99mTc- and 111In-labeled alpha-melanocyte-stimulating hormone peptides as imaging probes for primary and pulmonary metastatic melanoma detection.

It is highly desired to develop new imaging probes for early detection of melanoma as early diagnosis and prompt surgical removal are a patient's best hope for a cure. The purpose of this study was to determine whether (99m)Tc- and (111)In-labeled alpha-melanocyte-stimulating hormone (alpha-MSH) peptides could be used as imaging probes for primary and metastatic melanoma using dual-modality micro-SPECT/CT detection. METHODS: [Cys(3,4,10),d-Phe(7),Arg(11)]alpha-MSH(3-13) [(Arg(11))CCMSH] and [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]Re(Arg(11))CCMSH [DOTA-Re(Arg(11))CCMSH] were labeled with (99m)Tc and (111)In. The pharmacokinetics of (99m)Tc-(Arg(11))CCMSH were examined in B16/F1 flank and B16/F10 pulmonary metastatic murine melanoma-bearing C57 mice. The biodistribution of (111)In-DOTA-Re(Arg(11))CCMSH was performed in B16/F10 pulmonary metastatic murine melanoma-bearing C57 mice. SPECT/CT of (99m)Tc-(Arg(11))CCMSH and (111)In-DOTA-Re(Arg(11))CCMSH was determined in B16/F1 flank and B16/F10 pulmonary metastatic murine melanoma-bearing C57 mice. RESULTS: (99m)Tc-(Arg(11))CCMSH and (111)In-DOTA-Re(Arg(11))CCMSH exhibited high tumor uptakes (14.03 +/- 2.58 percentage injected dose/gram [%ID/g] at 1 h after injection and 17.29 +/- 2.49 %ID/g at 2 h after injection) in B16/F1 melanoma-bearing mice, and the flank melanoma tumors were clearly imaged by micro-SPECT/CT. Nontarget organ uptakes were considerably lower except for the kidneys. B16/F10 pulmonary melanoma metastases were also clearly visualized by micro-SPECT/CT using (99m)Tc-(Arg(11))CCMSH or (111)In-DOTA-Re(Arg(11))CCMSH as the imaging probe. (99m)Tc-(Arg(11))CCMSH exhibited images with greater resolution of metastatic melanoma lesions compared with (111)In-DOTA-Re(Arg(11))CCMSH. CONCLUSION: The favorable tumor imaging properties of (99m)Tc-(Arg(11))CCMSH and (111)In-DOTA-Re(Arg(11))CCMSH highlighted their potential as novel probes for primary and metastatic melanoma detection.     

Gallium-68-labeled DOTA-rhenium-cyclized alpha-melanocyte-stimulating hormone analog for imaging of malignant melanoma

INTRODUCTION: Diagnosis of malignant melanoma is critical, since a patient's prognosis is poor. Previous studies have shown that 64Cu- and 86Y-DOTA-ReCCMSH(Arg11) have the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of positron emission tomography (PET). This encouraged us to investigate DOTA-ReCCMSH(Arg11) labeled with another beta+-emitting radionuclide, 68Ga. METHODS: DOTA-ReCCMSH(Arg11) was successfully labeled with 68Ga at pH 3.8-4 at 85 degrees C. Acute biodistribution and small-animal PET imaging studies were performed in mice bearing B16/F1 melanoma tumor. RESULTS: Biodistribution studies showed moderate receptor-mediated tumor uptake, fast nontarget organ clearance and high tumor to nontarget tissue ratios. Preadministration of d-lysine significantly reduced kidney uptake without affecting the uptake of the agent in the tumor. Small-animal PET images showed that the tumor could be clearly visualized at all time points examined (0.5-2 h) with the standardized uptake value analysis following a similar trend as the biodistribution data. CONCLUSIONS: The preliminary data obtained suggest that 68Ga-DOTA-ReCCMSH(Arg11) is a promising PET imaging agent for early detection of malignant melanoma.     

Tetraphenylphosphonium as a novel molecular probe for imaging tumors.

