladder. Dosimetric evaluations were done using the OLINDA/EXM 1.0 software. Results A physiological uptake of ⁶⁸Ga-DOTANOC was seen in all patients in the pituitary gland, the spleen, the liver, and the urinary tract (kidneys and urinary bladder). Organs with the highest absorbed doses were kidneys . The mean effective dose equivalent (EDE) was . Discussion and conclusions The excretion of the compound was principally via urine, giving dose to the kidney and the urinary bladder wall. As SSTR2 is the most frequently expressed somatostatin receptor and ⁶⁸Ga-DOTANOC has high affinity to it, this compound might play an important role in PET oncology in the future. The dosimetric evaluation carried out by our team demonstrated that ⁶⁸Ga-DOTANOC delivers a dose to organs comparable to, and even lower than, analogous diagnostic compounds.     

Systemic Endoradiotherapy with Carrier-Added 4-[131I]Iodo-L-Phenylalanine: Clinical Proof-of-Principle in Refractory Glioma

Purpose

To explore feasibility, tolerability, dosimetry and probable efficacy of intravenous endoradiotherapy with carrier-added 4-[¹³¹I]iodo-L-phenylalanine (c.a. ¹³¹I-IPA) in refractory high-grade glioma.

Methods

Two male patients (45 and 50 years), with long-standing, extensively pre-treated gliomas and evidence of progression underwent single intravenous injections of 2 and 4 GBq of c.a. ¹³¹I-IPA, respectively. Tumour targeting was verified by ¹³¹I-IPA single-photon emission computed tomography (SPECT). Metabolic and morphological changes indicative of tumour response were assessed by sequential [¹⁸F]fluoroethyltyrosine (¹⁸F-FET) positron emission tomography (PET) and contrast-enhanced magnetic resonance imaging (MRI) following therapy. Further monitoring included clinical state, safety laboratory, quality of life and dosimetry. Absorbed mean organ and whole-body doses were determined according to the Medical Internal Radiation Dose (MIRD) scheme using OLINDAEXM based on serial planar scintigraphy.

Results

Both patients tolerated the treatment well. No evidence of acute or delayed organ toxicity was observed. ¹³¹I-IPA accumulated in the tumour recurrences identified by MRI/¹⁸F-FET. In patient 1, PET showed progressively decreasing maximum standardised uptake values (SUV_max) over 10 months, indicating metabolic response, paralleled by reduced contrast enhancement and tumour volume on MRI. Progression occurred 18 months after therapy. Treatment was repeated using 6.6 GBq of ¹³¹I-IPA, to which no response was observed. Patient 2, followed-up for 3 months after therapy, showed stable disease on MRI and PET. Mean absorbed whole body doses ranged from 0.13 to 0.17 mSv/MBq, with the highest absorbed organ doses to kidneys, bladder and heart (0.86-1.23; 0.49-0.6 and 0.45-0.56 mSv/MBq).

Conclusion

Systemic endoradiotherapy using up to 6.6 GBq of c.a.¹³¹I-IPA is not associated with clinically detectable toxicity. Measurable anti-tumour effects in gliomas were observed. ¹³¹I-IPA warrants further evaluation as glioma therapy.     

Radioimmunotherapy using 131I-rituximab in patients with advanced stage B-cell non-Hodgkin’s lymphoma: initial experience

