Head-to-Head Comparison of 68Ga-PSMA-11 and 131I in the Follow-Up of Well-Differentiated Metastatic Thyroid Cancer: A New Potential Theragnostic Agent.

Introduction: Thyroid cancer is the main endocrine neoplasia worldwide, for which 131I therapy is the cornerstone treatment. One of the main problems of follow up in patients with this type of cancer, is the need for thyroglobulin stimulation, not to mention the poor availability of 123I or 124I, to perform studies with a higher degree of sensitivity. Prostatic Specific Membrane Antigen (PSMA) PET/CT has demonstrated to be quite useful in a diversified number of neoplasms, on behalf of its capacity of evaluating the extent of type II carboxypeptidase expression in vascular endothelium. The end point of this article is to assess whether this novel image method possesses applicability in thyroid neoplasms follow up, for diagnostic and potentially therapeutic purposes. Methods: We retrospectively evaluated well differentiated metastatic thyroid cancer patients, who underwent a post therapeutic 131I dose whole body scan (WBS) and complementary SPECT/CT, as well as 68Ga-PSMA-11 PET/CT. Results: Ten patients with differentiated thyroid cancer were included, of whom 80% were women and 20% men, mean age was 58 years old (± 11.6). Sixty-four metastatic lesions were analyzed, 67.19% had papillary histology and 32.81% were follicular type, the most affected site of metastases was bone in 57.81%, followed by lung 17.19%, lymph nodes 7.81%, postoperative thyroid bed 4.69%, brain 4.69% and others 7.81%. 68Ga PSMA-11 PET/CT detected 64/64 lesions, all of them also identified by computed tomography (CT), whereas 131I SPECT/CT detected 55/64 lesions. Discrepant lesions were localized in lung 44.4%, brain 22.2%, postoperative thyroid bed 11.1%, lymph nodes 11.1% and bone 11.1%. The degree of correspondence among observers was outstanding for both radiotracers, but close upon perfect for PSMA-11 (κ = 0.98; 95% CI, 0.80 - 0.91), as opposed to 131 I (κ = 0.86; 95% CI, 0.71 - 0.76). Conclusions: 68Ga-PSMA PET/CT showed an utterly superior capability for metastatic lesion detection when compared to 131I SPECT/CT. These findings suggest that PSMA PET/CT could possibly and precociously identify radioiodine refractoriness. PSMA uptake values not only expedite diagnosis, but also award it the ability to be used for therapeutic intents.

In vivo preclinical evaluation of the new 68Ga-labeled beta-cyclodextrin in prostaglandin E2 (PGE2) positive tumor model using positron emission tomography.

The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays an important role in tumor development and formation of metastases. It was earlier reported that cyclodextrin derivatives have a high affinity to form complexes with PGE2. Based on these results radiolabeled cyclodextrins - as new radiopharmaceuticals - may open a new pathway in the in vivo imaging and diagnosis of PGE2 positive tumors. The aims of this study were to synthetize the PGE2 specific 68Ga-labeled NODAGA-randomly methylated beta-cyclodextrin (68Ga-NODAGA-RAMEB) and investigate its tumor-targeting properties. NODAGA-RAMEB was labeled with Gallium-68 (68Ga), and the radiochemical purity (RCP%), partition coefficient (logP values), and in vitro-in vivo stability of 68Ga-NODAGA-RAMEB were determined. After intravenous injection of 68Ga-NODAGA-RAMEB the accumulation in organs and tissues was monitored in vivo by positron emission tomography (PET) and ex vivo by gamma counter in BxPC-3 and PancTu-1 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized 68Ga-NODAGA-RAMEB was higher than 98%. The molar activity was 15.34 ± 1.93 GBq/µmol. The logP of 68Ga labeled NODAGA-RAMEB was - 3.63 ± 0.04. Biodistribution studies showed high accumulation of 68Ga-NODAGA-RAMEB in PGE2 positive BxPC-3 tumors; approximately 15-20-fold higher radiotracer uptake was observed, than that of the background. 68Ga-labeled RAMEB is a promising radiotracer in PET diagnostics of PGE2 positive tumors.

