Mapping of brain tissue hematocrit in glioma and acute stroke using a dual autoradiography approach.

Hematocrit (Hct) determines the ability of blood to carry oxygen. While changes in systemic Hct are known to impact stroke or tumor control, changes in local (tissue) Hct (tHct) induced by these diseases have however received little attention. In this study, we evaluate tHct in acute stroke and in glioma models using a new approach to map tHct across the brain, a dual isotope autoradiography, based on injections of 125I-labeled albumin and 99mTc-lalbeled red blood cells in the same animal. For validation purpose, tHct was mapped in the rat brain (i) under physiological conditions, (ii) following erythropoietin injection, and (iii) following hemodilution. Then, tHct was then mapped in stroke (middle cerebral artery occlusion) and tumor models (9LGS and C6). The mean tHct values observed in healthy brains (tHct = 29 ± 1.3%), were modified as expected by erythropoietin (tHct = 36.7 ± 2.6%) and hemodilution (tHct = 24.2 ± 2.4%). Using the proposed method, we observed a local reduction, spatially heterogeneous, in tHct following acute stroke (tHct = 19.5 ± 2.5%) and in both glioma models (9LGS: tHct = 18.5 ± 2.3%, C6: tHct = 16.1 ± 1.2%). This reduction and this heterogeneity in tHct observed in stroke and glioma raises methodological issues in perfusion imaging techniques where tHct is generally overlooked and could impact therapeutic strategies.

Targeted radionuclide therapy with RAFT-RGD radiolabelled with (90)Y or (177)Lu in a mouse model of αvß3-expressing tumours.

PURPOSE: The αvß3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvß3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with ß(-) emitters in a nude mouse model of αvß3 integrin-expressing tumours. METHODS: Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvß3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvß3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvß3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. RESULTS: Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvß3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvß3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvß3-negative tumours. CONCLUSION: (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvß3-expressing tumours for internal targeted radiotherapy.

Pre-clinical and clinical evaluation of nuclear tracers for the molecular imaging of vulnerable atherosclerosis: an overview.

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients.

Molecular imaging of vascular cell adhesion molecule-1 expression in experimental atherosclerotic plaques with radiolabelled B2702-p.

PURPOSE: VCAM-1 plays a major role in the chronic inflammatory processes present in vulnerable atherosclerotic plaques. The residues 75-84 (B2702-p) and 84-75/75-84 (B2702-rp) of the major histocompatibility complex-1 (MHC-1) molecule B2702 were previously shown to bind specifically to VCAM-1. We hypothesised that radiolabelled B2702-p and B2702-rp might have potential for the molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) expression in atherosclerotic plaques. METHODS: Preliminary biodistribution studies indicated that 125I-B2702-rp was unsuitable for in vivo imaging owing to extremely high lung uptake. 123I- or 99mTc-labelled B2702-p was injected intravenously to Watanabe heritable hyperlipidaemic rabbits (WHHL, n=6) and control animals (n=6). After 180 min, aortas were harvested for ex vivo autoradiographic imaging, gamma-well counting, VCAM-1 immunohistology and Sudan IV lipid staining. RESULTS: Robust VCAM-1 immunostaining was observed in Sudan IV-positive and to a lesser extent in Sudan IV-negative areas of WHHL animals, whereas no expression was detected in control animals. Significant 2.9-fold and 1.9-fold increases in 123I-B2702-p and 99mTc-B2702-p aortic-to-blood ratios, respectively, were observed between WHHL and control animals (p<0.05). Tracer uptake on ex vivo images co-localised with atherosclerotic plaques. Image quantification indicated a graded increase in 123I-B2702-p and 99mTc-B2702-p activities from control to Sudan IV-negative and to Sudan IV-positive areas, consistent with the observed pattern of VCAM-1 expression. Sudan IV-positive to control area tracer activity ratios were 17.0+/-9.0 and 5.9+/-1.8 for 123I-B2702-p and 99mTc-B2702-p, respectively. CONCLUSION: Radiolabelled B2702-p is a potentially useful radiotracer for the molecular imaging of VCAM-1 in atherosclerosis.

Assessment of non-reperfused and reperfused myocardial infarction using diffusible or deposited radiolabelled perfusion imaging agents.

PURPOSE: Incomplete microvascular reperfusion is often observed in patients undergoing thrombolytic therapy or angioplasty for acute myocardial infarction and has important prognostic implications. We compared the myocardial uptake of diffusible ((201)Tl) and deposited ((99m)TcN-NOET) perfusion imaging agents in the setting of experimental infarction. METHODS: Rats were subjected to permanent coronary occlusion (OCC, n=10) or to 45-min occlusion and reperfusion (REP, n=17). Seven days later, the tracers were co-injected and the animals were euthanised 15 min (all ten rats in the OCC group and 12 rats in the REP group) or 120 min (five rats from the REP group, euthanised at this time point to evaluate any redistribution of the tracers: REP-RED group) afterwards. Infarct size determination and (99m)TcN-NOET/(201)Tl ex vivo imaging were performed. Regional flow and tissue oedema were quantified using radioactive microspheres and (99m)Tc-DTPA, respectively. RESULTS: (99m)TcN-NOET and (201)Tl defect magnitudes were similar in OCC animals (0.11+/-0.01 vs 0.13+/-0.01). In REP animals, (201)Tl defect magnitude (0.25+/-0.02) was significantly lower than the magnitude of (99m)TcN-NOET and flow defects (0.14+/-0.03 and 0.17+/-0.01, respectively; p<0.05), despite the lack of (201)Tl redistribution (REP-RED animals). (99m)Tc-DTPA indicated the presence of oedema in the reperfused area. Blood distribution studies showed that, unlike (99m)TcN-NOET, (201)Tl plasma activity was mostly unbound to plasma proteins. CONCLUSION: (99m)TcN-NOET and (201)Tl delineated the non-viable area in chronic non-reperfused and reperfused myocardial infarction. The significantly decreased (201)Tl defect in reperfused infarction was likely due to partial diffusion of the tracer from the plasma into the oedema present in the infarcted area. Deposited perfusion tracers might be better suited than diffusible agents for the assessment of regional flow following reperfusion of myocardial infarction.