Purpose The aim of this study was to evaluate the safety, toxicity and therapeutic response of non-myeloablative radioimmunotherapy using ¹³¹I-rituximab in previously heavily treated patients with B-cell non-Hodgkins lymphoma (B-NHL).Methods Nine patients with relapsed, refractory or transformed B-NHL received ten radioimmunotherapies. Patients had a median of 5 (range 2–7) prior standard therapies. Four patients had received prior high-dose chemotherapy followed by autologous stem cell transplantation, and eight had received prior rituximab therapy. Histopathology consisted of four mantle cell, one follicular and four diffuse large B-cell lymphomas. Rituximab, a monoclonal chimeric anti-CD20 antibody (IDEC-C2B8), was labelled with ¹³¹I using the Iodogen method. The administered activity (2,200±600 MBq) was based on a dosimetrically calculated 45 cGy total-body radiation dose. All patients received an infusion of 2.5 mg/kg of rituximab prior to administration of the radiopharmaceutical.Results No acute adverse effects were observed after the administration of ¹³¹I-rituximab. Radioimmunotherapy was safe in our patient group and achieved one complete response ongoing at 14 months and two partial responses progressing at 12 and 13 months after treatment. One partial responder was re-treated with radioimmunotherapy and achieved an additional progression-free interval of 7 months. Four non-responders with bulky disease died 4.8±2.0 months after therapy. Three patients had an elevated serum lactate dehydrogenase (LDH) level prior to radioimmunotherapy and none of the patients responded. Of two patients who received radioimmunotherapy as an additional treatment after salvage chemotherapy, one continues to be disease-free at 9 months and one relapsed at 5 months follow-up. Reversible grade 3 or 4 haematological toxicity occurred in seven of nine patients. Median nadirs were 35 days for platelets, 44 days for leucocytes and 57 days for erythrocytes.Conclusion Radioimmunotherapy with ¹³¹I-rituximab in previously heavily treated B-NHL patients was safe and well tolerated, and four out of ten therapies induced responses. Radioimmunotherapy was less efficient in patients with bulky disease and elevated LDH. Severe haematological toxicity in seven patients did not cause significant clinical problems. Radioimmunotherapy seems to be an additional therapeutic option in carefully selected therapy-refractory B-NHL patients.     

Radioimmunotherapy with 131I-Rituximab in a Patient with Diffuse Large B-Cell Lymphoma Relapsed After Treatment with 90Y-Ibritumomab Tiuxetan

We report a case that demonstrates the efficacy of radioimmunotherapy (RIT) with radioiodinated rituximab (¹³¹I-rituximab) for relapsed diffuse large B-cell lymphoma (DLBCL). A 79-year-old male patient with DLBCL initially achieved a complete response (CR) after six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. However, the lymphoma relapsed 20 months later. Although the patient had achieved a second and a third CR after two cycles of ⁹⁰Y-ibritumomab tiuxetan, he experienced a third relapse approximately 3 years later. Between March and June 2011, the patient received three cycles of ¹³¹I-rituximab. Although he had achieved partial response after the second cycle, the disease progressed after the third cycle, and the total progression–free survival was thus 5 months. The patient suffered only relatively mild toxicity (grade 1 thrombocytopenia) during treatment. RIT with ¹³¹I-rituximab is therefore potentially effective in patients with relapsed DLBCL, even after the failure of ⁹⁰Y-ibritumomab tiuxetan therapy.     

Biokinetics and dosimetry for 195Au,evaluated in an animal model

The use of the generator produced radionuclide ^195mAu, half life 30 s, has become feasible for several different investigations, e.g. cardiac studies. To assess the absorbed dose from the long lived radionuclide ¹⁹⁵Au (the daughter of ^195mAu, half life 183 days), a biodistribution study of ¹⁹⁵Au was performed in animals. Seven rabbits were injected with eluate from a ^195mHg-^195mAu generator and the retention and the biodistribution of the long lived gold isotope was investigated. The activity was localized mainly in the liver and the kidneys. Transforming the data to man resulted in an absorbed dose from ¹⁹⁵Au from 1 elution (approximately 925 MBq ^195mAu) of 2.2 mGy to the kidney and 1.3 mGy to the liver and an effective dose equivalent of 0.26 mSv. The total effective dose equivalent from all radionuclides in the eluate (^195mAu, ¹⁹⁵Au, ^195mHg and ¹⁹⁵Hg), was estimated to be 0.65 mSv for a single injection (925 MBq ^195mAu).     

Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

Introduction

Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[¹²⁴I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of ¹³¹I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of ¹³¹I-MIP-1095.

Methods

Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of ¹²⁴I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of ¹³¹I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA.

Results

I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed.

Conclusion

Based on the biodistribution and dose calculations of the PSMA-targeted small molecule ¹²⁴I-MIP-1095 therapy with the authentic analog ¹³¹I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy.     