Targeting of vascular adhesion protein-1 by positron emission tomography visualizes sites of inflammation in Borrelia burgdorferi-infected mice.

BACKGROUND: In the present study, we sought to evaluate the feasibility of targeting vascular adhesion protein-1 (VAP-1) by positron emission tomography (PET) for the longitudinal quantitative assessment of Borrelia burgdorferi infection-induced inflammation in mice. METHODS: Mice with B. burgdorferi infection-induced arthritis were studied. During a 7-week follow-up period, the progression of arthritis was monitored weekly with 68Ga-DOTA-Siglec-9 PET/computed tomography (CT) and measurement of tibiotarsal joint swellings. A subgroup of infected mice was treated with ceftriaxone. Finally, histopathological assessment of joint inflammation was performed and VAP-1 expression in joints were determined. RESULTS: Explicit joint swelling and 68Ga-DOTA-Siglec-9 uptake could be demonstrated in the affected joints from B. burgdorferi-infected mice. By contrast, no obvious accumulation of 68Ga-DOTA-Siglec-9 was detected in joints of uninfected mice. The maximum swelling and highest uptake in the affected joints were observed 4 weeks after the infection. 68Ga-DOTA-Siglec-9 uptake in joints correlated with joint swelling (P < 0.0001) and histopathological scoring of inflammation (P = 0.020). Despite short-term antibiotic treatment, the arthritis persisted, and the PET signal remained as high as in nontreated mice. Immunohistochemistry revealed strong-to-moderate expression of VAP-1 in the synovium of B. burgdorferi-infected mice, while only weak expression of VAP-1 was detected in uninfected mice. CONCLUSIONS: The present study showed that 68Ga-DOTA-Siglec-9 can detect B. burgdorferi infection-induced arthritis in mice. Furthermore, longitudinal PET/CT imaging allowed monitoring of arthritis development over time.

Comparative preclinical evaluation of 68Ga-NODAGA and 68Ga-HBED-CC conjugated procainamide in melanoma imaging.

Malignant melanoma is the most aggressive form of skin cancer. The early detection of primary melanoma tumors and metastases using non-invasive PET imaging determines the outcome of this disease. Previous studies have shown that benzamide derivatives (e.g. procainamide) conjugated with PET radionuclides specifically bind to melanin pigment of melanoma tumors. 68Ga chelating agents can have high influence on physiological properties of 68Ga labeled bioactive molecules, as was experienced during the application of HBED-CC on PSMA ligand. The aim of this study was to assess this concept in the case of the melanin specific procaindamide (PCA) and to compare the melanin specificity of 68Ga-labeled PCA using HBED-CC and NODAGA chelators under in vitro and in vivo conditions. Procainamide (PCA) was conjugated with HBED-CC and NODAGA chelators and was labeled with Ga-68. The melanin specificity of 68Ga-HBED-CC-PCA and 68Ga-NODAGA-PCA was investigated in vitro and in vivo using amelanotic (MELUR and A375) and melanin containing (B16-F10) melanoma cell lines. Tumor-bearing mice were prepared by subcutaneous injection of B16-F10, MELUR and A375 melanoma cells into C57BL/6 and SCID mice. 21±2days after tumor cell inoculation and 90min after intravenous injection of the 68Ga-labelledlabeled radiopharmacons whole body PET/MRI scans were performed. 68Ga-NODAGA-PCA and 68Ga-HBED-CC-PCA were produced with excellent radiochemical purity (98%). In vitro experiments demonstrated that after 30 and 90min incubation time 68Ga-NODAGA-PCA uptake of B16-F10 cells was significantly (p≤0.01) higher than the 68Ga-HBED-CC-conjugated PCA accumulation in the same cell line. Furthermore, significant difference (p≤0.01 and 0.05) was found between the uptake of melanin negative and positive cell lines using 68Ga-NODAGA-PCA and 68Ga-HBED-CC-PCA. In vivo PET/MRI studies using tumor models revealed significantly (p≤0.01) higher 68Ga-NODAGA-PCA uptake (SUVmean: 0.46±0.05, SUVmax: 1.96±0.25,T/M ratio: 40.7±4.23) in B16-F10 tumors in contrast to 68Ga-HBED-CC-PCA where the SUVmean, SUVmax and T/M ratio were 0.13±0.01, 0.56±0.11 and 11.43±1.24, respectively. Melanin specific PCA conjugated with NODAGA chelator showed higher specific binding properties than conjugated with HBED-CC. The chemical properties of the bifunctional chelators used for 68Ga-labeling of PCA determine the biological behaviour of the probes. Due to the high specificity and sensitivity 68Ga-labeled PCA molecules are promising radiotracers in melanoma imaging.