Mitochondrial membrane potential (DeltaPsim)-dependent enhanced uptake of phosphonium salts, including (3)H-tetraphenylphosphonium ((3)H-TPP), in tumor cells, suggests the potential use of phosphonium salts as tracers for tumor imaging. In this study, we characterize the tumor accumulation of (3)H-TPP and compare it with (18)F-FDG in cell culture and in xenograft, metastatic, and inflammation models in living animals. METHODS: (3)H-TPP and (3)H-FDG accumulation was compared in cell culture with a variety of cell lines in different glucose concentrations. Normal biodistribution and tumor uptake were assessed using nude mice with or without subcutaneous xenograft tumors (C6). To compare the accumulation of (3)H-TPP and (18)F-FDG in a metastatic tumor, severe combined immunodeficiency mice were tail-vein injected with human melanoma cell lines (A375-FL). To characterize the accumulation of (3)H-TPP and (18)F-FDG in inflammation, an inflammatory reaction was induced by subcutaneous injection of Complete Freund's Adjuvant in the left hind paw of Sprague-Dawley rat. RESULTS: The DeltaPsim data from a separate study and the current (3)H-TPP uptake data showed good correlation (r(2) = 0.82, P < 0.05). (3)H-TPP accumulation was significantly greater than that of (3)H-FDG for glucose >/=100 mg/dL. The biodistribution study of (3)H-TPP showed low uptake in most tissues but high accumulation in the heart and kidneys. (3)H-TPP accumulation in xenograft or metastatic tumors was comparable with that of (18)F-FDG, whereas (3)H-TPP accumulation in inflammatory tissues was markedly lower than that of (18)F-FDG. CONCLUSION: The sensitive tumor accumulation of (3)H-TPP with less propensity for inflammatory regions warrants further investigation of radiolabeled phosphonium analogs for tumor imaging in living subjects.     

A gallium-labeled DOTA-alpha-melanocyte- stimulating hormone analog for PET imaging of melanoma metastases.

Although (18)F-FDG PET is widely used for metastatic melanoma diagnosis, it is less accurate than desirable, particularly for small foci. Since both melanotic and amelanotic melanomas overexpress receptors for alpha-melanocyte-stimulating hormone (alpha-MSH; receptor name, melanocortin type 1 receptor [MC1R]), radiolabeled alpha-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a positron emitter-labeled alpha-MSH analog suitable for PET imaging of melanoma metastases. METHODS: A short linear alpha-MSH analog, [Nle(4),Asp(5),D-Phe(7)]-alpha-MSH(4-11) (NAPamide), was newly designed and conjugated to the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to enable radiometal incorporation. Compared with our previously reported DOTA-alpha-MSH analog, DOTA-MSH(oct) ([DOTA-betaAla(3),Nle(4),Asp(5),D-Phe(7),Lys(10)]-alpha-MSH(3-10)), the major modification lies in the conjugation of DOTA to the C-terminal end of the peptide via the epsilon-amino group of Lys(11), as opposed to the N-terminal alpha-amino group. After labeling with (111)In, (67)Ga, and the short-lived positron emitter (68)Ga, DOTA-NAPamide was characterized in vitro and in vivo using the mouse melanoma B16F1cell line. RESULTS: DOTA-NAPamide exhibited an almost 7-fold higher MC1R binding potency as compared with DOTA-MSH(oct). In B16F1 melanoma-bearing mice, both (111)In-DOTA-NAPamide and (67)Ga-DOTA-NAPamide behaved more favorably than (111)In-DOTA-MSH(oct). Both radiopeptides exhibited higher tumor and lower kidney uptake leading to tumor-to-kidney ratios of the 4- to 48-h area under the curve that were 4.6 times ((111)In) and 7.5 times ((67)Ga) greater than that obtained with (111)In-DOTA-MSH(oct). In addition, the 4-h kidney uptake of (67)Ga-DOTA-NAPamide could be reduced by 64% by coinjection of 15 mg L-lysine, without affecting tumor uptake. Skin primary melanoma as well as lung and liver melanoma metastases could be easily visualized on tissue section autoradiographs after systemic injection of (67)Ga-DOTA-NAPamide. The melanoma selectivity of DOTA-NAPamide was confirmed by PET imaging studies using (68)Ga-DOTA-NAPamide. Tumor uptake was found to be highest when the smallest amount of peptide was administered. CONCLUSION: DOTA-NAPamide labeled with either (111)In or (67)Ga/(68)Ga is in every way superior to (111)In-DOTA-MSH(oct) in murine models of primary and metastatic melanoma, which makes it a promising agent for melanoma targeting. High-contrast images obtained in PET studies with an experimental tumor model 1 h after injection augurs well for its clinical potential as an imaging tool.     