Local delivery of <Superscript>131</Superscript>I-MIBG to treat peritoneal neuroblastoma

Internal radiotherapy involving systemic administration of iodine-131 metaiodobenzylguanidine (¹³¹I-MIBG) in neural crest tumours such as neuroblastoma has shown considerable success. Although peritoneal seeding of neuroblastoma occurs less often than metastases to organs such as the liver, no effective treatments exist in this clinical setting. Previous reports have demonstrated the effectiveness of peritoneal application of chemotherapeutic drugs or radiolabelled monoclonal antibodies in several kinds of carcinomas. Local delivery of ¹³¹I-MIBG should produce more favourable dosimetry in comparison with its systemic administration in the treatment of peritoneal neuroblastoma. In the current investigation, a peritoneal model of neuroblastoma was established in Balb/c nu/nu mice by i.p. injection of SK-N-SH neuroblastoma cells. Two weeks after cell inoculation, comparative biodistribution studies were performed following i.v. or i.p. administration of ¹³¹I-MIBG. Mice were treated with 55.5 MBq of ¹³¹I-MIBG administered either i.v. or i.p. at 2 weeks. Intraperitoneal injection of ¹³¹I-MIBG produced significantly higher tumour accumulation than did i.v. injection (P<0.01). Therapeutic ratios of i.p. injection were 4- to 14-fold higher than those of i.v. injection. Radiotherapy with i.v. administered ¹³¹I-MIBG failed to improve the survival of mice; mean survival of untreated mice and mice treated with i.v. administration of ¹³¹I-MIBG was 59.3±3.9 days and 60.6±2.8 days, respectively. On the other hand, radiotherapy delivered via i.p. administration of ¹³¹I-MIBG prolonged survival of mice to 94.7±17.5 days (P<0.02 vs untreated controls and mice treated with i.v. ¹³¹I-MIBG therapy). Radiation doses absorbed by tumours at 55.5 MBq of ¹³¹I-MIBG were estimated to be 4,140 cGy with i.p. injection and 450 cGy with i.v. injection. These results indicate the benefits of locoregional delivery of ¹³¹I-MIBG in the treatment of peritoneal neuroblastoma.     

Biodistribution and radiation dosimetry of [11C]raclopride in healthy volunteers

Purpose This study reports on the whole-body biodistribution and radiation dosimetry of [¹¹C]raclopride, a dopamine D₂ receptor antagonist.Methods In three healthy male volunteers, whole-body scans were performed up to 2 h following i.v. injection of 320±65 MBq [¹¹C]raclopride. Transmission scans (3 min per step, eight or nine steps according to the height of the subject) in 2D mode were used for subsequent attenuation correction of emission scans. Emission scans (1 min per step, eight or nine steps) were acquired over 2 h. Venous blood samples and urine were collected up to 2 h after injection of the radiotracer. For each subject, the percentage of injected activity measured in regions of interest over brain, intestine, lungs, kidneys and liver was fitted to a mono-exponential model, as an uptake phase followed by a mono-exponential washout, for urinary bladder to generate time–activity curves. Using the MIRD method, several source organs were considered in estimating residence time and mean effective radiation absorbed doses.Results Blood pressure and ECG findings remained unchanged after tracer injection. The analysed blood and urine pharmacological parameters did not change significantly after [¹¹C]raclopride injection. The primary routes of clearance were renal and intestinal. Ten minutes after injection, high activities were observed in the gall-bladder, kidneys and liver. High activity was observed in the gall-bladder during the whole study. The kidneys, urinary bladder wall, liver and gall-bladder received the highest absorbed doses. The average effective dose of [¹¹C]raclopride was estimated to be 6.7±0.4 Sv/MBq.Conclusion The amount of [¹¹C]raclopride required for adequate dopamine D₂ receptor imaging results in an acceptable effective dose equivalent, permitting two or three repeated clinical PET imaging studies, with the injection of 222 MBq for each study.     

Excretion of radionuclides in human breast milk after nuclear medicine examinations. Biokinetic and dosimetric data and recommendations on breastfeeding interruption

Purpose

To review early recommendations and propose guidelines for breastfeeding interruption after administration of radiopharmaceuticals, based on additional biokinetic and dosimetric data.

