Recent developments in the field of 123I-radiopharmaceuticals

Due to its advantageous nuclear physical properties iodine-123 is an excellent label for radiopharmaceuticals very well suited for measurements by gamma-cameras and single-photon emission tomography. The development of 123I-radiopharmaceuticals should be based on a clear biochemical concept, reliable labelling procedures and careful pharmacokinetic studies in order to evaluate the physiological behaviour of the radioiodinated compounds being analogues of metabolic substrates. The development of 123I-labelled fatty acids and biogenic amines clearly proved the successful use of 123I for labelling compounds applied in medical diagnosis.     

Allogenic bone graft viability after hip revision arthroplasty assessed by dynamic [18F]fluoride ion positron emission tomography.

The biological fate of allogenic bone grafts in the acetabular cavity and their metabolic activity after acetabular augmentation is uncertain but is most important for the stability of hip implants after hip revision arthroplasty. The aim of this study was to quantify regional bone metabolism after hip replacement operations. Dynamic [18F]fluoride ion positron emission tomography (PET) was used to investigate the metabolic activity of acetabular allogenic bone grafts and genuine bone, either 3-6 weeks (short-term group, n = 9) or 5 months to 9 years (long-term group, n = 10) after hip revision arthroplasty. Applying a three-compartment model, the fluoride influx constant was calculated from individually fitted rate constants (Knlf) and by Patlak graphical analysis (Kpat). The results were compared with genuine cancellous and cortical acetabular bone of contralateral hips without surgical trauma (n = 7). In genuine cortical bone, Knlf was significantly increased in short- (+140.9%) and long-term (+100.0%) groups compared with contralateral hips. Allogenic bone grafts were characterised by a significantly increased Knlf in the short-term group (+190.9%) compared with contralateral hips, but decreased almost to the baseline levels of contralateral hips (+45.5%) in the long-term. Values of Knlf cor-related with the rate constant K1 in genuine (r = 0.89, P<0.001) and allogenic bone regions (r = 0.79, P<0.001), indicating a coupling between bone blood flow and bone metabolism in genuine bone as well as allogenic bone grafts. Kpat values were highly correlated with Knlf measurements in all regions. In conclusion, [18F]fluoride ion PET revealed the presence of an increased host bone formation in allogenic bone grafts early after hip revision arthroplasty. In contrast to genuine cortical bone, allogenic bone graft metabolism decreased over time, possibly due to a reduced ability to respond to the same extent as genuine bone to elevated metabolic demands after surgery.     

Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study

Serotonergic dysfunction may contribute to negative mood states in affective disorders. Some in vivo imaging studies showed reduced availability of serotonin transporters (5-HTT) in the brainstem and thalamus of patients with major depression. We tested the hypothesis that 5-HTT availability is reduced in unmedicated unipolar patients with major depression compared to healthy control subjects matched for gender, age, genotype and smoking status. Availability of 5-HTT was measured in vivo with positron emission tomography and [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) in the midbrain, thalamus and amygdala. DASB binding was correlated with the severity of depression (Beck's Depression Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory) and personality traits (Temperament and Character Inventory). Patients with major depression displayed reduced 5-HTT availability in the thalamus (P=0.005). In patients, low serotonin transporter availability correlated with high anxiety (thalamus: r=-0.78, P=0.004; midbrain: r=-0.78, P=0.004; amygdala: r=-0.80, P=0.003). Correlations with severity of depression were weaker and did not survive correction for multiple testing. These results support the hypothesis that central serotonergic dysfunction is associated with negative mood states in affective disorders. In the thalamus, a low serotonin reuptake capacity may interfere with thalamic control of cortical excitability and contribute to anxiety rather than depression per se in major depression.     

