Production of carrier-free66Ga and labeling of antimyosin antibody for positron imaging of acute myocardial infarction

A method for labeling monoclonal antimyosin antibodies with⁶⁶Ga is described. The radionuclide is a positron emitter (t_1/2: 9.4 h) produced by means of the⁶³Cu (⁴He, n)⁶⁶Ga reaction. Purification of the⁶⁶Ga from the copper target is described in detail. Monoclonal antimyosin antibodies are labeled with⁶⁶Ga at a high yield (99%) by transcomplexation from an acetate buffer with the diethylenetriamine pentaacetic acid (DTPA)-labeled antibody and preliminary evaluated in two dogs for imaging of myocardial necrosis by positron emission tomography.     

Tomographic measurement of cerebral blood flow by the 68Ga-labelled-microsphere and continuous-C15O2-inhalation methods

The measurement of cerebral blood flow (CBF) by continuous C¹⁵O₂ inhalation has only been validated previously by indirect experimental protocols. In the present study using baboons, these measurements were compared directly with those obtained by injection of ⁶⁸Ga-labelled serum-albumin microspheres in the left cardiac ventricle. Using a modified labelling technique, no elution of ⁶⁸Ga occurred in vivo. Both methods provided similar regional CBF values, which could be described by a significant linear correlation ( =0.82 CBF_microspheres+5.7; P<0.001). The validity of the labelled-microsphere-injection method was verified. The feasibility of stable in vivo labelling of ⁶⁸Ga to serum-albumin microspheres provides a reference method for organ blood-flow measurements using positron-emission tomography.     

<Superscript>68</Superscript>Ga-labelled DOTA-derivatised peptide ligands

⁶⁸Ge/⁶⁸Ga generators provide cyclotron-independent access to positron emission tomography (PET) radiopharmaceuticals. We describe a system which allows the safe and efficient handling of ⁶⁸Ge/⁶⁸Ga generator eluates for labelling of DOTA-derivatised peptide ligands. The system comprises concentration and purification of the ⁶⁸Ga eluate as well as labelling and purification steps for peptides, and can be used with different ⁶⁸Ge/⁶⁸Ga generator types. The suitability and efficiency were tested with two different DOTA-derivatised somatostatin derivatives and a DOTA-derivatised bombesin derivative. Amounts of 10–20 nmol of the peptides were sufficient and resulted in labelling yields of 50% for all peptides. The built-in safety precautions have proven to be appropriate in allowing use of the method for routine clinical applications. The system was set up and operated in a hot lab by personnel with no previous experience in the preparation of PET radiopharmaceuticals.     

Synthesis and evaluation of a novel 68Ga-chelate-conjugated bisphosphonate as a bone-seeking agent for PET imaging

Introduction

⁶⁸Ga is a positron-emitting nuclide that has significant imaging potential given that, unlike cyclotron-produced ¹⁸F, the isotope can be produced on-site utilizing a ⁶⁸Ge/⁶⁸Ga generator. We recently synthesized a novel bone-seeking agent by coupling a bisphosphonate with the ⁶⁸Ga chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). This study presents a first report on the potential of this ⁶⁸Ga bone-seeking radiopharmaceutical in the detection of bone metastases.

Methods

4-Amino-1-hydroxybutylidene-1,1-bisphosphonate was conjugated with 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]pentanedioic acid, yielding 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]-5-[(4-hydroxy-4,4-diphosphonobutyl)amino]-5-oxopentanoic acid (NOTA-BP). ⁶⁸Ga-labeled NOTA-BP ([⁶⁸Ga]NOTA-BP) was prepared by complexation of NOTA-BP with [⁶⁸Ga] gallium chloride and evaluated in in vitro experiments, biodistribution experiments and micro-positron emission tomography (PET) imaging experiments.

Results

The labeling of NOTA-BP with ⁶⁸Ga was completed by heating for 10 min. [⁶⁸Ga]NOTA-BP was determined to have a radiochemical purity of over 95%, a high affinity for hydroxyapatite and a high stability in plasma. In in vivo biodistribution experiments, [⁶⁸Ga]NOTA-BP demonstrated high bone uptake potential. Compared with ^99mTc-labeled methylene diphosphonate ([^99mTc]MDP) and [¹⁸F]fluoride, [⁶⁸Ga]NOTA-BP exhibited faster blood clearance and a higher bone-to-blood ratio. In addition, mouse model bone metastasis was detected by micro-PET imaging at 1 h postinjection of [⁶⁸Ga]NOTA-BP.