Methods

Activity concentrations in breast milk from 53 breastfeeding patients were determined. The milk was collected at various times after administration of 16 different radiopharmaceuticals. The fraction of the activity administered to the mother excreted in the breast milk, the absorbed doses to various organs and tissues and the effective dose to the infant were estimated.

Results

The fraction of the administered activity excreted per millilitre of milk varied widely from 10^?10 to 10^?3 MBq/MBq administered. For ^99mTc-labelled radiopharmaceuticals, the total fraction of the administered activity excreted in the milk varied from 0.0057 % for ^99mTc-labelled red blood cells (RBC) to 19 % for ^99mTc-pertechnetate. The effective dose to an infant per unit activity administered to the mother ranged from 6.7?×?10^?6 mSv/MBq for ^99mTc-labelled RBC to 3.6?×?10^?2 mSv/MBq for ^99mTc-pertechnetate. For the other radiopharmaceuticals, the total fraction of administered activity excreted in the milk varied from 0.018 % (⁵¹Cr-EDTA) to 48 % (¹³¹I-NaI). The effective dose ranged from 5.6?×?10^?5 mSv_infant/MBq_mother (⁵¹Cr-EDTA) to 106 mSv_infant/MBq_mother (¹³¹I-NaI).

Conclusions

Based on an effective dose limit of 1 mSv to the infant and a typical administered activity, we recommend cessation of breastfeeding for ¹³¹I-NaI and interruption of feeding for 12 h for ¹²⁵I-iodohippurate, ¹³¹I-iodohippurate, ^99mTc-pertechnetate and ^99mTc-MAA. During this 12-h period all breast milk should be expressed at least three times and discarded. For the other radiopharmaceuticals included in this study, no interruption of breastfeeding is necessary.

     

Biodistribution and human dosimetry of enantiomer-1 of the synthetic leucine analog anti-1-amino-2-fluorocyclopentyl-1-carboxylic acid

Introduction

The enantiomerically enriched (ee=90%, enantiomer 1) synthetic amino acid (R,S)-anti-1-amino-2-fluorocyclopentyl-1-carboxylic acid (anti-2-[¹⁸F]FACPC-1) accumulates in malignant cells by elevated transport through the sodium-independent system-l (leucine preferring) amino acid transporter. The purpose of this study was to evaluate in vivo uptake and single-dose toxicity of anti-2-[¹⁸F]FACPC-1 in animals as well as the individual organ and whole-body dose in humans.

Methods

A DU145 xenograft rodent model was used to measure anti-2-[¹⁸F]FACPC-1 uptake at 15, 30 and 60 min post-injection. Animals were sacrificed and organs harvested to measure the percent injected activity per organ and to calculate residence time. Anti-2-[¹⁸F]FACPC-1 toxicity was assessed using a single microdose (37–74 MBq/kg) in nonhuman primates. Their vital signs were monitored for 2 h post-injection for drug-related effects. Human biodistribution studies were collected by sequential whole-body PET/CT scans on six healthy volunteers (three male and three female) for 120 min following a single 247±61 MBq bolus injection of anti-2-[¹⁸F]FACPC-1. Estimates of radiation dose from anti-2-[¹⁸F]FACPC-1 to the human body were calculated using recommendations of the MIRD committee and MIRDOSE 3.0 software.

Results

High anti-2-[¹⁸F]FACPC-1 residence time was observed in the pancreas of the rodent model compared to the human data. No abnormal treatment-related observations were made in the nonhuman primate toxicity studies. Human venous blood showed no metabolites of anti-2-[¹⁸F]FACPC-1 in the first 60 min post-injection. All volunteers showed initially high uptake in the kidneys followed by a rapid washout phase. The estimated effective dose equivalent was 0.0196 mSv/MBq.

Conclusion

Anti-2-[¹⁸F]FACPC-1 showed low background uptake in the brain, thoracic and abdominal cavities of humans, suggesting a possible use for detecting malignant tissues in these regions.     