Reduced availability of serotonin transporters in obsessive-compulsive disorder correlates with symptom severity – a [11C]DASB PET study

Summary Reduced availability of brainstem serotonin transporters (5-HTT) has been observed in vivo in obsessive-compulsive disorder (OCD). However, results vary and may be influenced by competition with endogenous serotonin. Using positron emission tomography (PET) and [¹¹C]DASB, a specific 5-HTT ligand that showed no competition with serotonin for 5-HTT binding in vitro, we tested the hypothesis that 5-HTT availability is reduced in OCD patients and correlated with OCD severity. Methods. 5-HTT availability in the thalamus and the midbrain was measured in nine drug-free OCD patients and compared with 19 healthy controls, matched for the individual combination of 5-HTT genotype, gender and smoking status. OCD severity was assessed with the Yale-Brown obsessive compulsive scale (Y-BOCS). Results. 5-HTT availability was significantly reduced in the thalamus and midbrain of OCD patients. Age and 5-HTT in the thalamus explained 83% of OCD severity in patients that were drug-free for at least 1 year. Conclusion. This PET study confirms a central role of the serotonergic system, particularly the thalamus in the pathogenesis of obsessive compulsive disorder. The first two authors contributed equally     

Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine.

We evaluated the predictive value of PET using the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA) for success of radiotherapy in combination with tirapazamine, a specific cytotoxin for hypoxic cells. METHODS: Imaging was performed on EMT6 tumor-bearing nude mice before allocating mice into 4 groups: radiochemotherapy (RCT: 8 fractions of 4.5 Gy within 4 d combined with tirapazamine, 14 mg/kg), radiotherapy alone (RT), chemotherapy alone (tirapazamine) (CHT), or control. Treatment success was assessed by several tumor growth assays, including tumor growth time from 70 to 500 microL and absolute growth delay (aGD). The median pretreatment (18)F-FAZA tumor-to-background ratio served as a discriminator between "hypoxic" and "normoxic" tumors. RESULTS: The mean tumor growth was significantly accelerated in hypoxic control tumors (growth time from 70 to 500 microL, 11.0 d) compared with normoxic control tumors (growth time from 70 to 500 microL, 15.6 d). Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was observed only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d). CONCLUSION: This study provides compelling evidence that hypoxia imaging using (18)F-FAZA PET is able to predict the success of RCT of tumor-bearing mice using the hypoxia-activated chemotherapeutic agent tirapazamine. Pretreatment (18)F-FAZA PET, therefore, offers a way for the individualization of tumor treatment involving radiation. The data suggest that by reserving hypoxia-directed therapy to tumors with high (18)F-FAZA uptake, improvement of the therapeutic ratio is possible, as the therapeutic effect of tirapazamine seems to be restricted to hypoxic tumors.     

Interferon-gamma and interleukin-12 gene polymorphisms and their relation to aggressive and chronic periodontitis and key periodontal pathogens

BACKGROUND: The gene polymorphisms interferon-gamma (IFN-gamma) 874 T/A and interleukin (IL)-12 1188 A/C have been associated with the altered production of cytokines. Therefore, they might be indicative of the occurrence of chronic periodontitis (CP) or aggressive periodontitis (AgP) and the prevalence of key periodontal pathogens. For this purpose, we analyzed these polymorphisms in subjects with generalized AgP or generalized CP. Moreover, we assessed the relationship between these polymorphisms and five periodontopathic bacteria. METHODS: A total of 124 unrelated German white subjects with periodontitis (AgP=72 and CP=52) and 74 periodontitis-free subjects were studied. Gene polymorphisms were determined by polymerase chain reaction with sequence-specific primers. Subgingival bacteria were molecular biologically analyzed using multiplex polymerase chain reaction and reverse hybridization. The distributions of alleles and genotypes were calculated by the chi(2) test with Yates correction. Risk factor analyses were carried out by logistic regression considering established confounders for periodontitis. RESULTS: Allele and genotype frequencies of both investigated polymorphisms were not significantly different between subjects with periodontitis and periodontitis-free controls. However, in the total study group, IL-12 AA-positive subjects had a significantly higher bleeding index than individuals who expressed IL-12 CC (68.2% versus 50.0%, P=0.025). Moreover, IFN-gamma AA carriers had a decreased odds ratio (OR) for the individual presence of Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) (OR=0.39, P=0.012) after adjustment for age, gender, smoking, and probing depth. IFN-gamma TA predisposed an individual to infection with Prevotella intermedia (OR=2.15, P=0.019). CONCLUSION: Although a relationship between the bleeding index and the presence of bacteria was shown, IFN-gamma and IL-12 polymorphisms are not suitable diagnostic features for AgP and CP.     