Conclusion

We have developed a novel ⁶⁸Ga-radiolabeled bone-seeking agent. This [⁶⁸Ga]NOTA-BP complex was found to have a high bone affinity and rapid blood clearance, and may thus prove to be useful as a bone-seeking agent for clinical PET.     

Labeling of monoclonal antibodies with a 67Ga-phenolic aminocarboxylic acid chelate

As a chelating agent for labeling antibodies (Abs) with metallic radionuclides, a propionic acid substituted ethylenediamine N,N-di-[(o-hydroxyphenyl) acetic acid] (P-EDDHA), which tighly complexes ⁶⁷Ga, was synthesized. The ⁶⁷Ga-P-EDDHA chelate was coupled in aqueous solution to IgG at a molar ratio of 1:1 via carbodiimide. The average coupling yield was 15%. A specific activity of 4 mCi/mg IgG could be obtained with commercially supplied ⁶⁷Ga. In vitro stability was evaluated in human serum at 37° C and showed a half-life of about 120 h for the release of ⁶⁷Ga from the labeled Ab during the initial phase of incubation. This in vitro halflife is similar to that measured for ¹¹¹In-DTPA labeled Abs. Because of the high stability of the ⁶⁷Ga-P-EDDHA chelate, the in vivo formation of radioactive labeled transferrin by transchelation, as described for ¹¹¹In-DTPA labeled Abs, should, however, be reduced by this labeling technique.     

Biological behavior of 67Ga-citrate in New Zealand White rabbits

The pharmacokinetics, protein binding, excretion and tissue distribution of ⁶⁷Ga after the administration of ⁶⁷Ga-citrate to New Zealand White rabbits is described. Data for ⁶⁷Ga blood levels were best described by an equation with three exponential components exhibiting half lives of 0.25 h, 7.4 h and 19.5 h, with almost all of the activity in a protein bound form. Weekly urinary excretion ( 27%), possibly in a metabolized form, and fecal elimination (20%) were greater than the reported values in man, but there was a similar organ distribution pattern in these animals as in man. The overall biological handling was judged to be similar in both species making the rabbit a suitable model for further ⁶⁷Ga-citrate studies in vivo.     

Cyclotron production of carrier-free 66Ga as a positron emitting label of albumin colloids for clinical use

A method for producing carrier free 66Ga (T1/2:9.4 h; beta +) by 4He bombardment of natural copper targets is presented. 66Ga is formed by means of the 63Cu (4He, n) 66Ga reaction. Production yields are given in the 17.5 to 8 MeV 4He energy range. Chemical purification of 66Ga from the copper target is described. The only radionuclidic impurity found in the final product was 67Ga. Albumin colloids from commercially available kits designed for use with 99mTc could easily be labeled with 66Ga and employed for studies of the lymphatic system by positron emission tomography.     

Quantitative H and hyperpolarized He magnetic resonance imaging: Comparison in chronic obstructive pulmonary disease and healthy never-smokers

Objective

The aim of this study was to quantitatively evaluate the relationship between short echo time pulmonary ¹H magnetic resonance imaging (MRI) signal intensity (SI) and ³He MRI apparent diffusion coefficients (ADC), high-resolution computed tomography (CT) measurements of emphysema, and pulmonary function measurements.

Materials and methods

Nine healthy never-smokers and 11 COPD subjects underwent same-day plethysmography, spirometry, short echo time ((TE) = 1.2 ms) ¹H and diffusion-weighted hyperpolarized ³He MRI (b = 1.6 s/cm²) at 3.0 T. In addition, for COPD subjects only, CT densitometry was also performed.

Results

Mean ¹H SI was significantly greater for never-smokers (12.1 ± 1.1 arbitrary units (AU)) compared to COPD subjects (10.9 ± 1.3 AU, p = 0.04). The ¹H SI AP-gradient was also significantly greater for never-smokers (0.40 AU/cm, R² = 0.94) compared to COPD subjects (0.29 AU/cm, R² = 0.968, p = 0.05). There was a significant correlation between ¹H SI and ³He ADC (r = −0.58, p = 0.008) and significant correlations between ¹H MR SI and CT measurements of emphysema (RA₉₅₀, r = −0.69, p = 0.02 and HU₁₅, r = 0.66, p = 0.03).