肝胆肿瘤患者68Ga-FAPI-04 PET显像的内照射剂量及分布研究

目的 评估⁶⁸Ga-FAPI-04 PET/CT检查在肝胆肿瘤患者中的内照射剂量及生物分布。方法 本研究纳入因肝脏占位于北京协和医院接受PET/CT检查的6例患者,经静脉注射⁶⁸Ga-FAPI-04（170.57 ±14.43） MBq后分别于第3、10、15、20、30和60 min进行全身显像。观察显像剂的生物分布;手动勾画感兴趣区;所有靶器官的内照射剂量应用OLINDA/EXM软件计算。结果 ⁶⁸Ga-FAPI-04在肝脏内放射性本底消退较快,在肿瘤组织内放射性摄取较为稳定,病灶平均SUV_max在注射后20 min达到最大（13.87 ±2.55）;病灶平均靶本比逐渐升高,在注射后30 min达到最大（10.09 ±8.17）。1次⁶⁸Ga-FAPI-04 PET/CT扫描的全身有效剂量为（0.020 ±0.002） mSv/MBq,吸收剂量最高的器官是膀胱壁,为（0.146 ±0.035） mSv/MBq。结论 ⁶⁸Ga-FAPI-04与¹⁸F-FDG全身有效剂量相近;肿瘤摄取快速,肝脏背景低,且不受血糖水平影响,有望成为潜在的肝胆肿瘤PET/CT显像药物。     

Radiation dosimetry of <Superscript>68</Superscript>Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing

Purpose

The clinical introduction of ⁶⁸Ga-PSMA-11 (“HBED-CC”) ligand targeting the prostate-specific membrane antigen (PSMA) has been regarded as a significant step forward in the diagnosis of prostate cancer (PCa). In this study, we provide human dosimetry and data on optimal timing of PET imaging after injection.

Methods

Four patients with recurrent PCa were referred for ⁶⁸Ga-PSMA-11 PET/CT. Whole-body PET/CT_low-dose scans were conducted at 5 min, and 1, 2, 3, 4 and 5 h after injection of 152–198 MBq ⁶⁸Ga-PSMA-11. Organs of moderate to high uptake were used as source organs; their total activity was determined at all measured time points. Time–activity curves were created for each source organ as well as for the remainder. The radiation exposure of a ⁶⁸Ga-PSMA-11 PET was identified using the OLINDA-EXM software. In addition, tracer uptake was measured in 16 sites of metastases.

Results

The highest tracer uptake was observed in the kidneys, liver, upper large intestine, and the urinary bladder. Mean organ doses were: kidneys 0.262?±?0.098 mGy/MBq, liver 0.031?±?0.004 mGy/MBq, upper large intestine 0.054?±?0.041 mGy/MBq, urinary bladder 0.13?±?0.059 mGy/MBq. The calculated mean effective dose was 0.023?±?0.004 mSv/MBq (=0.085?±?0.015 rem/mCi). Most tumor lesions (n?=?16) were visible at 3 h p.i., while at all other time points many were not qualitatively present (10/16 visible at 1 h p.i.).

Conclusions

The mean effective dose of a ⁶⁸Ga-PSMA-11 PET is 0.023 mSv/MBq. A 3-h delay after injection was optimal timing for ⁶⁸Ga-PSMA-11 PET/CT in this patient cohort.

     

High treatment efficacy by dual targeting of Burkitt’s lymphoma xenografted mice with a <Superscript>177</Superscript>Lu-based CD22-specific radioimmunoconjugate and rituximab

Purpose

Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin’s lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter ¹⁷⁷Lu. Both RICs were evaluated as single agents in a human Burkitt’s lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored.

Methods

The binding activity of CHX-A″-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of ¹⁷⁷Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1 ^null ) interleukin-2 receptor common gamma chain (IL2rγ ^null ) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt’s lymphoma cells. ¹⁷⁷Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 – 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy.

Results

Conjugation of CHX-A”-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the ¹⁷⁷Lu-labelled anti-CD22 IgG than of ¹⁷⁷Lu-labelled rituximab. Treatment with ¹⁷⁷Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with ¹⁷⁷Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab.

Conclusion

These findings suggest that dual targeting with ¹⁷⁷Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.