Therapeutic efficacy of a 188Re-labeled alpha-melanocyte-stimulating hormone peptide analog in murine and human melanoma-bearing mouse models.

The purpose of this study was to examine the therapeutic efficacy of (188)Re-(Arg(11))[Cys(3,4,10),d-Phe(7)]alpha-melanocyte-stimulating hormone(3-13) (CCMSH) in the B16/F1 murine melanoma- and TXM13 human melanoma-bearing mouse models. METHODS: (Arg(11))CCMSH was synthesized and labeled with (188)Re to form (188)Re-(Arg(11))CCMSH. B16/F1 melanoma-bearing mice were administrated 7.4 MBq, 22.2 MBq, and 2 x 14.8 MBq of (188)Re-(Arg(11))CCMSH via the tail vein. TXM13 melanoma-bearing mice were separately injected with 22.2 MBq, 2 x 14.8 MBq, and 37.0 MBq of (188)Re-(Arg(11))CCMSH through the tail vein. Two groups of 10 mice bearing either B16/F1 or TXM13 tumors were injected with saline as untreated controls. RESULTS: In contrast to the untreated control group, (188)Re-(Arg(11))CCMSH yielded rapid and lasting therapeutic effects in the treatment groups with either B16/F1 or TXM13 tumors. The tumor growth rate was reduced and the survival rate was prolonged in the treatment groups. Treatment with 2 x 14.8 MBq of (188)Re-(Arg(11))CCMSH significantly extended the mean life of B16/F1 tumor mice (P < 0.05), whereas the mean life of TXM13 tumor mice was significantly prolonged after treatment with 22.2-MBq and 37.0- MBq doses of (188)Re-(Arg(11))CCMSH (P < 0.05). High-dose (188)Re-(Arg(11))CCMSH produced no observed normal tissue toxicity. CONCLUSION: The therapy study results revealed that (188)Re-(Arg(11))CCMSH yielded significant therapeutic effects in both B16/F1 murine melanoma- and TXM13 human melanoma-bearing mouse models. (188)Re-(Arg(11))CCMSH appears to be a promising radiolabeled peptide for targeted radionuclide therapy of melanoma.     

Technetium-99m-labeled Arg-Gly-Asp-conjugated alpha-melanocyte stimulating hormone hybrid peptides for human melanoma imaging

IntroductionThe purpose of this study was to examine whether ^99mTc-labeled Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone (α-MSH) hybrid peptide targeting both melanocortin-1 (MC1) and α_vβ₃ integrin receptors was superior in melanoma targeting to ^99mTc-labeled α-MSH or RGD peptide targeting only the MC1 or α_vβ₃ integrin receptor.MethodsRGD-Lys-(Arg¹¹)CCMSH, RAD-Lys-(Arg¹¹)CCMSH and RGD-Lys-(Arg¹¹)CCMSHscramble were designed to target both MC1 and α_vβ₃ integrin receptors, MC1 receptor only and α_vβ₃ integrin receptor only, respectively. The MC1 or α_vβ₃ integrin receptor binding affinities of three peptides were determined in M21 human melanoma cells. The melanoma targeting properties of ^99mTc-labeled RGD-Lys-(Arg¹¹)CCMSH, RAD-Lys-(Arg¹¹)CCMSH and RGD-Lys-(Arg¹¹)CCMSHscramble were determined in M21 human melanoma-xenografted nude mice. Meanwhile, the melanoma uptake of ^99mTc-RGD-Lys-(Arg¹¹)CCMSH was blocked with various non-radiolabeled peptides in M21 melanoma xenografts.ResultsRGD-Lys-(Arg¹¹)CCMSH displayed 2.0 and 403 nM binding affinities to both MC1 and α_vβ₃ integrin receptors, whereas RAD-Lys-(Arg¹¹)CCMSH or RGD-Lys-(Arg¹¹)CCMSHscramble lost their α_vβ₃ integrin receptor binding affinity by greater than 248-fold or MC1 receptor binding affinity by more than 100-fold, respectively. The melanoma uptake of ^99mTc-RGD-Lys-(Arg¹¹)CCMSH was 2.49 and 2.24 times (P < .05) the melanoma uptakes of ^99mTc-RAD-Lys-(Arg¹¹)CCMSH and ^99mTc-RGD-Lys-(Arg¹¹)CCMSHscramble at 2 h post-injection, respectively. Either RGD or (Arg¹¹)CCMSH peptide co-injection could block 42% and 57% of the tumor uptake of ^99mTc-RGD-Lys-(Arg¹¹)CCMSH, whereas the coinjection of RGD+(Arg¹¹)CCMSH peptide mixture could block 66% of the tumor uptake of ^99mTc-RGD-Lys-(Arg¹¹)CCMSH.ConclusionsTargeting both MC1 and α_vβ₃ integrin receptors enhanced the melanoma uptake of ^99mTc-RGD-Lys-(Arg¹¹)CCMSH in M21 human melanoma xenografts. Flank M21 human melanoma tumors were clearly visualized by single photon emission computed tomography/computed tomographic imaging using ^99mTc-RGD-Lys-(Arg¹¹)CCMSH as an imaging probe, highlighting its potential use as a dual-receptor-targeting imaging probe for human melanoma detection.     