Studies on the 67Ga uptake mechanism by Ehrlich ascites tumor cells.

In order to obtain more information concerning the mechanism of Gallium (67Ga) accumulation in malignant tissue, an investigation was carried out using Ehrlich ascites tumor cells. Chlorpromazine, a phospholipid stabilizer decreased the uptake of 67Ga and Calcium 45 (45Ca) by the cells at low dose, but increased them at high dose. On the other hand, the uptake of both radionuclides by the cells was inhibited by ruthenium red, a Ca ATPase inhibitor in a dose dependent manner. The time course of 67Ga and 45Ca uptake were quite different from each other. Moreover, the subcellular distribution patterns of 67Ga and 45Ca were also different from each other; 67Ga accumulated in the lysosomal fraction and 45Ca mainly in the mitochondrial fraction. These results suggest that there may be a commonality for 67Ga and 45Ca uptake by the tumor cells, whereas the behaviour of these two radionuclides in the cells is dissimilar.

Relation between 67Ga uptake and the stage of inflammation induced by turpentine oil in rats.

For the establishment of the experimental system to judge easily the effect of anti-inflammatory drug, 67Ga-citrate was used. The weight of granuloma tissues induced by inflammable agent, turpentine oil, gradually increased and reached a maximum at 6 days after the administration of turpentine oil. Gallium-67 accumulation in the inflammatory lesions showed also a maximum at 6 days after that. Both patterns were closely similar each other. These results showed that the processes and/or stages of inflammation could be indicated by the pattern of 67Ga uptake.

Different actions of deferoxamine and iron on Ga-67 abscess detection in rats.

The contrast-enhancing properties of iron (Fe) and deferoxamine (DFO) in abscess imaging with Ga-67 citrate were compared in rats bearing turpentine-induced abscesses. Iron administration shifted Ga-67 from plasma into tissues such as muscle and fat. As a result, the abscess-to-plasma ratio increased whereas the abscess-to-muscle ratio decreased. DFO enhanced the abscess-to-muscle and abscess-to-plasma ratios by increasing urinary Ga-67 excretion. In contrast to Fe, DFO removed abscess-bound Ga-67, thus representing a disadvantage of DFO compared with Fe. As a result, the abscess-to-plasma ratio was more effectively enhanced by Fe than by DFO. We conclude that abscess imaging with Ga-67 citrate may be improved by administration of Fe for detection of abscesses masked by blood activity, or DFO for detection of abscesses surrounded by muscle tissue.

Pharmacologic enhancement of gallium-67 tumor-to-blood ratios for EMT-6 sarcoma (BALB/c mice).

At various intervals after intravenous injection of carrier-free 67Ga-citrate, iron dextrane or deferoxamine mesylate was injected into EMT-6 tumor-bearing BALB/c mice. After treatment, rapid clearance of 67Ga from soft tissues was observed. Tumor uptake was not greatly affected, and so increased tumor-to-blood ratios were observed. The authors conclude that these drugs can enhance target-to-nontarget uptake ratios for tumors.