     

123I-2-iodo-tyrosine, a new tumour imaging agent: human biodistribution, dosimetry and initial clinical evaluation in glioma patients

Purpose ¹²³I-2-iodo-tyrosine (¹²³I-2IT) has been identified as a promising new amino acid tracer in animals. Uptake is mediated by LAT1 transport, which is increased in tumour cells. In this study we present the human biodistribution and first clinical results in glioma patients. Methods For the biodistribution study, six male volunteers received 60–95 MBq ¹²³I-2IT. Whole-body scans and blood and urine samples were obtained up to 24 h after injection; dosimetry was calculated using OLINDA 1.0 software. Initial clinical evaluation of ¹²³I-2IT SPECT was performed in 35 patients with suspected or known glioma, either as primary diagnosis or for detection of recurrence. Tumour-to-background (T/B) ratios were calculated for semi-quantitative analysis. The results were correlated with clinical and MRI follow-up data or histology. Results ¹²³I-2IT showed both renal and intestinal clearance. Bladder (0.12 mGy/MBq) and small intestine (0.03 mGy/MBq) received the highest absorbed doses. The effective dose equivalent and effective dose were estimated at 0.020 and 0.016 mSv/MBq, respectively. In patients, ¹²³I-2IT SPECT did not differentiate between neoplastic and non-neoplastic lesions after an indeterminate MRI. In follow-up of known glioma, 13/15 patients with disease recurrence had increased T/B values (range 1.39–3.91). Out of seven recurrence-negative patients, two showed an important increase in T/B, in one case due to radionecrosis (T/B 1.59) and in the other probably due to residual but stable disease (T/B 2.07). Conclusion ¹²³I-2IT has a favourable biodistribution for a tumour imaging agent. It shows increased uptake in central nervous system glioma and is potentially useful in the follow-up of glioma patients. M. Keyaerts is an “aspirant” of the FWO-Vlaanderen.     

Mouse-specific antibody responses to a monoclonal antibody during repeated immunoscintigraphy investigations: Comparison of antibody titres and imaging studies in a rat model

As a model for human mouse-specific antibody responses in patients undergoing immunoscintigraphy, we have investigated in rats the production of mouse-specific antibodies (MA) to the mouse monoclonal antibody 791T/36. At intervals of between 5 and 16 weeks the rats were given repeated cycles of intravenous (IV) injections of antibody with or without a simultaneous intradermal (ID) injection. The IV dose was 60 gmg/kg, a dose similar to that used in many clinical immunoscintigraphy studies. The ID injection was 2 g, which mimicks the skin test dose often given in clinical imaging protocols. The study was carried out with both¹³¹I-labelled antibody and with antibody labelled with¹¹¹In by diethylenetriamine-penta-acetic acid (DTPA) chelation. MA was measured with a passive haemagglutination assay using sheep red blood cells coated with the monoclonal antibody. Of rats given ID injections of unlabelled antibody at the same time as the IV imaging doses, 9/20 produced MA during 4 cycles of injections. In contrast, only 2/16 rats given only the IV dose produced MA. Both¹³¹I- and¹¹¹In-labelled antibody appeared equally immunogenic with 5/18 and 6/18 overall responders, respectively. The production of MA was associated with a significant perturbation in the biodistribution of the IV dose of labelled antibody as seen by gamma-camera imaging of the rats given¹¹¹In-labelled antibody. There was clearance of immune complexes to the liver, this organ accumulating up to 90% of the whole body count rate of radiolabel. MA titres of between 1/100 and 1/78000 caused equal perturbation of biodistribution, although below 1/100 the effect was more variable.     

Estimates of the effective dose equivalent,HE, in positron emission tomography studies

The effective dose equivalent, H_E, can be used as a standard radiation dose parameter in all imaging modalities that use ionizing radiation, including positron emission tomography (PET). A simplified method for evaluating approximate HE values for the positron emitters carbon 11, nitrogen 13, oxygen 15 and fluorine 18 is presented. HE values for a range of PET studies have been computed based on biodistribution data available in the scientific literature. Low-dose PET studies include a bolus administration of 1030 MBq CO¹⁵O (H_E = 1 mSv) and 74 MBq [¹⁸F]-l dopa (H_E = 1.3 mSv). High-dose PET studies include a 1-h (steady-state) inhalation of a total of 9250 MBq C¹⁵OO (H_E = 9.4 mSv). The mean H_E value of 13 diverse PET studies was computed to be 4.5 mSv.     

