Current Radiopharmaceuticals - Volume 6, Issue 1, 2013

Sodium-proton exchangers, NHEs are plasma membrane proteins that are essential in the regulation of intracellular pH of the myocardium. There are nine known variously expressed isoforms of NHEs with NHE-1 being the predominant isoform in the heart. N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (1) is a potent NHE 1inhibitor with good pharmacokinetics. It was prepared labeled with deuterium and carbon-14 to aid in drug metabolism, pharmacokinetics, and other studies. The combination of Comins' reaction and reduction under deuterium gas was used to access deuterium labeled (1) starting from deuterium labeled pyridine. Carbon-14 labeled zinc cyanide was used to prepare [14C]-(1) in three steps, with a specific activity of 55.6 mCi/mmol.

Vascular endothelial growth factor (VEGF) is one of the classic factors involved in tumor-induced angiognesis in several solid tumors. Bevacizumab, a monoclonal antibody against VEGF, can be used as an imaging tool in preclinical studies. The aim of this study was to radiolabel Bevacizumab with 99mTc and to evaluate in vivo its imaging properties in an adenocarcinoma animal model. For this purpose, Bevacizumab was derivatized with Suc-HYNIC as a bifunctional coupling agent. A mixture of Tricine/SnCl2.2H2O was added to Bevacizumab-HYNIC and radiolabeled with 99mTcO4 -. The radiochemical stability of the radiolabeled antibody was assessed. Biodistribution and scintigraphy imaging were performed in normal CD1 female mice and in spontaneous adenocarcinoma tumor bearing CD1 mice (n = 5). We demonstrated that 99mTc-HYNIC-Bevacizumab was stable. In vivo biodistribution studies revealed that tumor uptake of 99mTc- HYNIC-Bevacizumab was 1.37 ± 0.51% and 5.33 ± 2.13% at 4 and 24 h postinjection, respectively. Scintigraphy image studies showed tumor selective uptake of 99mTc-HYNIC-Bevacizumab in the tumor-bearing mice. We conclude that 99mTc-HYNIC-Bevacizumb has the potential to be used as a tracer for tumor imaging in preclinical studies.

The biodistribution of the anti-CD37 radioimmunoconjugate 177Lu-tetraxetan-tetulomab (177Lu-DOTA-HH1) was evaluated. Biodistribution of 177Lu-tetraxetan-tetulomab was compared with 177Lu-tetraxetan-rituximab and free 177Lu in nude mice implanted with Daudi lymphoma xenografts. The data showed that 177Lu-tetulomab had a relevant stability and tumor targeting properties in the human lymphoma model. The half-life of 177Lu allowed significant tumor to normal tissue ratios to be obtained indicating that 177Lu-tetraxetan-tetulomab could be suitable for clinical testing. The biological and effective half-life in blood was higher for 177Lu-tetraxetan-tetulomab than for 177Lu-tetraxetan-rituximab. The biodistribution of 177Lu-tetraxetan-tetulomab did not change significantly when the protein dose was varied from 0.01 to 1 mg/kg. Dosimetry calculations showed that the absorbed radiation doses to normal tissues and tumor in mice were not significantly different for 177Lu-tetraxetan-tetuloma b and 177Lu-tetraxetan-rituximab. The absorbed radiation doses were extrapolated to human absorbed radiation doses. These extrapolated absorbed radiation doses to normal tissues for 177Lutetraxetan- tetulomab at an injection of 40 MBq/kg were significantly lower than the absorbed radiation doses for 15 MBq/kg Zevalin, suggesting that higher tumor radiation dose can be reached with 177Lu-tetraxetan-tetulomab in the clinic.

A novel zoledronate derivative, 1-hydroxy-4-(2-butyl-1H-imidazol-1-yl)butane-1,1- diyldiphosphonic acid (BIBDP) was prepared and labeled with 99mTc successfully in a high radiochemical purity and good stability in vitro. The biodistribution in mice shows that 99mTc-BIBDP has high specificity and efficacy in bone uptake with a maximum of 12.14 ± 0.53 %ID/g at 120 min. Kinetics of blood clearance showed that distribution half life (T1/2α), elimination half life (T1/2β) and total clearance rate (CL) of 99mTc-BIBDP were 4.67 min, 91.9 min and 1.21 %ID/g·min-1, respectively. Moreover, 99mTc-BIBDP has higher uptake in the bone and faster clearance from soft tissues than 99mTc-MDP and 99mTc-ZL. A plain and clear bone image was obtained at 1 h with SPECT bone imaging. The present findings indicate that 99mTc- BIBDP holds great potential for bone imaging.

Somastostatin (SS) scintigraphy (SRS) is an effective diagnostic tool for neuroendocrine tumours (NET). High diagnostic accuracy is based on the high affinity binding between SS and its receptors (sstr) expressed both in NET and in some non neoplastic cells. Different SS analogues have been proposed in clinical practice because of the short half-life of the native peptide. Among all synthetic compounds Pentetreotide labelled with In-111 is the most widely used for imaging because of high affinity for sstr 2 and 5. New tracers, showing a different and/or wider affinity, are now available and radio- labelling has been obtained both with gamma and positron emitters. The broader spectrum of interaction with sstr gives a better chance to detect, over NET, other pathological conditions, as chronic inflammation, because of the sstr expression on inflammatory cells, including activated lymphocytes, epithelioid and monocytes.

The skeleton is one of the preferential sites for metastases of solid tumors, and metastatic disease is the most common malignancy of the bone. Diagnosis and evaluation of skeletal metastases require more frequently a combined approach of different diagnostic methods. Between the currently available imaging modalities, a major role is devoted to two radionuclide functional techniques namely scintigraphy and positron emission tomography (PET) imaging. Both these techniques require the use of different radiopharmaceuticals. The aim of this paper is to review the most important radiocompounds that can be successfully used to detect and/or characterize bone metastases.

Epidermal growth factor receptors (EGFRs) belong to the ErbB family of receptor tyrosine kinases (TKs). Based on the role of EGFR signaling pathway in malignant progression of various types of tumors, a growing interest in the use of EGFR-TK inhibitors as probes for molecular imaging of EGFR-overexpressing tumors via positron emission tomography (PET) and single photon emission computed tomography (SPECT) is being notable. On one side, such noninvasive and repetitive monitoring of the activity of EGFR at the kinase level is intended to provide a direct measure of EGFR occupancy and inhibition by EGFR-targeting drugs. On the other side, all oncologic imaging tracers are molecularly targeted radiopharmaceuticals, which are strongly dependent on the tumor biochemistry including increased metabolism, hyperproliferation, angiogenesis, hypoxia, apoptosis, and specific tumor biomarkers (tumor specific antigens and tumor-specific receptors). The present article is an attempt to reconcile these two vital standpoints influencing the choice of appropriate radiolabeled agents for PET and SPECT imaging aimed to support the development of a new generation of multi-targeted kinase inhibitors in the time ahead, because the routine accomplishment of drug selectivity for particular protein kinases is a substantial challenge.