The slotted cylinder: an efficient probe for NMR imaging

The slotted cylinder, an inductive structure with low self-inductance, low electric field, has been studied as a probe for NMR imaging applications. A theoretical calculation allows us to map the magnetic field and to evaluate electrical parameters of the structure. Several implementations, including new designs, have been experimentally tested over a wide range of frequencies (4-40 MHz), and compared to a classical coil probe. This study demonstrates the efficiency of the slotted cylinder for NMR imaging. It is optimized for large conductive samples when imaging at high frequencies (for human head, above 20 MHz).     

Radioiodinated peptide probe for selective detection of oxidized low density lipoprotein in atherosclerotic plaques

IntroductionDespite the significant effort in developing radioprobes for atherosclerosis, few have low molecular weight. Oxidized LDL (OxLDL), a highly proinflammatory and proatherogenic factor that is abundant in atherosclerotic plaques, plays a pivotal role in plaque destabilization, which makes OxLDL a relevant probe target. We developed a radioiodinated short peptide, AHP7, as a low molecular weight probe for specific OxLDL imaging and evaluated its utility using myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits (WHHLMI).Methods[¹²⁵I]AHP7 was designed and synthesized based on the sequence of Asp-hemolysin, an OxLDL binding protein extracted from Aspergillus fumigatus. In vitro binding studies with OxLDL having varying degrees of oxidation were performed. Radioactivity accumulation in the aorta was measured 30 min post-administration in rabbits. Autoradiography and histological studies were performed using serial aorta sections. A radioiodinated scrambled peptide ([¹²⁵I]AHP scramble) was used as a negative control.Results[¹²⁵I]AHP7 bound to OxLDL in proportion to the degree of oxidation (R = 0.91, P < 0.0001) and was inhibited by unlabeled AHP7 in a concentration-dependent manner. The aorta accumulation level and aorta/blood and aorta/muscle ratios of [¹²⁵I]AHP7 in WHHLMI were 2.8-, 1.3- and 1.8-fold higher, respectively, than those in control rabbits (P < 0.001). Co-administration of AHP7 significantly reduced [¹²⁵I]AHP7 radioactivity in aorta sections (P < 0.0001). Regional radioactivity levels in the aorta sections showed nonuniformity but similarity to the immunohistochemical OxLDL density.ConclusionsThe potential of radioiodinated AHP7 for selectively imaging OxLDL was demonstrated both in vitro and in vivo.     

A novel DOTA-alpha-melanocyte-stimulating hormone analog for metastatic melanoma diagnosis.