Conclusions

The significant and moderately strong relationship between ¹H SI and ³He ADC, as well as between ¹H SI and CT measurements of emphysema suggests that these imaging methods and measurements may be quantifying similar tissue changes in COPD and that pulmonary ¹H SI may be used to monitor emphysema as a complement to CT and noble gas MRI.     

111In-Oxine-labelled autologous leucocytes in inflammatory bowel disease: New scintigraphic activity index

The usefulness of scintigraphy with ¹¹¹In-oxinelabelled autologous leucocytes was investigated in 27 patients with inflamatory bowel disease (IBD): 16 with ulcerative colitis and 11 with Crohn's disease. Scans were performed 2–4 h (early scan) and at 24 h (late scan) after leucocyte reinjection. No false-negative results occurred in the early scan; however, in the late scan, 2 patients with Crohn's disease had a normal scintigram. A new index of activity (I _l) based on the number and relative activity of abnormal ¹¹¹In-leucocyte zones was used for scan quantitation. All patients with clinically active IBD had I _l2. The scintigraphic index showed a significant correlation with the Harvey clinical index, especially in patients with ulcerative colitis. Our results suggest that an early scan (2–4 h) provides useful information in cases of IBD, and that I _l2 is indicative of the degree of disease activity in such patients.     

Repeated injections of 131I-rituximab show patient-specific stable biodistribution and tissue kinetics

Purpose It is generally assumed that the biodistribution and pharmacokinetics of radiolabelled antibodies remain similar between dosimetric and therapeutic injections in radioimmunotherapy. However, circulation half-lives of unlabelled rituximab have been reported to increase progressively after the weekly injections of standard therapy doses. The aim of this study was to evaluate the evolution of the pharmacokinetics of repeated ¹³¹I-rituximab injections during treatment with unlabelled rituximab in patients with non-Hodgkins lymphoma (NHL).Methods Patients received standard weekly therapy with rituximab (375 mg/m²) for 4 weeks and a fifth injection at 7 or 8 weeks. Each patient had three additional injections of 185 MBq ¹³¹I-rituximab in either treatment weeks 1, 3 and 7 (two patients) or weeks 2, 4 and 8 (two patients). The 12 radiolabelled antibody injections were followed by three whole-body (WB) scintigraphic studies during 1 week and blood sampling on the same occasions. Additional WB scans were performed after 2 and 4 weeks post ¹³¹I-rituximab injection prior to the second and third injections, respectively.Results A single exponential radioactivity decrease for WB, liver, spleen, kidneys and heart was observed. Biodistribution and half-lives were patient specific, and without significant change after the second or third injection compared with the first one. Blood T_1/2, calculated from the sequential blood samples and fitted to a bi-exponential curve, was similar to the T_1/2 of heart and liver but shorter than that of WB and kidneys. Effective radiation dose calculated from attenuation-corrected WB scans and blood using Mirdose3.1 was 0.53+0.05 mSv/MBq (range 0.48–0.59 mSv/MBq). Radiation dose was highest for spleen and kidneys, followed by heart and liver.Conclusion These results show that the biodistribution and tissue kinetics of ¹³¹I-rituximab, while specific to each patient, remained constant during unlabelled antibody therapy. RIT radiation doses can therefore be reliably extrapolated from a preceding dosimetry study.     

An automated SPE-based high-yield synthesis of [11C]acetate and [11C]palmitate: no liquid-liquid extraction, solvent evaporation or distillation required

Introduction

An automated method is described for the rapid and high-yield synthesis of two of the most commonly used radioactive fatty acids: [¹¹C]acetate and [¹¹C]palmitate.

Methods

Reaction of [¹¹C]CO₂ with the respective Grignard reagents in diethyl ether solution proceeded for 2 min at 40°C. Quenching of the reaction and liberation of nonreacted [¹¹C]CO₂ occurred upon addition of a fourfold molar excess of aqueous 0.1 M HCl (acetate) or nonaqueous HCl/Et₂O (palmitate). Labeled products were then purified by adsorption to an Alumina-N Sep-Pak Plus cartridge and eluted with either aqueous NaH₂PO₄ solution (acetate) or 100% ethanol (palmitate).