Kinetics and dosimetry of iodine-131-labelled antibody fragments after local administration in patients with rectal cancer

In 11 patients with rectal cancer, a mixture of F(ab)₂ fragments of anti-carcinoembryonic antigen and anti-CA 19.9 labelled with a diagnostic dose of iodine-131 (3–10 MBq) was administered submucosally around the tumour. In this study, the local kinetics in and the dose to the rectal wall, the whole body kinetics and the effective dose equivalent are presented. The early disappearance of the activity from the injection spot was characterized by a T _1/2 of 21 h. Initially, about 50% of the plasma activity was due to free ¹³¹I. After 4 h, the plasma activity was almost completely protein bound (86%). Maximum plasma activity was observed after the 2nd day. From 72 h p.i., the plasma activity decreased with a T _1/2 of 53 h. In the first 24 h, 14% of the injected dose was excreted in the urine and within 4 days about half of the administered activity. The absorbed radiation dose to the rectal wall was estimated to be 0.2 Gy/MBq, presuming a 20 cm³ distribution volume. The dose to the bone marrow was 0.2 mGy/MBq or 0.4 mGy/MBq, assuming a homogeneous tracer distribution or equal blood and bone marrow activity concentrations, respectively. The effective dose equivalent is 1.9 mSv/MBq, mainly determined by the dose to the rectal wall and to a lesser extent by the dose to the remaining body. Postulating comparable kinetics, ¹²³I- or ¹¹¹In- or ^99mTc-labelled fragments would result in 4-25-fold lower effective dose equivalents. We conclude that the theoretical advantages of the local administration of ¹³¹I-labelled antibodies for diagnostic purposes in patients with rectal cancer are not limited by our dosimetric data. Nevertheless, we advocate the use of other radiolabels with more appropriate imaging qualities and probably a lower radiation burden. Offprint requests to: E.J. Derksen     

Dosimetry of 60/61/62/64Cu-ATSM: a hypoxia imaging agent for PET

Purpose Cu-diacetyl-bis(N⁴-methylthiosemicarbazone (Cu-ATSM) is an effective marker for the delineation of hypoxic tissue. Dosimetry calculations by the established Medical Internal Radionuclide Dose (MIRD) approach were performed with both animal and patient data.Methods Human absorbed dose estimates extrapolated from rat data were based on the biodistribution of ⁶¹Cu-ATSM in adult rats. Eighteen tissues were harvested and time–activity curves generated. The measured residence times and the MIRD S-values for ⁶⁰Cu-ATSM were used to estimate human absorbed doses. The biodistribution of the tracer was directly measured in five patients injected with approximately 480 MBq of ⁶⁰Cu-ATSM and imaged by positron emission tomography (PET) with a whole-body protocol. The combined data from all patients were used to derive organ residence times, and organ doses were calculated by MIRD methodology for ⁶⁰Cu-ATSM, ⁶¹Cu-ATSM, ⁶²Cu-ATSM, and ⁶⁴Cu-ATSM.Results Human absorbed dose estimates extrapolated from rat biodistribution data indicated that the kidneys appeared to be the dose-limiting organ (0.083 mGy/MBq) with a whole-body dose of 0.009 mGy/MBq. Based on the human PET imaging data, the liver appeared as the dose-limiting organ, with an average radiation dose of 0.064 mGy/MBq. The whole-body dose was 0.009 mGy/MBq and the effective dose was 0.011 mSv/MBq.Conclusion These relatively small absorbed doses to normal organs allow for the safe injection of 500–800 MBq of ⁶⁰Cu-ATSM, which is sufficient for PET imaging in clinical trials.     