Scintigraphic imaging of metastatic melanoma lesions requires highly tumor-specific radiolabeled compounds. Because both melanotic and amelanotic melanomas overexpress receptors for alpha-melanocyte-stimulating hormone (alpha-MSH; receptor name: melanocortin type 1 receptor, or MC1R), radiolabeled alpha-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a melanoma-selective radiolabeled alpha-MSH analog suitable for melanoma diagnosis. METHODS: The very potent alpha-MSH analog [Nle(4), D-Phe(7)]-alpha-MSH (NDP-MSH) and a newly designed alpha-MSH octapeptide analog, [betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (MSH(oct)), were conjugated to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to enable radiometal incorporation. The resulting DOTA conjugates were evaluated in vitro for their MC1R-binding affinity and melanogenic activity in isolated mouse B16F1 cells and in vivo for their biodistribution in mouse models of primary and metastatic melanoma after labeling with (111)In. RESULTS: DOTA-MSH(oct) was shown to bind with high affinity (inhibitory concentration of 50% [IC(50)] = 9.21 nmol/L) to the MC1R, although with lower potency than does DOTA-NDP-MSH (IC(50) = 0.25 nmol/L). In B16F1 melanoma-bearing mice, both (111)In-DOTA-NDP-MSH and (111)In-DOTA-MSH(oct) exhibited high MC1R-mediated uptake by melanoma, which differed by a factor of only 1.5 at 4 h after injection. The main route of excretion for both radioconjugates was the kidneys, whereby (111)In-DOTA-MSH(oct) led to somewhat higher kidney values than did (111)In-DOTA-NDP-MSH. In contrast, the latter was much more poorly cleared from other nonmalignant tissues, including bone, the most radiosensitive organ. Therefore, (111)In-DOTA-MSH(oct) displayed higher uptake ratios of tumor to nontarget tissue (e.g., tumor-to-bone ratio 4 h after injection was 4.9 for (111)In-DOTA-NDP-MSH and 53.9 for (111)In-DOTA-MSH(oct)). Lung and liver melanoma metastases could easily be visualized on tissue section autoradiographs after injection of (111)In-DOTA-MSH(oct). Radio-reversed-phase high-performance liquid chromatography analysis of urine samples revealed that most (111)In-DOTA-MSH(oct) is excreted intact 4 h after injection, indicating good in vivo stability. CONCLUSION: (111)In-DOTA-MSH(oct) exhibits more favorable overall performance than does (111)In-DOTA-NDP-MSH in murine models of primary and metastatic melanoma, making it a promising melanoma imaging agent.     

The use of a chelating derivative of alpha melanocyte stimulating hormone for the clinical imaging of malignant melanoma.

A novel chelating derivative of alpha melanocyte stimulating hormone, bis MSH-DTPA, has been used for the diagnostic targeting of malignant melanoma. 15 patients were investigated of whom nine were shown by other means to have active disease at the time of the scan. Tumours were imaged in all of these nine patients. Of a total of 46 lesions over 10 mm encountered, 41 (89%) were imaged. There were no false positives and in two cases bisMSH-DTPA was instrumental in reversing diagnoses made using ultrasound. Derivatives of melanocyte stimulating hormone may be of considerable value in targeting melanomas.     

Ocular melanoma: detection using iodine-123-iodoamphetamine and SPECT imaging

Uptake of iodine-123-iodoamphetamine has been demonstrated in malignant melanoma using planar imaging techniques and has been used to detect an ocular melanoma at 12 hr postinjection. Using SPECT technique, an ocular melanoma is identified in a 64-yr-old male at 1 hr postinjection.     

Improved detection of metastatic melanoma by T2*-weighted imaging

BACKGROUND AND PURPOSE: The imaging features of metastatic melanomas are distinctive due to the presence of melanin and the propensity for hemorrhage. Both hemorrhage and melanin can produce T1-weighted hyperintensity and T2*-weighted signal intensity loss. We hypothesized that T2*-weighted images would improve detection of metastatic melanoma. METHODS: The T2* and T1 characteristics of 120 newly detected metastatic brain lesions from 31 patients with malignant melanoma were compared with those of 120 brain metastases from 23 patients with lung cancer. RESULTS: Melanoma metastases were 5 times more likely to demonstrate prominent T2*-related signal intensity loss (susceptibility effect) than were lung metastases (42% vs 8%; P < .01), and 4.5 times more likely to demonstrate T1 hyperintensity (55% vs 12%; P < .01). Patients with melanoma had lesions that were either hypointense on T2*-weighted images, hyperintense on T1 images, or both, in 71% (85/120), compared with 19% (23/120) of lung carcinoma metastases (P < .01). Melanoma lesions were 16 times more likely than lung cancer lesions to show combined T2* related signal intensity loss and T1 hyperintensity (P < .01). Remarkably, 8 melanoma lesions (7%) in 3 patients were detectable principally on the T2*-weighted sequences, whereas no lung cancer lesion was detected solely on susceptibility images. We found a direct correlation between melanin content and T1 hyperintensity but no correlation between T2* intensity and melanin. CONCLUSION: T2*-weighted images improve lesion detection in patients with melanoma metastases, and in conjunction with T1-weighted sequences, can suggest melanoma as the etiology of an intracranial mass. This sequence should be employed for evaluation of possible brain metastasis in patients without a known primary malignancy and in studies for melanoma staging.     