Results

High-performance liquid chromatography analysis confirmed that the radiochemical purity of each product was >98%, and decay-corrected radiochemical yields averaged 33% for [¹¹C]palmitate and 40% for [¹¹C]acetate.

Conclusion

The method requires no liquid–liquid extraction, solvent evaporation or distillation capabilities and can be readily adapted to existing radiosynthesis modules.     

Difference of 14C turnovers in brain and in transplanted glioma after intravenous injection of 14C-1-pyruvate into rats

Carbon 14 from ¹⁴C-1-pyruvate injected intravenously into glioma-transplanted rats was incorporated into various compounds in the brain and in the tumor. In the brain the majority of activity was found in CO₂ (60%), and minor activities were found in alanine, lactate (15%), glutamate, and aspartate, with decreasing order, 5 min after injection. In the tumor, at 5 min, the largest activity was in lactate (56%), and lower activities were found in CO₂ (24%), alanine, glutamate, and aspartate. The total ¹⁴C concentration in the tumor was twice that in the brain at 5 min and 15 min. The result was in accordance with the prediction that in brain, where the mitochondrial function is active, ¹⁴C-1-pyruvate will be oxidized completely into ¹⁴CO₂, and that in tumor, where the mitochondrial function is insufficient, ¹⁴C-1-pyruvate will be converted only into ¹⁴C-lactate and prevent further degradation. It may be assumed that this difference in the turnover of ¹⁴C of ¹⁴C-1-pyruvate between brain and tumor could constitute a basis for the hot visualization of human brain tumor using cyclotron-produced ¹¹C-1-pyruvate and positronemission tomography.     

Comparison of methodologies for the in vivo assessment of <Superscript>18</Superscript>FLT utilisation in colorectal cancer

Fluorine-18 3-deoxy-3-fluorothymidine (¹⁸FLT) is a tissue proliferation marker which has been suggested as a new tumour-specific imaging tracer in positron emission tomography (PET). The objectives of this study were to investigate the pharmacokinetics of ¹⁸FLT in patients with colorectal cancer, defining methodologies for the quantitative analysis of the in vivo ¹⁸FLT uptake and subsequently assessing the accuracy of semi-quantitative measures. Dynamic acquisitions over a single field of view of interest identified by computed tomography were carried out for up to 60 min following injection of ¹⁸FLT (360±25 MBq). Dynamic arterial blood sampling was carried out in order to provide a blood input function. Simultaneous venous samples were also taken in order to investigate their potential utilisation in deriving a hybrid input function. Arterial and venous blood samples at 5, 15, 30, 60 and 90 min p.i. were used for metabolite analysis. Eleven patients with primary and/or metastatic colorectal cancer were studied on a lesion by lesion basis (n=21). All acquired images were reconstructed using ordered subsets expectation maximisation and segmented attenuation correction. Time-activity curves were derived by image region of interest (ROI) analysis and image-based input functions were obtained using abdominal or thoracic aorta ROIs. Standardised uptake values (SUVs) were calculated to provide semi-quantitative indices of uptake, while non-linear regression (NLR) methodology in association with a three-compartment model and Patlak analysis were carried out to derive the net influx constant K _i . The metabolite analysis revealed two radioactive metabolites, with the parent compound representing ~80% of the total radioactivity in the 30-min plasma sample. In the case of NLR, better fits were obtained with a 3k model (i.e. k ₄=0) for both lesion and bone marrow time-activity curves. For the same lesions, a high correlation was observed between the K _i derived from either Patlak analysis or NLR(3k) and the corresponding SUVs. Our results also suggest that the quantitative behaviour of ¹⁸FLT in vivo (up to 60 min p.i.) may be characterised using a 3k model or Patlak analysis in combination with image-derived input functions. The good correlation found between the SUVs (at 60 min) and K _i values supports the use of semi-quantitative indices to assess the proliferation rate of colorectal cancer lesions in vivo with ¹⁸FLT.The work included in this paper was selected for consideration in the Marie-Curie award during the European Association of Nuclear Medicine 2002 meeting in Vienna.     