Neuroimaging in Alcoholism: Ethanol and Brain Damage

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) μ-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.     

Decarbonylation of multi-substituted [18F]benzaldehydes for modelling syntheses of 18F-labelled aromatic amino acids.

For 18F-labelling of aromatic amino acids such as tyrosine and DOPA simple and efficient procedures have been under development for quite a while. The direct introduction of 18F using [18F]fluoride can principally be realized by nucleophilic aromatic substitution (SNAr). However, this requires the presence of an appropriate leaving group and an auxiliary substituent, which is able to reduce the electron density of the benzene ring. Furthermore, this auxiliary substituent should be removable easily after the introduction of 18F. The electron-withdrawing formyl substituent meets both requirements. It facilitates nucleophilic attack in the ortho and/or para position and is easily removed in a decarbonylation reaction mediated by Wilkinson's catalyst (RhCl(PPh3)3). In order to evaluate the reaction conditions for a possible synthesis of 2-[18F]fluoro-5-hydroxyphenylalanine ([18F]-m-tyrosine), 2-[18F]fluoro-4-hydroxyphenylalanine ([18F]-p-tyrosine) or 2-[18F]fluoro-4,5-hydroxyphenylalanine ([18F]FDOPA), the dependence of the decarbonylation reaction on solvent, temperature, reaction time and catalyst concentration was studied using appropriate model compounds. Optimum yields of 81%, 89% and 88% could be achieved using benzonitrile as solvent and 2M equivalents of RhCl(PPh3)3 (based on labelling precursor) at 150 degrees C reaction temperature within 20 min reaction time for compounds modelling [18F]-m-tyrosine, [18F]-p-tyrosine and [18F]FDOPA, respectively.     

Allogenic bone graft viability after hip revision arthroplasty assessed by dynamic [18F]fluoride ion positron emission tomography

The biological fate of allogenic bone grafts in the acetabular cavity and their metabolic activity after acetabular augmentation is uncertain but is most important for the stability of hip implants after hip revision arthroplasty. The aim of this study was to quantify regional bone metabolism after hip replacement operations. Dynamic [¹⁸F]fluoride ion positron emission tomography (PET) was used to investigate the metabolic activity of acetabular allogenic bone grafts and genuine bone, either 3–6 weeks (short-term group, n = 9) or 5 months to 9 years (long-term group, n = 10) after hip revision arthroplasty. Applying a three-compartment model, the fluoride influx constant was calculated from individually fitted rate constants (K _nlf) and by Patlak graphical analysis (K _pat). The results were compared with genuine cancellous and cortical acetabular bone of contralateral hips without surgical trauma (n = 7). In genuine cortical bone, K _nlf was significantly increased in short- (+140.9%) and long-term (+100.0%) groups compared with contralateral hips. Allogenic bone grafts were characterised by a significantly increased K _nlf in the short-term group (+190.9%) compared with contralateral hips, but decreased almost to the baseline levels of contralateral hips (+45.5%) in the long-term. Values of K _nlf cor-related with the rate constant K ₁ in genuine (r = 0.89, P<0.001) and allogenic bone regions (r = 0.79, P<0.001), indicating a coupling between bone blood flow and bone metabolism in genuine bone as well as allogenic bone grafts. K _pat values were highly correlated with K _nlf measurements in all regions. In conclusion, [¹⁸F]fluoride ion PET revealed the presence of an increased host bone formation in allogenic bone grafts early after hip revision arthroplasty. In contrast to genuine cortical bone, allogenic bone graft metabolism decreased over time, possibly due to a reduced ability to respond to the same extent as genuine bone to elevated metabolic demands after surgery. Received 6 October 1998 and in revised form 30 January 1999