111In-labeled galectin-3-targeting peptide as a SPECT agent for imaging breast tumors.

Galectin-3 is a member of the galectin family of beta-galactoside-binding animal lectins. Galectin-3 is overexpressed in a wide range of neoplasms and is associated with tumor growth and metastases. Given this fact, radiolabeled galectin-3-targeting molecules may be useful for the noninvasive imaging of tumors expressing galectin-3, as well as for targeted radionuclide therapy. In this study, the tumor cell-targeting and SPECT properties of a galectin-3-avid peptide identified from bacteriophage display were evaluated in human breast carcinoma cells and in human breast tumor-bearing mice. METHODS: The galectin-3-avid peptide G3-C12 (ANTPCGPYTHDCPVKR) was synthesized with a Gly-Ser-Gly (GSG) linker at the amino terminus. After conjugation with 1,4,7,10-tetra-azacyclododecane-N,N',N'N'-tetraacetic acid (DOTA), the peptide was labeled with (111)In. The radiochemical purity and stability of the compound was assessed by high-performance liquid chromatography. MDA-MB-435 human breast carcinoma cells expressing galectin-3 were used to characterize the in vitro binding properties of the radiolabeled compound. SCID mice bearing MDA-MB-435 xenografts were used as an in vivo model for biodistribution and imaging studies with the (111)In-labeled peptide. RESULTS: (111)In-DOTA(GSG)-G3-C12 bound specifically to galectin-3-expressing MDA-MB-435 cells. The radiolabeled peptide was stable in serum and was found intact in excreted urine for at least 1 h. Competitive binding experiments indicated that the radiolabeled peptide exhibited an inhibitory concentration of 50% of 200.00+/-6.70 nM for cultured breast carcinoma cells. In vivo biodistribution studies revealed that tumor uptake was 1.2+/-0.24, 0.75+/-0.05, and 0.6+/-0.04 (mean +/- SD) percentage injected dose per gram at 30 min, 1.0 h, and 2.0 h after injection of the radiotracer, respectively. SPECT/CT studies with (111)In-DOTA(GSG)-G3-C12 showed excellent tumor uptake and contrast in the tumor-bearing mice. Specificity of peptide binding was demonstrated by successful blocking (52%) of in vivo tumor uptake of (111)In-DOTA(GSG)-G3-C12 in the presence of its nonradiolabeled counterpart at 2 h after injection. CONCLUSION: This study demonstrated the successful use of a new radiolabeled peptide for the noninvasive imaging of galectin-3-positive breast tumors. This peptide may be a promising candidate for future clinical applications.     

Guidelines for imaging in cutaneous melanoma

The preceding article reviewed the available data on imaging modalities in cutaneous melanoma. Based on this review, this article aims to provide guidelines for the use of the various imaging modalities in cutaneous melanoma and to indicate the level of supporting evidence and strength of recommendation with associated explanatory notes.     

IMPY, a potential beta-amyloid imaging probe for detection of prion deposits in scrapie-infected mice

INTRODUCTION: A potential single-photon emission computed tomography imaging agent for labeling of A beta plaques of Alzheimer's disease, IMPY (2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine), would be effective in detection of prion amyloid deposits in transmissible spongiform encephalopathies (TSEs). METHODS: In vitro autoradiographic studies were carried out with [125 I]IMPY on brain sections from scrapie-infected mice and age-matched controls. Competition study was performed to evaluate the prion deposit binding specificity with nonradioactive IMPY. RESULTS: Binding of [125 I]IMPY was observed in infected brain sections, while on age-matched control brain sections, there was no or very low labeling. Prion deposit binding was confirmed by histoblots with prion protein-specific monoclonal antibody 2D6. In the presence of nonradioactive IMPY, the binding of [125 I]IMPY was significantly inhibited in all regions studied. CONCLUSIONS: These findings indicate that IMPY can detect the prion deposits in vitro in scrapie-infected mice. Labeled with 123 I, this ligand may be useful to quantitate prion deposit burdens in TSEs by in vivo imaging.     