Prostate cancer: a comparative study of 11C-choline PET and MR imaging combined with proton MR spectroscopy

Purpose Prostate cancer is difficult to visualise in its early stages using current imaging technology. The present study aimed to clarify the utility of ¹¹C-choline PET for localising and evaluating cancer lesions in patients with prostate cancer by conducting a prospective comparison with magnetic resonance (MR) imaging combined with proton MR spectroscopy.Methods PET and MR imaging combined with proton MR spectroscopy were performed in 20 patients with prostate cancer. Correlations among the metabolite ratio of choline + creatine to citrate (Cho+Cr/Ci) on MR spectroscopy, serum PSA and maximum standardised uptake value (SUV_max) of ¹¹C-choline were assessed. The location of the primary lesion was assessed by the site of SUV_max and the laterality of the highest Cho+Cr/Ci ratio and confirmed by examination of surgical pathology specimens (n=16).Results PET exhibited a diagnostic sensitivity of 100% (20/20) for primary lesions, while the sensitivities of MR imaging and MR spectroscopy were 60% (12/20) and 65% (13/20), respectively. Weak linear correlations were observed between SUV_max and serum PSA (r=0.52, p<0.05), and between SUV_max and Cho+Cr/Ci ratio (r=0.49, p<0.05). Regarding the localisation of main primary lesions, PET results agreed with pathological findings in 13 patients (81%) (=0.59), while MR spectroscopy results were in accordance with pathological findings in eight patients (50%) (=0.11).Conclusion This preliminary study suggests that ¹¹C-choline PET may provide more accurate information regarding the localisation of main primary prostate cancer lesions than MR imaging/MR spectroscopy. A further clinical study of ¹¹C-choline PET in a large number of patients suspected of prostate cancer will be necessary to determine the clinical utility of ¹¹C-choline PET in patients who clinically require biopsy.     

Biokinetic and dosimetric studies of Re-hyaluronic acid: a new radiopharmaceutical for treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has very limited therapeutic options. Recently, it has been found that hyaluronic acid (HA) shows selective binding to CD44 receptors expressed in most cancer histotypes. Since the trend in cancer treatment is the use of targeted radionuclide therapy, the aim of this research was to label HA with rhenium-188 and to evaluate its potential use as a hepatocarcinoma therapeutic radiopharmaceutical.

Methods

¹⁸⁸Re-HA was prepared by a direct labelling method to produce a ReO(O-COO)₂-type coordination complex. ¹⁸⁸Re-HA protein binding and its stability in saline, phosphate buffer, human serum and cysteine solutions were determined. Biokinetic and dosimetric data were estimated in healthy mice (n=60) using the Medical Internal Radiation Dose methodology and mouse model beta-absorbed fractions. To evaluate liver toxicity, alanine aminotranferase (AST) and aspartate aminotranferase (ALT) levels in mice were assessed and the liver maximum tolerated dose (MTD) of ¹⁸⁸Re-HA was determined.

Results

A stable complex of ¹⁸⁸Re-HA was obtained with high radiochemical purity (>90%) and low serum protein binding (2%). Biokinetic studies showed a rapid blood clearance (T_1/2α=21 min). Four hours after administration, ¹⁸⁸Re-HA was almost totally removed from the blood by the liver due to the selective uptake via HA-specific receptors (73.47±5.11% of the injected dose). The liver MTD in mice was 40 Gy after 7.4 MBq of ¹⁸⁸Re-HA injection.

Conclusions

¹⁸⁸Re-HA complex showed good stability, pharmacokinetic and dosimetric characteristics that confirm its potential as a new agent for HCC radiation therapy.     

Prospective dosimetry with <Superscript>99m</Superscript>Tc-MDP in metabolic radiotherapy of bone metastases with <Superscript>153</Superscript>Sm-EDTMP

Purpose

On the basis of the encouraging results achieved in several clinical trials and its proven therapeutic efficacy, ¹⁵³Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP) has become widely used to palliate pain from bone metastases. The results reported in the literature have led the product suppliers (QUADRAMET®, Schering) to suggest administering a fixed activity per kilogram (37 MBq/kg). However, considering the observed extreme inter-patient variability of skeletal uptake of ¹⁵³Sm-EDTMP, a real therapy optimization would require the individualization of the activity to be administered on a dosimetric basis. This should be planned taking into account the generally accepted 2-Gy dose constraint to the haematopoietic red marrow, the critical organ in palliative treatments with beta-emitting, bone-seeking radiopharmaceuticals.

