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Abstract: Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [67Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with 67GaCl3 according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: 67Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%±0.75% ID/g, 1 h pi and 6.08%±0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of 67Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel 67Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR-positive cancer and potentially inflammatory diseases. Due to its rapid blood clearance properties, this tracer is also a promising candidate for positron emission tomography imaging if radiolabeled with the short-lived [68Ga]-gallium radionuclide. [Copyright &y& Elsevier]

Introduction 44 Sc, a PET radionuclide, has promising decay characteristics (T 1/2 = 3.97 h, Eβ + av = 632 keV) for nuclear imaging and is an attractive alternative to the short-lived 68 Ga (T 1/2 = 68 min, Eβ + av = 830 keV). The aim of this study was the optimization of the 44 Sc production process at an accelerator, allowing its use for preclinical and clinical PET imaging. Methods 44 CaCO 3 targets were prepared and irradiated with protons (~ 11 MeV) at a beam current of 50 μA for 90 min. 44 Sc was separated from its target material using DGA extraction resin and concentrated using SCX cation exchange resin. Radiolabeling experiments at activities up to 500 MBq and stability tests were performed with DOTANOC by investigating different scavengers, including gentisic acid. Dynamic PET of an AR42J tumor-bearing mouse was performed after injection of 44 Sc-DOTANOC. Results The optimized chemical separation method yielded up to 2 GBq 44 Sc of high radionuclidic purity. In the presence of gentisic acid, radiolabeling of 44 Sc with DOTANOC was achieved with a radiochemical yield of ~ 99% at high specific activity (10 MBq/nmol) and quantities which would allow clinical application. The dynamic PET images visualized increasing uptake of 44 Sc-DOTANOC into AR42J tumors and excretion of radioactivity through the kidneys of the investigated mouse. Conclusions The concept “from-bench-to-bedside” was clearly demonstrated in this extended study using cyclotron-produced 44 Sc. Sufficiently high activities of 44 Sc of excellent radionuclidic purity are obtainable for clinical application, by irradiation of enriched calcium at a cyclotron. This work demonstrates a promising basis for introducing 44 Sc to clinical routine of nuclear imaging using PET. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Radiolabeled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumors in which BN2/gastrin-releasing peptide (GRP) receptors are overexpressed. However, the low in vivo stability of BN conjugates may limit their clinical application. In an attempt to improve their pharmacokinetics and counteract their rapid enzymatic degradation, we prepared a series of polyethylene glycol (PEG)-ylated BN(7-14) analogues for radiolabeling with 99mTc(CO)3 and evaluated them in vitro and in vivo. Methods: Derivatization of a stabilized (NαHis)Ac-BN(7-14)[Cha13,Nle14] analogue with linear PEG molecules of various sizes [5 kDa (PEG5), 10 kDa (PEG10) and 20 kDa (PEG20)] was performed by PEGylation of the ɛ-amino group of a β3hLys-βAla-βAla spacer between the stabilized BN sequence and the (NαHis)Ac chelator. The analogues were then radiolabeled by employing the 99mTc-tricarbonyl technique. Binding affinity and internalization/externalization studies were performed in vitro in human prostate carcinoma PC-3 cells. Stability was investigated in vitro in human plasma and in vivo in Balb/c mice. Finally, single photon emission computed tomography (SPECT)/X-ray computed tomography studies were performed in nude mice bearing PC-3 tumor xenografts. Results: PEGylation did not affect the binding affinity of BN analogues, as the binding affinity for BN2/GRP receptors remained high (K d<0.9 nM). However, in vitro binding kinetics of the PEGylated analogues were slower. Steady-state condition was reached after 4 h, and the total cell binding was 10 times lower than that for the non-PEGylated counterpart. Besides, PEGylation improved the stability of BN conjugates in vitro and in vivo. The BN derivative conjugated with a PEG5 molecule showed the best pharmacokinetics in vivo, i.e., faster blood clearance and preferential renal excretion. The tumor uptake of the 99mTc-PEG5-Lys-BN conjugate was slightly higher compared to that of the non-PEGylated analogue (3.91%±0.44% vs. 2.80%±0.28% injected dose per gram 1 h postinjection, p.i.). Tumor retention was also increased, resulting in a threefold higher amount of radioactivity in the tumor at 24 h p.i. Furthermore, decreased hepatobiliary excretion and increased tumor-to-nontarget ratios (tumor-to-blood: 17.1 vs. 2.1; tumor-to-kidney: 1.1 vs. 0.4; tumor-to-liver: 5.8 vs. 1.0, 24 h p.i.) were observed and further confirmed via small-animal SPECT images 1 h p.i. Conclusion: PEGylation proved to be an effective strategy to enhance the tumor-targeting potential of 99mTc-labeled BN-based radiopharmaceuticals and probably other radiolabeled peptides. [Copyright &y& Elsevier]