Postmenopausal osteoporosis. Early diagnosis as an indication for preventive hormone therapy

Idiopathic osteoporosis mainly affects postmenopausal women. The normal trabecular volume of the lumbar vertebrae in a sample of healthy perimenopausal women was established by monoenergetic computed tomography. Early diagnosis of diminished bone mass is crucial for the identification of women at risk for involuntary osteoporosis following climacteric estrogen depletion. Body weight, endogenous levels of sex steroids, renal calcium and hydroxyproline excretions are not related to individual bone mass in the lumbar spine.     

CT halo sign as an imaging marker for response to adoptive cell therapy in metastatic melanoma with pulmonary metastases

Objectives

The halo sign refers to a zone of ground-glass attenuation surrounding a pulmonary nodule. Pulmonary metastatic nodules exhibiting a halo sign are seen mainly in hypervascular tumours. We describe the appearance of a halo sign following treatment of adoptive transfer of autologous tumour-infiltrating lymphocytes (TIL) to melanoma patients with lung metastases.

Methods

The study included 29 melanoma patients with pulmonary metastases who received TIL therapy. Pre- and post-treatment chest CTs were retrospectively reviewed for the presence of a halo sign and its correlation with therapeutic response.

Results

A pulmonary halo sign was not seen in any pre-treatment CT. It was observed in four of 12 patients who responded to the therapy but not in those who failed to respond. Significant differences were found between response ratio in patients in whom post-TIL halo sign appeared compared with those without the halo sign (p?=?0.02).

Conclusions

The appearance of a CT halo sign in melanoma with lung metastases following TIL therapy may indicate antitumoral effect and a good response to therapy. Our findings emphasize the importance of applying new assessment criteria for immunological anticancer therapies.

Key Points

? Tumour-infiltrating lymphocytes (TIL) in melanoma patients is a promising novel immunotherapy ? Post-therapy pulmonary halo sign appeared in one-third of TIL responders ? Pulmonary halo sign may serve as an imaging marker for antitumoral activity     

Small-animal PET of melanocortin 1 receptor expression using a 18F-labeled alpha-melanocyte-stimulating hormone analog.

(18)F-Labeled small synthetic peptides have emerged as attractive probes for imaging various molecular targets with PET. The alpha-melanocyte-stimulating hormone (alpha-MSH) receptor (melanocortin type 1 receptor [MC1R]) is overexpressed in most murine and human melanomas. It is a promising molecular target for diagnosis and therapy of melanomas. However, (18)F compounds have not been successfully developed for imaging the MC1R. METHODS: In this study, an alpha-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH(2) (NAPamide), was radiolabeled with N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB). The resulting radiopeptide was evaluated as a potential molecular probe for small-animal PET of melanoma and MC1R expression in melanoma xenografted mouse models. RESULTS: The binding affinity of (19)F-SFB-conjugated NAPamide, (19)F-FB-NAPamide, was determined to be 7.2 +/- 1.2 nM (mean +/- SD) using B16/F10 cells and (125)I-(Tyr(2))-[Nle(4),D-Phe(7)]-alpha-MSH [(125)I-(Tyr(2))-NDP] as a radioligand. The biodistribution of (18)F-FB-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16/F10 melanoma tumors with high expression of MC1Rs and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Biodistribution experiments showed that tumor uptake values (percentage injected dose per gram of tumor [%ID/g]) of (18)F-FB-NAPamide were 1.19 +/- 0.11 %ID/g and 0.46 +/- 0.11 %ID/g, in B16/F10 and A375M xenografted melanoma at 1 h after injection, respectively. Furthermore, the B16/F10 tumor uptake was significantly inhibited by coinjection with excess alpha-MSH peptide (P < 0.05), indicating that (18)F-FB-NAPamide specifically recognizes the MC1R in living mice. Small-animal PET of (18)F-FB-NAPamide in mice bearing B16/F10 and A375M tumors at 1 h after tail vein injection revealed good B16/F10 tumor-to-background contrast and low A375M tumor-to-background ratios. CONCLUSION: (18)F-FB-NAPamide is a promising molecular probe for alpha-MSH receptor-positive melanoma PET and warrants further study.