Methods

Seven to 14 days before treatment with ¹⁵³Sm-EDTMP, 44 patients underwent ^99mTc-methylene diphosphonate (MDP) total-body bone scan with two scans (the first within 10 min of injection, the second after 6 h). The percentage bone uptake (Tc_%) was evaluated as the ratio between total counts at 6 h, adjusted for decay, and total counts at the first scan. Tc_% was then compared to Sm_% similarly derived from 10-min and 24-h whole-body scans. Tc_% and Sm_% were compared both with and without Brenner’s method for soft tissue uptake.

Results

The correlation between Tc_% and Sm_% was R ²?=?0.81 and R ²?=?0.88 with and without soft tissue correction, respectively. The difference between their average values was statistically significant (Sm_%?=?64.3?±?15.2, Tc_%?=?56.2?±?16.0; p?=?0.017) with soft tissue correction, while was not statistically significant (Sm_%?=?68.2?±?15.5, Tc_%?=?66.9?±?14.0; p?=?0.670) without soft tissue correction.

Conclusions

The rate of retention of ^99mTc-MDP in bone provides a reliable estimate of the ¹⁵³Sm-EDTMP rate of retention. The proposed method can be usefully adopted for prospective dosimetry seeing its extreme simplicity, and it requires no special investment in terms of human or instrumental resources. This allows an optimization of administered ¹⁵³Sm-EDTMP activity.

     

Quantification of disease activity in patients undergoing leucocyte scintigraphy for suspected inflammatory bowel disease

Purpose Whole-body gamma camera counting is an alternative to faecal ¹¹¹In collection for quantifying disease activity in inflammatory bowel disease (IBD) but requires administration of imaging activities of ¹¹¹In. The aim of this study was to explore a dedicated whole-body counter which requires 20-fold less activity than gamma camera counting.Methods Thirty patients with known or suspected IBD received ^99mTc-granulocytes (200 MBq) and ¹¹¹In-granulocytes (0.5 MBq). The ^99mTc-cells were injected 45 min after the ¹¹¹In-cells and immediately after a baseline ¹¹¹In whole-body count. The decay-corrected count at 120 h was expressed as a fraction of baseline to give whole-body ¹¹¹In retention (WBR). One patient was excluded as the injected cells were non-viable.Results Median 45-min intravascular ¹¹¹In recovery was 35% in patients compared with 43% in six normal volunteers (p<0.05). WBR in normals ranged from 91% to 93% and in 11 patients with negative ^99mTc imaging from 87% to 96%. Only one of 11 patients with negative imaging had WBR <90% while 11/12 patients with WBR <90% had abnormal imaging. Ten of 13 patients with Crohns disease (CD) had abnormal imaging. The lowest WBR in these ten was 77% and six had values of >90%. There was a significant association between WBR and ^99mTc image grade (R_s=0.73, p<0.002) in 16 patients without CD, but not in 13 patients with CD (R_s=0.54, p>0.05).Conclusion Dedicated whole-body counting is able to quantify disease activity in IBD but may give normal values in active CD.     

Carbon-11 labelled tyrosine to study tumor metabolism by positron emission tomography (PET)

To measure the rate of protein synthesis in human neoplasms by positron emission tomography, we prepared no carrier added DL-(1-¹¹C)-tyrosine by ¹¹C-carboxylation of the appropriate -lithioisocyanide followed by hydrolysis of the isocyanide function and removal of the protecting methoxy group. The purification, resolution and solvent switch to saline was performed by high performance liquid chromatography (HPLC). DL-(1-¹¹C)-Tyrosine in 0.1 N NaH₂PO₄ buffer was prepared with a radiochemical yield of 8%–16% (EOS, 35 min). The enantiomeric separation and solvent switch to saline were achieved in 5 min and 10 min respectively. Consequently L-(1-¹¹C)-tyrosine in physiological saline was obtained in 2%–4% radiochemical yield. Tumor accumulation in rats with the experimental WALKER 256 carcinosarcoma was observed for both the L- and D-isomer. Using positron emission tomography a tumor/muscle ratio of two was observed for the L-isomer 15 min after injection. The corresponding figure for the D-isomer was 2.5. The first clinical results with DL-(1-¹¹C)-tyrosine show accumulation of radioactivity in meningioma, a primary breast carcinoma and in liver metastases of a colonic carcinoma.     