Biodistribution and radiation dosimetry of <Superscript>68</Superscript>Ga-PSMA HBED CC—a PSMA specific probe for PET imaging of prostate cancer

Purpose

Positron emission tomography (PET) agents targeting the prostate-specific membrane antigen (PSMA) are currently under broad clinical and scientific investigation. ⁶⁸Ga-PSMA HBED-CC constitutes the first ⁶⁸Ga-labelled PSMA-inhibitor and has evolved as a promising agent for imaging PSMA expression in vivo. The aim of this study was to evaluate the whole-body distribution and radiation dosimetry of this new probe.

Methods

Five patients with a history or high suspicion of prostate cancer were injected intravenously with a mean of 139.8?±?13.7 MBq of ⁶⁸Ga-PSMA HBED-CC (range 120–158 MBq). Four static skull to mid-thigh scans using a whole-body fully integrated PET/MR-system were performed 10 min, 60 min, 130 min, and 175 min after the tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses (ED) were calculated using OLINDA/EXM.

Results

Injection of a standard activity of 150 MBq ⁶⁸Ga-PSMA HBED-CC resulted in a median effective dose of 2.37 mSv (Range 1.08E-02 – 2.46E-02 mSv/MBq). The urinary bladder wall (median absorbed dose 1.64E-01 mGv/MBq; range 8.76E-02 – 2.91E-01 mGv/MBq) was the critical organ, followed by the kidneys (median absorbed dose 1.21E-01 mGv/MBq; range 7.16E-02 – 1.75E-01), spleen (median absorbed dose 4.13E-02 mGv/MBq; range 1.57E-02 – 7.32E-02 mGv/MBq) and liver (median absorbed dose 2.07E-02 mGv/MBq; range 1.80E-02 – 2.57E-02 mGv/MBq). No drug-related pharmacological effects occurred.

Conclusion

The use of ⁶⁸Ga-PSMA HBED-CC results in a relatively low radiation exposure, delivering organ doses that are comparable to those of other ⁶⁸Ga-labelled PSMA-inhibitors used for PET-imaging. Total effective dose is lower than for other PET-agents used for prostate cancer imaging (e.g. ¹¹C- and ¹⁸F-Choline).

     

Optimal dose of <Superscript>18</Superscript>F-FDG required for whole-body PET using an LSO PET camera

Reducing the acquisition time of whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) (corrected for attenuation) is of major importance in clinical practice. With the introduction of lutetium oxyorthosilicate (LSO), the acquisition time can be dramatically reduced, provided that patients are injected with larger amounts of tracer and/or the system is operated in 3D mode. The aim of this study was to determine the optimal dose of ¹⁸F-FDG required in order to achieve good-to-excellent image quality when a "3-min emission, 2-min transmission/bed position" protocol is used for an LSO PET camera. A total of 218 consecutive whole-body ¹⁸F-FDG PET studies were evaluated retrospectively. After excluding patients with liver metastases, hyperglycaemia and paravenous injections, the final study population consisted of 186 subjects (112 men, 74 women, age 59±15 years). Patients were injected with an activity of ¹⁸F-FDG ranging from 2.23 to 15.21 MBq/kg. Whole-body images corrected for attenuation (3 min emission, 2 min transmission/bed position) were acquired with an LSO PET camera (Ecat Accel,Siemens) 60 min after tracer administration. Patients were positioned with their arms along the body. Image reconstruction was done iteratively and a post-reconstruction filter was applied. Image quality was scored visually by two independent observers using a five-point scoring scale (poor, reasonable, good, very good, excellent). In addition, the coefficient of variability (COV) was measured in a region of interest over the liver in order to quantify noise. Of the images obtained in 118 patients injected with 8 MBq/kg ¹⁸F-FDG, 92% and 90% were classified as good, very good or excellent by observer 1 and observer 2, respectively. The COV averaged 10.63%±3.19% for doses 8 MBq/kg and 16.46%±5.14% for doses <8 MBq/kg. Administration of an ¹⁸F-FDG dose of 8 MBq/kg results in images of good to excellent quality in the vast majority of patients when using an LSO PET camera and applying a 3-min emission, 2-min transmission/bed position acquisition protocol. At lower doses, a rapid decline in image quality and increasing noise are observed. Alternative protocols should be adopted in order to compensate for the loss in image quality when doses <8 MBq/kg are used.