Detection of bone marrow and extramedullary involvement in patients with non-Hodgkin’s lymphoma by whole-body MRI: comparison with bone and <Superscript>67</Superscript>Ga scintigraphies

The aim of this study was to evaluate the diagnostic potential of whole-body MRI (WB-MRI) for the detection of bone marrow and extramedullary involvement in patients with non-Hodgkins lymphoma. WB-MRI, which was performed on 34 patients, consisted of the recording of T1-weighted spin-echo images and a fast STIR sequence covering the entire skeleton. The WB-MRI findings for bone marrow and extramedullary involvement were compared with those from ⁶⁷Ga and bone scintigraphies and bone marrow biopsy results. Two MRI specialists reviewed the WB-MRI results and two expert radiologists in the field of nuclear medicine reviewed the bone and ⁶⁷Ga scintigraphy findings. Bone marrow and extramedullary involvement of non-Hodgkins lymphoma were confirmed by follow-up radiographs and CT and/or a histological biopsy. The detection rate of WB-MRI was high. More bone marrow involvement was detected by biopsy, and more lesions were detected by scintigraphies. In total, 89 lesions were detected by WB-MRI, whereas 15 were found by biopsy, 5 by ⁶⁷Ga scintigraphy, and 14 by bone scintigraphy. WB-MRI could also detect more extramedullary lesions than ⁶⁷Ga scintigraphy; i.e., 72 lesions were detected by WB-MRI, whereas 54 were discovered by ⁶⁷Ga scintigraphy. WB-MRI is useful for evaluating the involvement of bone marrow and extramedullary lesions throughout the skeleton in patients with non-Hodgkins lymphoma.     

Pharmacokinetics and biodistribution of 177Lu-labeled multivalent single-chain Fv construct of the pancarcinoma monoclonal antibody CC49

Purpose Lutetium-177 (¹⁷⁷Lu) is a radionuclide of interest for radioimmunoimaging (RII) and radioimmunotherapy (RIT) on account of its short half-life (161 h) and the ability to emit both and radiation. Single-chain Fv (scFv) constructs have shown advancement in cancer diagnosis and therapy due to the pharmacokinetics advantage and seem to be intriguing tools in oncology. The objective of this study was to evaluate the pharmacokinetics and biodistribution characteristics of the ¹⁷⁷Lu-labeled tetravalent scFv of CC49 MAb and intact CC49 IgG in vivo.Methods Conjugation and labeling conditions of multivalent scFv with ¹⁷⁷Lu were optimized without affecting integrity and immunoreactivity. For this purpose, multivalent scFv constructs {dimer, sc(Fv)₂; tetramer, [sc(Fv)₂]₂} of the MAb CC49 were expressed as secretory proteins in Pichia pastoris. The purified scFv constructs and IgG form of CC49 were conjugated with a bifunctional chelating agent, ITCB-DTPA, and labeled with ¹⁷⁷Lu. The comparative biodistribution, blood clearance, and tumor-targeting characteristics of ¹⁷⁷Lu-labeled tetravalent [sc(Fv)₂]₂ construct of CC49 MAb and intact CC49 IgG were investigated in the athymic mice bearing LS-174T xenografts.Results Approximately, 90% of ¹⁷⁷Lu incorporation was achieved using ITCB-DTPA chelator, and the labeled immunoconjugates maintained integrity and immunoreactivity. Blood clearance studies demonstrated an alpha half-life (t_1/2) of ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ and IgG of CC49 at 4.40 and 9.50 min and a beta half-life (t_1/2) at 375 and 2,193 min, respectively. At 8 h post administration, the percent of the injected dose accumulated/gram (%ID/g) of the LS-174T tumor was 6.4±1.3 and 8.9±0.6 for ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ and IgG of CC49, respectively, in the absence of l-lysine. The corresponding values were 8.0±0.6 and 8.4±1.2 in the presence of l-lysine. Renal accumulation of [sc(Fv)₂]₂ was significantly (p<0.005) reduced in the presence of l-lysine.Conclusion The results of this study demonstrate that the ITCB-DTPA conjugation and ¹⁷⁷Lu-labeling of scFvs are feasible without influencing the antibody characteristics. ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ showed faster clearance and equivalent tumor uptake at 8 h compared with its IgG form, with a markedly reduced renal uptake in the presence of l-lysine. Therefore, ¹⁷⁷Lu-labeled [sc(Fv)₂]₂ may be a potential radiopharmaceutical for the treatment of cancer.